Investment to support treatment of patients using virtual reality – Wales247

The Crowdcube fundraise, only launched this week, has already hit its 300k target at a pre-money valuation of 3.1m, with significant pledges already secured from angel investors and Development Bank of Wales.

Through Crowdcube, Rescape now has the opportunity to overfund, giving investors a stake from as little as 11.76 in a fast-moving sector that has really shown its value during the pandemic.

Rescape partnered with Cwm Taf Morgannwg University Health Board and the Centre for Trials Research at Cardiff University to demonstrate the very human benefits VR has brought to frontline NHS teams facing COVID-19, and the potential to roll out this technology and increase the adoption of VR in a range of future medical treatment plans.

Rescape already has a track record in the use of VR to support patient recovery and rehabilitation, working with cancer patients at Velindre Hospital, and Cystic Fibrosis patients in Cardiff and Vale Health Board, and the value of VR has also been evidenced in mums in childbirth. Now, for the first time, theyve been successfully using virtual reality through their DR.VR platform to help reduce anxiety and stress amongst NHS staff tackling the pandemic, which has far reaching implications on NHS costs. In January this year alone, before the pandemic struck, over 434,000 work days were lost to anxiety, stress, depression and other psychiatric illnesses amongst NHS staff, and to give an idea of scale, a reduction of one day per staff member per year saves the NHS 150m.

Launching the Crowdcube fundraise, Rescape Innovation CEO Matt Wordley said: This is the latest push in our aim tobecome the leading global provider of immersive technology solutions, including VR, in healthcare and associated marketplaces. It gives anyone the opportunity to have a stake in this innovative technology for as little as 11.76, which, apart from being a great investment in a growing company, gives people the warm feeling they are providing proven benefits to patients, staff and reducing costs in the NHS. We already have interest from over 10 hospitals and trusts across the UK in the next scale-up of trials.

Luke Lang, co-founder of Crowdcube commented: Rescape joins a growing list of healthcare technology businesses that have successfully fundraised with Crowdcube since the Covid-19 pandemic started earlier this year. Rescapes mission to use virtual reality to help reduce stress and anxiety for NHS employees and improve patient wellbeing has clearly inspired people to invest in the innovative business, which is now overfunding.

Dr Michelle Smalley is a Clinical Psychologist working in Intensive Care Units in Royal Glamorgan and Prince Charles Hospitals in Cwm Taf Morgannwg University Health Board Dr. Smalley said: Roles radically changed on March 13, with a dramatic increase in stress and anxiety amongst frontline medical and nursing teams for both themselves and their loved ones. My role pivoted to focus on staff wellbeing and support, and trying to limit burn out, so we worked with Rescape to bring in DR.VR headsets to see if it would prove a useful aid in reducing anxiety, and give the medical teams some much needed relief.

Being a clinical psychologist in unprecedented times has called for unprecedented measures to help support staff. From the moment I tried these headsets out myself, I realised their potential for helping with anxiety and stress, but we have to be evidence based in our approach.

The DR.VR Frontline Relief evaluation is available on the new FutureVision.Health web platform, a portal set up to promote the benefits of immersive technologies in healthcare. The main results from the evaluation suggest that staff found using VR was an enjoyable experience, and they would recommend use to their colleagues to aid relaxation and for reducing stress. In particular, staff valued the meditative spaces and breathing exercises.

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Investment to support treatment of patients using virtual reality - Wales247

E-Learning Virtual Reality Market 2020 Size by Product Analysis, Application, End-Users, Regional Outlook, Competitive Strategies and Forecast to 2027…

New Jersey, United States,- Market Research Intellect aggregates the latest research on E-Learning Virtual Reality Market to provide a concise overview of market valuation, industry size, SWOT analysis, revenue approximation, and regional outlook for this business vertical. The report accurately addresses the major opportunities and challenges faced by competitors in this industry and presents the existing competitive landscape and corporate strategies implemented by the E-Learning Virtual Reality market players.

The E-Learning Virtual Reality market report gathers together the key trends influencing the growth of the industry with respect to competitive scenarios and regions in which the business has been successful. In addition, the study analyzes the various limitations of the industry and uncovers opportunities to establish a growth process. In addition, the report also includes a comprehensive research on industry changes caused by the COVID-19 pandemic, helping investors and other stakeholders make informed decisions.

Key highlights from COVID-19 impact analysis:

Unveiling a brief about the E-Learning Virtual Reality market competitive scope:

The report includes pivotal details about the manufactured products, and in-depth company profile, remuneration, and other production patterns.

The research study encompasses information pertaining to the market share that every company holds, in tandem with the price pattern graph and the gross margins.

E-Learning Virtual Reality Market, By Type

E-Learning Virtual Reality Market, By Application

Other important inclusions in the E-Learning Virtual Reality market report:

A brief overview of the regional landscape:

Reasons To Buy:

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Market Research Intellect provides syndicated and customized research reports to clients from various industries and organizations with the aim of delivering functional expertise. We provide reports for all industries including Energy, Technology, Manufacturing and Construction, Chemicals and Materials, Food and Beverage, and more. These reports deliver an in-depth study of the market with industry analysis, the market value for regions and countries, and trends that are pertinent to the industry.

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E-Learning Virtual Reality Market 2020 Size by Product Analysis, Application, End-Users, Regional Outlook, Competitive Strategies and Forecast to 2027...

Virtual Reality in Automotive Market 2026 by Scope, Size, Opportunities and Growth Rate analysis – Fresno Observer

The Latest research report onVirtual Reality in Automotive Marketoffers an in-depth analysis of the market. It further provides detailed description on the adoption of different products across several regions. Information on trends, drivers, opportunities, threats, and restraints of the market can further help stakeholders to gain valuable insights into the market. The report offers a detailed competitive landscape by presenting information on key players, along with their strategies, in the market.

For More Information Visit https://www.fortunebusinessinsights.com/industry-reports/virtual-reality-vr-in-automotive-market-101702

Global Virtual Reality in Automotive Market2020 Industry Research Report is a professional and in-depth study on the current state industry and competitive landscape details in this niche sector.Virtual Reality in Automotive Market is split by Type and by Application. For the period 2015-2025, the growth among segments provide accurate calculations and forecasts for sales by Type and by Application in terms of volume and value. This analysis can help you expand your business by targeting qualified niche markets.

Regional analysis is another highly comprehensive part of the research and analysis study of the global Virtual Reality in Automotive Market presented in the report. This section sheds light on the sales growth of different regional and country-level Virtual Reality in Automotive Markets. For the historical and forecast period 2020 to 2026, it provides detailed and accurate country-wise volume analysis and region-wise market size analysis of the global Virtual Reality in Automotive Market.

Among other players domestic and global, Virtual Reality in Automotive Market share data is available for global, North America, Europe, Asia-Pacific, Middle East and Africa and South America separately. Our analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Highlights of the Report:

In-depth analysis of various insights, namely, Sterilization Containers Market trends, growth drivers, opportunities, and other related challenges.

Comprehensive details of key market players, their core competencies, and Sterilization Containers Market share.

The potency of suppliers and buyers to make better business decisions.

Lists out the market size in terms of volume.

Key questions answered in the report:

What will the market growth rate of market in 2025?

What are the key factors driving the global market?

Who are the key manufacturers in market space?

What are the market opportunities, market risk and market overview of the market?

What are sales, revenue, and price analysis of top manufacturers of market?

Who are the distributors, traders and dealers of market?

What are the market opportunities and threats faced by the vendors in the global industry?

What are sales, revenue, and price analysis by types and applications of market?

What are sales, revenue, and price analysis by regions of industry?

Table of Content:

Introduction

Research Scope

Market Segmentation

Research Methodology

Definitions and Assumptions

Executive Summary

Market Dynamics

Market Drivers

Market Restraints

Continued

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10 beauty brands that let you try before you buy with virtual swatching tools – VOGUE India

The year may have started like any other, but a global health crisis compelled beauty stores to lower their shutters in March. With in-store product swatching put on ice following hygiene concerns, its virtual counterpart has now assumed its place under the mainstream spotlight. While online makeup try-on tools have been pedalling through the beauty-verse for a while now, the cutting-edge facial mapping technology of today serves as a far cry from the artificial, super-imposed experiences you tried for laughs at sleepovers.

A closer look at the record books offers definitive proof that virtual realitys presence on the beauty landscape is nothing newL'Oral famously inked a deal with ModiFace, a Toronto-based beauty tech company, in 2018 to acquire access to its numerous patents within the world of augmented reality. The onset of the pandemic afforded further momentum, with brands like Ulta Beauty recording a spike in virtual apps as a safer alternative to in-store testing. To ensure our guests safety, product testers are on display only to offer guests a truer sense of colours and textures. We know the discovery inherent to the beauty shopping experience includes swatching. Virtual try-on experiences serve as a safe alternative to product testers for guests who seek to continue colour swatching and testing products, says a spokesperson from the brand. If youre looking to give yourself a virtual makeover before opting for a real one in the salon chair, here are the hair, makeup and nail brands that youll want to bookmark.

If youve always wondered whether you could pull off rainbow-hued eyeshadow or go mother-of-dragons platinum blonde, the L'Oral virtual makeup try-on hub promises answers. Fuelled with ModiFace technology under the hood, the tool allows users to dabble with the brands full range of colour cosmetics and hair colour options.

Beauty enthusiasts might find their fidelity to Ruby Woo questioned with the brands virtual try-on functionality that offers up over 200 shades for online swatching. When browsing the official website, keep an eye out for the try it on widget that allows you to swatch shades directly through live camera, on an uploaded photo orif youre not in the mood to face the lenson an online model.

Eyebrow hair is notorious as the trickiest facial component to render artificially, and the brow experts looked to ModiFace for a transformation technology that replicates every unique strand. Before you make an appointment with your tweezers during the lockdown, choose from the brands roster of eyebrow shapes and sizes to find the look that works best for you.

The French couture house makes its way to the augmented reality scene with a virtual try-on experience available on its UK website. If youve been on the hunt for your next investment buy, sample the labels lip shade offerings from your desktop or mobile without ever having to move off the couch.

Even before you get your hands on the brands newest drops, you can test-drive the products with the virtual try-on functionalities available on its official website. If your weekend plans involve a virtual makeover, the brand offers access to its entire range of colour cosmetics along with advanced capabilities that include a foundation finder and brow studio.

If youd rather not have any surprises while youre hunched over the sink, it pays to do your homework beforehand on the hair colours that work for you. Schwarzkopf allows you to do a dry run in advance with its colour advice tool imbued with split-screen technology, so you can compare your dream hair colour against your current shade and make an informed decision.

As the host to the latest and the greatest in the world of beauty, Sephora Virtual Artist goes beyond the usual swatching gig to serve up step-by-step tutorials that take the guesswork out of where precisely you should be applying products on your face.

If you miss arm-swatching the brands pigmented lip colours, the virtual experience will help keep FOMO at bay. Like its counterparts in the industry, the tool employs facial mapping to offer a true-to-life makeover through the live camera, your favourite selfie or a model.

On those days when youre missing a mani appointment, look to OPI Nail Studio for the next best thing. Since its launch over a decade ago, the virtual try-on studio has been offering beauty enthusiasts the chance to find the perfect manicure by adjusting the skin colour and nail length on a virtual hand before playing around with nail polish shades.

In light of the pandemic, the American e-tailer has been positioning its interactive virtual experience as an alternative to in-store product swatching. Spanning a wide range of products, from eye and lip makeup to lesser-known candidates, such as false eyelashes, GLAMlab serves as an easy way to dabble with colours to find your perfect match.

This Vogue writer took a full year to find her perfect foundation shade

How will technology change our relationship with beauty after COVID-19?

How to buy makeup online: Your complete guide to a good shopping experience

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10 beauty brands that let you try before you buy with virtual swatching tools - VOGUE India

Virtual Reality(VR) For Healthcare Market 2020 Size by Product Analysis, Application, End-Users, Regional Outlook, Competitive Strategies and Forecast…

New Jersey, United States,- Market Research Intellect aggregates the latest research on Virtual Reality(VR) For Healthcare Market to provide a concise overview of market valuation, industry size, SWOT analysis, revenue approximation, and regional outlook for this business vertical. The report accurately addresses the major opportunities and challenges faced by competitors in this industry and presents the existing competitive landscape and corporate strategies implemented by the Virtual Reality(VR) For Healthcare market players.

The Virtual Reality(VR) For Healthcare market report gathers together the key trends influencing the growth of the industry with respect to competitive scenarios and regions in which the business has been successful. In addition, the study analyzes the various limitations of the industry and uncovers opportunities to establish a growth process. In addition, the report also includes a comprehensive research on industry changes caused by the COVID-19 pandemic, helping investors and other stakeholders make informed decisions.

Key highlights from COVID-19 impact analysis:

Unveiling a brief about the Virtual Reality(VR) For Healthcare market competitive scope:

The report includes pivotal details about the manufactured products, and in-depth company profile, remuneration, and other production patterns.

The research study encompasses information pertaining to the market share that every company holds, in tandem with the price pattern graph and the gross margins.

Virtual Reality(VR) For Healthcare Market, By Type

Virtual Reality(VR) For Healthcare Market, By Application

Other important inclusions in the Virtual Reality(VR) For Healthcare market report:

A brief overview of the regional landscape:

Reasons To Buy:

About Us:

Market Research Intellect provides syndicated and customized research reports to clients from various industries and organizations with the aim of delivering functional expertise. We provide reports for all industries including Energy, Technology, Manufacturing and Construction, Chemicals and Materials, Food and Beverage, and more. These reports deliver an in-depth study of the market with industry analysis, the market value for regions and countries, and trends that are pertinent to the industry.

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Virtual Reality(VR) For Healthcare Market 2020 Size by Product Analysis, Application, End-Users, Regional Outlook, Competitive Strategies and Forecast...

How Covid-19 Impact Could Open The Door For Virtual Reality Content Creation Market. – Owned

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The major players in the Virtual Reality Content Creation Market are 360 Labs, Blippar, Koncept VR, Matterport, Panedia Pty Ltd., SubVRsive, Vizor, Voxelus, WeMakeVR, and WevrWe also need a market analysis section solely dedicated to major players such as where analysts give us an insight into the financial statements of all the major players, along with product benchmarking and SWOT analysis. Global Virtual Reality Content Creation market with great emphasis on its market share, recent developments, business overview, market served, and growth strategies.

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Virtual Reality Content Creation Market: Research Methodology

Coherent Market Insights follows a comprehensive research methodology focused on providing the most precise market analysis. The company leverages a data triangulation model which helps company to gauge the market dynamics and provide accurate estimates. Key components of the research methodologies followed for all our market reports include:

As part of Primary research, our analysts interviewed a number of primary sources from the demand and supply sides of the global Virtual Reality Content Creation Market. This helped them to obtain both quantitative and qualitative data and information. On the demand side of the global Virtual Reality Content Creation Market are end-users, whereas on the supply side are distributors, vendors, and manufacturers.

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During our Secondary research, we collect information from different sources such as databases, regulatory bodies, gold and silver-standard websites, articles by recognized authors, certified publications, white papers, investor presentations and press releases of companies, and annual reports.

COVID-19 Impact on Virtual Reality Content Creation Market

This research study also includes the analyses related to the impact of Covid-19 on the Virtual Reality Content Creation Market. The global impacts of the coronavirus disease 2019 (COVID-19) may significantly affect the growth of the Virtual Reality Content Creation Market in near future. As per the experts viewpoints, it affects the global economy in 3 major ways:

Virtual Reality Content Creation Market: Regional Analysis

This part of the report includes detailed information on the market in various regions. Each region offers different scope for markets because every region has different government policies and other factors. The regions included in this report areNorth America, Europe, The Asia Pacific, and the Middle East and Africa. Information about the different areas helps the reader to understand better the global market.

Complete SWOT Analysis of the Global Virtual Reality Content Creation Market

SWOT analysisis one technique that is quite that helps to gain an insight into the past and find a solution for the benefit of current or future blemish, useful for existing companies as well as the new plan. SWOT-analysis helps reduce weaknesses while maximizing the strong side of the company. Its can also be used when it comes to achieving certain goals in non-profit organizations or private companies. This tool can be used to make a reconsideration during the study.

Importance of SWOT Analysis in Business :

The mostimportantpart of aSWOT analysisis to improve the viability of your company.Importantthreats coupled with a company weakness typically put at risk your companys future, and theSWOT analysisidentifies these risks. You can eliminate internal weaknesses by assigning company resources to fix the problems.

Factors of SWOT-analysis will help businesses to understand their strengths to the threat that what is the strength of the company and what could be a threat or a risk in the future. With the help of SWOT analysis, companies can increase the chances of success and reduce the possibility of failure.

When the company conducted a SWOT analysis they need to know what are the weak points of the company. Then, managers can provide training to employees who help the company to improve employee performance.

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When managers know each and every aspect of the company from strength to threats. Time strategy formulation becomes easy. It helps companies to formulate a strategy.

It helps the company to motivate employees because when companies must know their weaknesses are trying to remove and send employees. When employees know their weaknesses are also working hard to eliminate the weaknesses

It helps companies to identify potential opportunities. SWOT analysis company because when they come to know about any potential opportunities that can help a business to grow.

Competitor analysis is critical to any marketing plan and SWOT analysis provides a perfect way to do this. Typically, PEST analysis is done before a SWOT analysis to provide details on opportunities and threats sections. Once you have a complete SWOT diagram you and your competitors, you can make better decisions about your marketing plan.

PESTEL Analysis :

APESTEL analysisor more recently named PESTELE is a framework or tool used by marketers to analyse and monitor the macro-environmental (external marketing environment) factors that have an impact on an organisation. The result of which is used to identify threats and weaknesses which are used in a SWOTanalysis.

Opportunities come in various forms, then the value of doing a PESTEL analysis. PESTEL stands for:

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How SWOT Analysis Is Important for Virtual Reality Content Creation Market ?

There are three steps to follow in this analysis.

In this stage, and we collect all the information regarding the first two internal factors, strengths and weaknesses. However, this information collection can be done in a number of different ways. One-to-one interview or a group discussion can be carried to gather information. There will be a number of different views, questions, and issues related to these elements.

Here, we can make a list of all the opportunities that it may encounter in the future. It can make another list of all the future possible threats within the organization.

In this stage, the plan of action will have carried out to meet these opportunities and to secure the company from the threats. In this stage, the organization makes sure that they can maintain the strengths, change or stop the weaknesses, prioritize opportunism and minimize threats.

If you are not doing a SWOT analysis for your business or new start-ups you will face some of these Problems or Issues:

Appendix

Virtual Reality Content Creation Market report gives you details about the market research finding and conclusion which helps you to develop profitable market strategies to gain a competitive advantage. Supported by comprehensive primary as well as secondary research, the Virtual Reality Content Creation Market the report is then verified using expert advice, quality check and final review. The market data was analyzed and foretasted using market dynamics and consistent models.

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How Covid-19 Impact Could Open The Door For Virtual Reality Content Creation Market. - Owned

What is Nanomedicine? : Center for Nanomedicine

Nanomedicine is defined as the medical application of nanotechnology. Nanomedicine can include a wide range of applications, including biosensors, tissue engineering, diagnostic devices, and many others. In the Center for Nanomedicine at Johns Hopkins, we focus on harnessing nanotechnology to more effectively diagnose, treat, and prevent various diseases. Our entire bodies are exposed to the medicines that we take, which can lead to unpleasant side effects and minimize the amount of medicine that reaches the places where it is needed. Medications can be more efficiently delivered to the site of action using nanotechnology, resulting in improved outcomes with less medication.

For example, treating cancer with current chemotherapy delivery techniques is like spraying an entire rose garden with poison in order to kill a single weed. It would be far more effective to spray a small amount of poison, directly on the weed, and save the roses. In this analogy, a cancer patients hair follicles, immune cells, and epithelia are the roses being poisoned by the chemotherapy. Using nanotechnology, we can direct the chemotherapy to the tumor and minimize exposure to the rest of the body. In addition, our nanotechnologies are more capable of bypassing internal barriers (see Technologies), further improving upon conventional nanotechnologies. Not only is our approach more effective at eradicating tumors (see Cancer under Research), but it also results in much higher quality of life for the patient.

Nanotechnology can also reduce the frequency with which we have to take our medications. Typically, the human body can very quickly and effectively remove medications, reducing the duration of action. For example, the current treatment for age-related macular degeneration (AMD) requires monthly injections into the eye in a clinical setting. However, if the medication is slowly released from the inside of a nanoparticle, the frequency of injection can be reduced to once every 6 months (see Eye under Research). The nanoparticle itself also slowly biodegrades into components that naturally occur in the body, which are also removed from the body after the medication has done its job. This exciting technology is currently being commercialized and moved toward clinical trials (see Commercialization).

Nanomedicine will lead to many more exciting medical breakthroughs. Please explore our various nanotechnology platforms and the numerous areas in which we are pursuing nanomedicine-based medical solutions.

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What is Nanomedicine? : Center for Nanomedicine

Nanomedicine | medicine | Britannica

Nanomedicine, branch of medicine that seeks to apply nanotechnologythat is, the manipulation and manufacture of materials and devices that are smaller than 1 nanometre [0.0000001 cm] in sizeto the prevention of disease and to imaging, diagnosis, monitoring, treatment, repair, and regeneration of biological systems.

Although nanomedicine remains in its early stages, a number of nanomedical applications have been developed. Research thus far has focused on the development of biosensors to aid in diagnostics and vehicles to administer vaccines, medications, and genetic therapy, including the development of nanocapsules to aid in cancer treatment.

An offshoot of nanotechnology, nanomedicine is an emerging field and had garnered interest as a site for global research and development, which gives the field academic and commercial legitimacy. Funding for nanomedicine research comes both from public and private sources, and the leading investors are the United States, the United Kingdom, Germany, and Japan. In terms of the volume of nanomedicine research, these countries are joined by China, France, India, Brazil, Russia, and India.

Working at the molecular-size scale, nanomedicine is animated with promises of the seamless integration of biology and technology, the eradication of disease through personalized medicine, targeted drug delivery, regenerative medicine, as well as nanomachinery that can substitute portions of cells. Although many of these visions may not come to fruition, some nanomedicine applications have become reality, with the potential to radically transform the practice of medicine, as well as current understandings of the health, disease, and biologyissues that are of vital importance for contemporary societies. The fields global market share totalled some $78 billion dollars in 2012, driven by technological advancements. By the end of the decade, the market is expected to grow to nearly $200 billion.

Nanomedicine derives much of its rhetorical, technological, and scientific strength from the scale on which it operates (1 to 100 nanometers), the size of molecules and biochemical functions. The term nanomedicine emerged in 1999, the year when American scientist Robert A. Freitas Jr. published Nanomedicine: Basic Capabilities, the first of two volumes he dedicated to the subject.

Extending American scientist K. Eric Drexlers vision of molecular assemblers with respect to nanotechnology, nanomedicine was depicted as facilitating the creation of nanobot devices (nanoscale-sized automatons) that would navigate the human body searching for and clearing disease. Although much of this compelling imagery still remains unrealized, it underscores the underlying vision of doctors being able to search and destroy diseased cells, or of nanomachines that substitute biological parts, which still drives portrayals of the field. Such illustrations remain integral to the field, being used by scientists, funding agencies, and the media alike.

Attesting to the fields actuality are numerous dedicated scientific and industry-oriented conferences, peer-reviewed scientific journals, professional societies, and a growing number of companies. However, nanomedicines identity, scope, and goals are a matter of controversy. In 2006, for instance, the prestigious journal Nature Materials discussed the ongoing struggle of policy makers to understand if nanomedicine is a rhetorical issue or a solution to a real problem. This ambivalence is reflected in the numerous definitions of nanomedicine that can be found in scientific literature, that range from complicated drugs to the above mentioned nanobots. Despite the lack of a shared definition, there is a general agreement that nanomedicine entails the application of nanotechnology in medicine and that it will profoundly impact medical practice.

A further topic of debate is nanomedicines genealogy, in particular its connections to molecular medicine and nanotechnology. The case of nanotechnology is exemplary: on one hand, its potentialin terms of science but also in regard to funding and recognitionis often mobilized by nanomedicine proponents; on the other, there is an attempt to distance nanomedicine from nanotechnology, for fear of being damaged by the perceived hype that surrounds it. The push is then for nanomedicine to emerge not as a subdiscipline of nanotechnology but as a parallel field.

Although nanomedicine research and development is actively pursued in numerous countries, the United States, the EU (particularly Germany), and Japan have made significant contributions from the fields outset. This is reflected both in the number of articles published and in that of patents filed, both of which have grown exponentially since 2004. By 2012, however, nanomedicine research in China grew with respect to publications in the field, and the country ranked second only to the United States in the number of research articles published.

In 2004, two U.S. funding agenciesthe National Institutes of Health and the National Cancer Instituteidentified nanomedicine as a priority research area allocating $144 million and $80 million, respectively, to its study. In the EU meanwhile, public granting institutions did not formally recognize nanomedicine as a field, providing instead funding for research that falls under the headers of nanotechnology and health. Such lack of coordination had been the target of critiques by the European Science Foundation (ESF), warning that it would result in lost medical benefits. In spite of this, the EU ranked first in number of nanomedicine articles published and in 2007 the Seventh Framework Programme (FP7) allocated 250 million to nanomedicine research. Such work has also been heavily funded by the private sector. A study led by the European Science and Technology Observatory found that over 200 European companies were researching and developing nanomedicine applications, many of which were coordinating their efforts.

Much of nanomedicine research is application oriented, emphasizing methods to transfer it from the laboratory to the bedside. In 2005 the ESF pointed to four main subfields in nanomedicine research: analytical tools and nanoimaging, nanomaterials and nanodevices, novel therapeutics and drug delivery systems, and clinical, regulatory, and toxicological issues. Research in analytical tools and nanoimaging seeks to develop noninvasive, reliable, cheap, and highly sensitive tools for in vivo diagnosis and visualization. The ultimate goal is to create fully functional mobile sensors that can be remotely controlled to conduct in vivo, real-time analysis. Research on nanomaterials and nanodevices aims to improve the biocompatibility and mechanical properties of biomaterials used in medicine, so as to create safer implants, substitute damaged cell parts, or stimulate cell growth for tissue engineering and regeneration, to name a few. Work in novel therapeutics and drug delivery systems strives to develop and design nanoparticles and nanostructures that are noninvasive and can target specific diseases, as well as cross biological barriers. Allied with very precise means for diagnosis, these drug delivery systems would enable equally precise site-specific therapeutics and fewer side effects. The area of drug delivery accounts for a large portion of nanomedicines scientific publications.

Finally, the subfield of clinical, regulatory, and toxicological issues lumps together research that examines the field as a whole. Questions of safety and toxicology are prevalent, an issue that is all the more important given that nanomedicine entails introducing newly engineered nanoscale particles, materials, and devices into the human body. Regulatory issues revolve around the management of this newness, with some defending the need for new regulation, and others the ability of systems to deal with it. This subfield should also include other research by social scientists and humanists, namely on the ethics of nanomedicine.

Combined, these subfields build a case for preventive medicine and personalized medicine. Building upon genomics, personalized medicine envisions the possibility of individually tailored diagnostics and therapeutics. Preventive medicine takes this notion further, conjuring the possibility of treating a disease before it manifests itself. If realized, such shifts would have radical impacts on understandings of health, embodiment, and personhood. Questions remain concerning the cost and accessibility of nanomedicine and also about the consequences of diagnostics based on risk propensity or that lack a cure.

medicine

Medicine, the practice concerned with the maintenance of health and the prevention, alleviation, or cure of disease. The

nanotechnology

Nanotechnology, the manipulation and manufacture of materials and devices on the scale of atoms or small groups of atoms. The nanoscale is typically measured in nanometres, or billionths of a metre (nanos, the Greek word for dwarf, being the source of the prefix), and materials built at this scale often

disease

Disease, any harmful deviation from the normal structural or functional state of an organism, generally associated with certain signs and symptoms and differing in nature from physical injury. A diseased organism commonly exhibits signs or symptoms indicative of its abnormal state. Thus, the normal condition of an organism must be

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Nanomedicine | medicine | Britannica

Nanomedicine – an overview | ScienceDirect Topics

17.8 Commentary on Hurdles in Clinical Translation of Various Nanotechnology Products

Research regarding nanoconstructs development in the cancer treatment field has witnessed a noticeable increase after discovery of the EPR effect. However, the number of anticancer drugs that actually reached the market was considered extremely low, as out of 200,000 anticancer drugs only 15 made it by 2017 (Greish et al., 2018). The reasons why most of the nanomedicines cannot even reach the market are the hardship or inability to maintain detailed characterization of these products, unsuccessful manufacturing on large scales, and issues in their safety and efficacy. These hurdles require many developmental processes to overcome them including a precise understanding of every component and all the possible interactions between them, determination of key characteristics to understand in which possible ways they affect performance, and the extent of it. If key characteristics can be replicated under manufacturing conditions (scaling up), the efficacy of targeting at the site of action and their stability and sterility can be enhanced and/or assessed (Desai, 2012). The majority of these hurdles are summarized in Table 17.5 (Tinkle et al., 2014).

Table 17.5. Major Hurdles That Face the Commercialization of Nanomedicine

Lack of standard nano nomenclature: imprecise definition for nanomedicines

Currently used compounds/components for nanodrug synthesis often pose problems for large-scale good manufacturing (cGMP) production

Lack of precise control over nanoparticle manufacturing parameters and control assays

Lack of quality control: issues pertaining to separation of undesired nanostructures (byproducts, catalysts, starting materials) during manufacturing

Reproducibility issues: control of particle size distribution and mass

Scalability complexities: enhancing the production rate to increase yield

High fabrication costs

Lack of rational preclinical characterization strategies via multiple techniques

Biocompatibility, biodistribution and toxicity issues: lack of knowledge regarding the interaction between nanoparticles and biosurfaces/tissues

Consumer confidence: the publics general reluctance to embrace innovative medical technologies without clearer safety or regulatory guidelines

The relative scarcity of venture funds

Ethical issues and societal issues are hyped up by the media

Big Pharmas continued reluctance to seriously invest in nanomedicine

Patent review delays, patent thickets, and issuance of invalid patents by the US Patent and Trademark Office

Regulatory uncertainty and confusion due to baby steps undertaken by US Food and Drug Administration: a lack of clear regulatory/safety guidelines

One of the major concerns related to NPs is their potential incompatibility and toxicity. Studies showed that inhaling NPs can cause pulmonary inflammation as well as inducing endothelial dysfunction that might lead to further complications in the cardiovascular system. A study for evaluation of iron oxide toxicity showed that monocyte-mediated dissolution and phagocytosis of the NPs have caused severe endothelial toxicity by initiating oxidative stress. Nanomaterials used in oral DDS have been shown to accumulate in hepatic cells, which might induce the immune response and eventually cause permanent damage to the liver. The accumulation of NPs in cells has been found to cause cancer by transforming cells into the tumorous state (Jain et al., 2018; Riehemann et al., 2009). Thus, handling these nanosystems requires special equipment and caution, which increases the cost of the production process and requires further investigations of the safety of nanomaterials to have a better understanding and optimize safety during manufacturing (Hammed et al., 2016). Production of NPs in the laboratory often requires complex, multistep synthesis processes to yield the nanomaterials with the required properties. Aside from the complexity of the process, controlling conditions such as temperature and concentrations precisely is significant to achieve homogeneity of NPs in terms of desired characteristics. However, retaining temperature and concentration in large systems is harder to achieve resulting in NPs with different characteristics (Gomez et al., 2014).

NPs tend to aggregate forming clusters with several microns in size. Aggregation of NPs alters their characteristics such as reactivity, transport, toxicity, and risk in the environment. Dissolution reduces when aggregation occurs due to the decrease in available surface area that will eventually reduce the activity of NPs. For example, dechlorination rate of CT (carbon tetrachloride) by magnetite NPs has shown to decrease when aggregation of the NPs increases resulting in an inverse relationship between dechlorination rate of carbon tetrachloride and aggregation of magnetite NPs (Hotze et al., 2010; Hou and Jafvert, 2009).

All these requirements are extremely important because the majority of the nanomedicines have failed to reach the commercialization step even though their efficacy in animal models was considerably high. Due consideration must be given regarding the several difficulties such as their low targeting, low safety, low efficacy, heterogeneity of disease between individuals, inability to scale-up successfully, and unavailability in determining a convenient characterization methods (Agrahari and Agrahari, 2018; Hare et al., 2017; Kaur et al., 2014). These hurdles that face the research process of accelerated translation are summarized in Fig. 17.8 (Satalkar et al., 2016).

Figure 17.8. Major issues that face accelerated translation process of nanoparticles.

Therefore, more understanding in all aspects of nanomedicine production, characterization, and clinical processes must be fulfilled to control and improve the development processes, and increase the efficacy of the translational methods. Other significant hurdles hindering clinical translation are the insignificant incentives regarding technology transfer, as well as socioeconomic uncertainties along with the safety problems faced. In the majority of cases, consideration of commercialization aspects in early stages of development is hardly even considered thus eliminating the market-oriented development (Rsslein et al., 2017).

Nanomedicines face tough, challenging concerns when it comes to determining the applicable analytical tests in terms of chemical, physical, or biological characterization. This is mainly achieved due to their complex nature in comparison with other pharmaceutical products. Hence, there is a need for more complex and advanced levels of testing to ensure a full accurate characterization of nanomedicine products. Quantification of each component of nanomedicine is considered essential alongside the identification and evaluation of interactions between them. For more possibility in achieving successful manufacturing processes with reproducibility, these products should be investigated and understood more during the early developmental stages to identify their key characteristics. The challenges for nanomedicine during scale-up and manufacturing are considered relatively unique because other pharmaceutical manufacturing processes systems are not three-dimensional multicomponent in nature on the nanometer scale. Therefore, a certain series of obstacles in the scale-up process is required. To reach the desired safety, pharmacokinetic and pharmacodynamic parameters to produce the therapeutic effect are needed. These are further determined by the proper selections of the essential components, determination of the critical manufacturing steps, and key characteristics identification. Several methods of orthogonal analysis are essential for in-process quality controls of nanoparticle products and any deviations from key parameters could result in a significant negative impact on both the safety and efficacy of nanomedicines (Desai, 2012).

Each step in the manufacturing process of NPs must be understood extensively with the need of experienced technicians. The development process also requires more enhancements in both complexity and cost. Inadequate data regarding scaling-up processes of nanomedicine products is a major concern in the commercialization step as there are only a few reports supporting scaling-up developments. Many formulation methods have been developed for manufacturing nanomedicine products. The most common methods are nanoprecipitation and emulsion-based approaches. Generally, formulations are prepared either by precipitating the dissolved molecules (bottom-up method) or by reducing the size of larger drug particles (top-down method). Removal of the solvent in the bottom-up method is not an easy process and it cannot be controlled well either, thus explaining why this method is less often applied in industrial manufacturing (Agrahari and Agrahari, 2018; Vauthier and Bouchemal, 2009). Investments in innovative projects face several issues with the major one being the knowledge that should be obtained from the innovation. Its confidentiality is easily breached when a company uses that knowledge as it cannot prevent other companies from using it. Thus, investors are not attracted to this type of project because the total return on the investment cannot be easily appropriated (Morigi et al., 2012).

The complexities in formulating nanoproducts on large scales are due to the inability of optimization of formulation processes and achieving reproducibility. Whereas formulation steps including size reduction, homogenization, centrifugation, sonication, solvent evaporation, lyophilization, extrusion, and sterilization can be easily optimized on small-scales, its still a challenging process on large-scales. Accordingly, variations between batches cannot be controlled sufficiently thereby limiting the possibility of nanomedicine to get through commercial translation (Anselmo et al., 2017; Desai, 2012).

Another problem is that even slight changes in either the formulation or the manufacturing process can have a significant effect on the nanomedicine physiochemical properties (crystallinity, size, surface charge, release profile), which will ultimately influence the therapeutic outcome. Most of the pharmaceutical industrial facilities cannot manufacture nanomedicines because of the lack of the right equipment for the process. As nanomedicine manufacturing usually involves the use of organic solvents, the ability to correctly process and handle nanoproducts is crucial to control their safety and sterility (Anselmo et al., 2017; Desai, 2012; Kaur et al., 2014). These steps require an expensive and complicated equipment, well-trained staff, and precise control to get the required product in the right quality (Desai, 2012; Kaur et al., 2014; Ragelle et al., 2017).

To date, only 58 nanoformulations are approved based on their clinical efficacy but only a quarter of them are meant for cancer treatment. Majority of the nanoformulations could not even be reproduced successfully due to several factors including the study design, overall analysis, protocols, data collection, and the quality and purity of materials used. Besides, the poor establishment of the correlation and prediction of safety and efficacy of the nanomedicine on patients hinders the successful DDS. Targeting and drug accumulation of anticancer drugs in the site of action is considered relatively poor in mouse models. Many nanoformulations were faced with failure in different clinical trial phases. Some of them got approved but then withdrawn from the market such as peginesatide. Unfortunately, the increased failures will most probably affect the development movement in the pharmaceutical industry (Greish et al., 2018).

At the present time, regulatory agencies such as the FDA and EMEA are examining every new nanomedicine on a product-by-product basis. They are considered a unique category due to the fact that there are no true standards in their examination process (Desai, 2012). Two of the major regulatory issues that emerged at the start of nanomedicine is the lack of scientific experts in the FDA and the difficulty in classifying the product (Morigi et al., 2012). The unique characteristics of nanomedicines are directly related to their regulation hurdles, which is the same as other pharmaceutical systems such as liposomes and polymeric systems (Sainz et al., 2015).

Researchers keep investigating nanomedicines when attached to prodrugs, drugs, tracking entities, and targeting molecules. Development of robust methods and assays in quality control of nanomedicines are required for more effective monitoring and characterizations. Also, estimation of their overall performance in releasing drugs, binding to proteins, and the specificity in cellular uptake must be considered (Sainz et al., 2015; Tinkle et al., 2014).

Nanomedicine products are both complex and diverse requiring explanation of challenges to have a clear definition and an effective regulation. The lack of regulatory guidelines for these products hinders their clinical potential. Drug regulatory authorities must keep up with the rapid pace of the knowledge and technological development as they play a major role translating nanomedicines towards the market. The European Medicines Agency (EMEA) and the FDA have different requirements in evaluating new nanomedicines as well as different definitions regarding nanomedicine. Agreeing on specific regulatory procedures internationally is very important to ease the translational researches of nanomedicines. Also, better long-term monitoring of toxicity should be achieved by prolonging postmarketing surveillance especially for a patient with chronic diseases (Sainz et al., 2015; Tinkle et al., 2014).

Nanomedicines just like any other pharmaceutical formulations must offer higher value to patients to become commercially successful, and have better efficacy and safety. New nanomedicine products follow the same steps in clinical trials as other drugs. It starts with preclinical tests, then be submitted to get the IND (investigational new drug) approval and following that it enters the three stages of clinical trials, one after another to evaluate safety and efficacy of the new drug (Agrahari and Agrahari, 2018).

In recent years, toxicities caused by nanomedicines have drawn attention and been recognized to be unique to nanoparticulate systems. Hence, a minimum set of measurements for the nanoparticle like surface charge, size, and solubility are monitored so as to predict the possible toxicity of NPs. Besides, NPs can stimulate the immune system by acting as an antigen. Immunogenicity is mainly affected by the size of the nanoparticle, its surface characteristics, hydrophobicity, charge, and solubility. Hematologic safety concerns have also been observed such as hemolysis and thrombogenicity (Desai, 2012).

In vivo and in vitro studies provide the proper characterization of the interactions between the product and the biological system. The problem is that the data attained from current toxicity tests are not from clinical trials and it cannot always be extrapolated to humans. Monolayers of cell cultures are currently used to characterize immunogenicity, drug release, cellular uptake, and toxicity. However, the cellular uptake process of nanoformulations is majorly influenced by physicochemical characteristics. Thus, 3D cell systems will probably provide better outcomes (Gupta et al., 2016). More caution should be given when handling any nanosized powder due to the ability of such particles to penetrate the skin and because it can also show pulmonary toxicity (Agrahari and Hiremath, 2017; Nel et al., 2006).

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Cleaning the Nano-Texture Glass on Your New iMac – The Mac Observer

With Apples refresh of the 27-inch iMac, a new option is available that previously was only offered on the Pro Display XDR. You can now ordet your iMac with a nano-texture display. This reduces glare to a bare minimum, but cleaning the nano-texture glass on your new iMac is quite different from other display options.

When you order your 27-inch iMac with nano-texture glass, Apple actually etches the coating into the display at the nanometer level. Apple claims that it reduces glare while preserving contrast, for jaw-dropping image quality. The texturing scatters light as it hits the display, minimizing glare and reducing the undesirable haze and sparkle of the normal matte coatings.

Apple provides a special cleaning cloth for the nano-texture glass. The company says you should never use any other material on the display or you risk damaging the glass. So, how can you clean the nano-texture glass on your new 27-inch iMac if it gets really dirty?

As it turns out, the key to removing difficult smudges is something you probably already have around the house. Take that 70-percent isopropyl alcohol (IPA) solution out of your medicine cabinet. Moisten the cleaning cloth with it, and you can easily wipe away those hard-to-remove smudges.

Once done, you should clean the polishing cloth to remove excess isopropyl alcohol. Just follow these steps:

Should you lose the polishing cloth, or want a spare, you can order a replacement directly from Apple Support.

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Cleaning the Nano-Texture Glass on Your New iMac - The Mac Observer

THE FUTURE JUST ARRIVED: THE ROLE OF BANKS IN A POST-COVID WORLD – Forbes Africa

THE COVID-19 GLOBAL pandemic has brought forward the future. It has brought about humanitys biggest challenge in a century, to choose between life and livelihoods. In the immediate aftermath of the pandemic, banks have played a supporting role to clients and communities. Standard Chartered announced a commitment of US$1 billion globally to support companies in the health delivery supply chain to combat the COVID-19 pandemic, and an additional US$50 million to assist communities in presence markets, especially Africa.

Generally, banks have entered the COVID crisis much stronger and resilient than they did before the global nancial crisis of 2008. This resilience is owed in part to the raft of regulatory reforms and stronger supervision since 2008, aimed at ensuring adequate capital and liquidity buffers against market-wide stress and also to avoid future taxpayer bailouts. Bank resilience notwithstanding, there is a catch! Well, several!

Many jurisdictions have placed ghting this pandemic at par with war by employing emergency measures and massive scal stimulus packages to provide relief to businesses and households and hopefully to bring the public health crisis under control. Relative to Q1 2020, total lockdown is now perceived as a blunt instrument in responding to the pandemic due to its potential for economic destruction and jeopardizing livelihoods. There is some convergence of views towards recalibrating easing of lockdown alongside placing high emphasis on both corporate and individual responsibility to obey public health recommendations and to observe good hygiene.

As the world emerges from lockdown, the nature and shape of the recovery is an important variable. Whether the recovery is a V-shape, U-shape or a W- shape makes a world of a difference to how banks will respond. We are only beginning to understand and measure the true economic cost of the pandemic, transmitted through lockdown and the deleterious effects on growth and the viability of some sectors. Many companies around the world face the grim prospect of possible collapse, necessitating tough survival decisions on rationalizations, write-downs of asset values and other corporate actions.

National governments need to determine the right balance between restarting economic activity and growth without compromising the capacity of healthcare infrastructure. The ability to do so would in turn inuence the nature and shape of the recovery as well as which companies or sectors can survive the new reality, and which would fail. Then there is digitization. Digitization and the new ways of working will dene who stays competitive, productive and can survive. Almost every sector or industry and even governments will need to invest in digital solutions to future-proof their survival and relevance.

While banks certainly have a critical role to play during and post crisis, the reality is there is no certainty or clarity on how events might unfold. In the meantime, a better understanding of the nature, virulence and measures to conquer the invisible enemy remains elusive, thereby drawing parallels with the expression fog of war. The unfolding challenges and after-effects of the pandemic are not sequential or in any particular order. Neither will the responses be. Responses need to be diligent, intelligent and wise in order to safeguard the future. The pre-COVID bank resilience is a necessary and comforting condition but insufficient for post-COVID recovery unless banks themselves can successfully navigate the fog of this new war to avoid joining the casualty list that is beginning to grow around the world. They will certainly be dealing with elevated credit risk, strains to capital and liquidity and heightened operational and cyber security risk, among others. Livelihoods and economic security look fragile in the short run as the pandemic exposes cracks, ssures and chasms in the existing socio-economic order globally. This systemic stress could precipitate a repurposing of legacy political, economic, social and security arrangements by national governments which could be consequential to businesses recovery and viability, household incomes and social cohesion. For the banks, it becomes a waiting game!

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THE FUTURE JUST ARRIVED: THE ROLE OF BANKS IN A POST-COVID WORLD - Forbes Africa

Emerging T-cell Therapy Treatment for Mesothelioma Shows Significant Tumor Reduction – MesoWatch

TCR2 Therapeutics announced on July 26 the first positive results for a new T-cell therapy to treat cancer patients, according to the press release on July 26th.

The first five patients treated in phase I of the clinical trial showed mesothelin-expressing tumor regression within six months of treatment. All patients received the same dose of TC-210 TRuC-T cell products. Four patients received lymphodepletion as well and one received TC-210 T cell products without lymphodepletion. Lymphodepletion is when lymphocytes (the cells that fight bacterial and viral infections) are destroyed. Only one patient experienced toxicity as a result of t-cell therapy.

The median reduction range for the sum of the diameters of target lesions was 42 percent.

Garry Menzel, President and Chief Executive Officer of TCR2 Therapeutics expressed gratitude for the results but mentioned that this is just the start of getting T-cell therapy approved for cancer patients.

We are delighted that our very first dose of TC-210 induced consistent tumor regression and clinical benefit in heavily pre-treated cancer patients, Menzel said. There are very few options for patients with solid tumors and those expressing mesothelin represent a significant frontier of unmet medical need. While these are early data requiring further study, we are encouraged by the potential of our TRuC-T cells as we continue to enroll and treat patients with the goal of quickly finding a recommended Phase 2 dose for TC-210.

Phase I of most clinical trials is mainly to assess the safety and efficacy of treatment before increasing dosage in patients. Phase two will use the dosage data from one and test the efficacy in tumor control and regression in about 50 patients, according to TCR2. Phase three is the stage where a treatment seeks approval from the Food and Drug Administration.

Patients in phase two will have a current diagnosis of non-small cell lung cancer, ovarian cancer, malignant pleural/peritoneal mesothelioma, or cholangiocarcinoma and all dosages will reflect the specific cancer type.

While more tests need to be run, Alfonso Quints-Cardama, M.D., Chief Medical Officer of TCR2 Therapeutics, said that this will bring some hope to cancer patients who have failed multiple lines of therapy.

Based on my prior experience working with both TCR-T and CAR-T cells, including the FDA approval of Kymriah, observing consistent clinical benefit in patients at presumably suboptimal T cell doses is quite meaningful, saidQuints-Cardama. These early TC-210 data suggest our approach may overcome the challenges faced by many T cell therapies in the hostile solid tumor microenvironment. Our enrolled patients have failed multiple lines of therapy, including standard chemotherapy, checkpoint inhibitors, and in some cases other mesothelin-directed approaches, in indications where survival has been historically shorter than six months.

According to clinicaltrials.gov, recruiting is still happening for this trial and people can still sign up for phase one.

T-cell therapy is still an emerging treatment for cancers such as mesothelioma. Chimeric antigen receptor T-cell therapy or CAR-T-cell therapy is the only other T-cell treatment that shows promising results. TRuC-T cells would add another form of treatment for mesothelioma, which normally has a poor prognosis.

TCR2 Therapeutics hosted a live webcast and conference call on July 27. The webcast can still be replayed on this webpage until approximately August 26.

For more information on mesothelioma treatment options, visit our webpage on treatments. If you have been diagnosed with mesothelioma or asbestos-related cancer, visit the contact page to talk to an advocate for compensation.

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Emerging T-cell Therapy Treatment for Mesothelioma Shows Significant Tumor Reduction - MesoWatch

Targeted phototherapy study Shows low-risk and effective treatment for Pleural Mesothelioma – MesoWatch

A new study shows that near-infrared phototherapy could be a promising treatment for individuals with pleural mesothelioma, according to a press release from Nagoya University.

The study, which tested mice and 12 human cell lines with malignant tumors, concluded that near-infrared photoimmunotherapy was a low-risk and effective method of killing cancer cells without harming surrounding cells due to the nature of near-infrared light, according to Kazuhide Sato, a researcher for the Institute for Advanced Research. There are several studies that suggest that near-infrared photoimmunotherapy is an effective cancer treatment, but little or no studies that focus on using this treatment for mesothelioma.

Malignant mesothelioma can be detected with high levels of podoplanin, a protein typically found in cancer cells. This type of treatment targets the expression of podoplanin. First, an anti-podoplanin antibody called NZ-1-IR700 was injected into the mice. This compound binds to podoplanin to both illuminate tumor cells and allow them to absorb light energy. This type of antibody is non-toxic to the body. When Satos team focused a near-infrared light into the chest cavity of mice, they saw the tumor cells rupture.

Sato suggested that further studies look into using a drainage device similar to the one used in patients to drain excess fluid in the lungs. The divide would help diffuse light directly into the chest cavity and cause more effective results.

One possible benefit of this treatment is that healthy cells are less likely to be destroyed. Sato acknowledged that NZ-1 would also bind to podoplanin on lymphatic epithelial cells, but he also suggested using CasMab, an antibody that detects the differences between cancer cells and healthy cells. With or without CasMab, the immunotherapy is regional and can help preserve the lungs. The anti-podoplanin antibodies are also not toxic to cells unless a near-infrared light is on them.

That being said, Sato said that there need to be more studies to ensure that the treatment will not unnecessarily harm the body. This study was partially performed on human cell lines with malignant tumors, but not on human beings.

Near-infrared photoimmunotherapy is a treatment that is perfect for patients with mesothelioma since it is usually localized to the lungs. Sato explained why this therapy works in the chest cavity.

"The lungs and chest cavity contain a large amount of air and are thus very good at effectively transmitting near-infrared light," says Sato. "NIR-PIT is a safe phototherapy option that can target a region of interest. The antibody-IR700 conjugate is also non-toxic to the body in the absence of near-infrared light irradiation. We thus thought that NIR-PIT could be an effective strategy for controlling localized MPM."

Currently, near-infrared photoimmunotherapy is in phase III clinical trials for head and neck cancer treatments for individuals who have failed at least two lines of therapy. The Food and Drug Administration has fast-tracked approval and this could be a possible treatment in the next few years, according to Sato.

Near-infrared light is not visible to the naked eye, but the wavelengths can penetrate the skin up to four inches. The body detects near-infrared light as heat. This type of light does not damage the skin as ultraviolet light would.

Mesothelioma is a rare type of cancer that affects the epithelial lining in the lungs, heart, and other organs. Typically mesothelioma is diagnosed in the late stage with very limited treatment options and a poor prognosis. Near-infrared photoimmunotherapy could bring hope to people with mesothelioma or their families.

For a full copy of the study, go to PubMed.

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New Study Shows that Surgery Can Improve Prognosis in Patients with Peritoneal Mesothelioma – MesoWatch

An analysis of mesothelioma patients who underwent cytoreductive surgery concludes that surgical treatment can improve the survival rate of a patient and should be the first choice for early treatment.

A study from the Annals of Surgical Oncology examined the survival rates of over 2000 peritoneal mesothelioma patients from 2003 to 2014. About 51% of patients did not have any kind of surgery to treat their cancer, while 34% received radical surgery according to the study. The patients who received surgery had an average survival rate of about 38.4 months compared to the non-surgery group which was 7.1 months.

Another group was made up of patients who received both radical surgery and chemotherapy. Those patients had a survival rate of about 41.8 months.

The results indicate a major improvement in prognosis. Before the year 2000, the average prognosis of patients with peritoneal mesothelioma was less than a year, according to the study.

The most recent study recommends that more doctors suggest surgery to a newly diagnosed patient to improve life-expectancy should he or she be fit enough to receive it.

Cytoreductive surgery is a lengthy process that involves surgeons inspecting each organ and removing any tumors. Generally, it is a curative treatment in the early stages of mesothelioma and palliative treatment in late stages to improve the quality of life in the terminal stage.

During some surgeries, treatment will also include hyperthermic intraperitoneal chemotherapy, a process where a doctor usually administers chemotherapy drugs directly into the peritoneum to kill cancer cells more. Using cytotoxic drugs post-operatively can prevent more tumors from forming afterward. Furthermore, the direct application of chemotherapy in high concentrations keeps systemic drug levels low, according to one study from the World Journal for Gastrointestinal Oncology.

Hyperthermic intraperitoneal chemotherapy cannot penetrate tumors deeply so surgery is the best preliminary treatment, according to the study.

Cytoreductive surgery can be beneficial for patients who are fit and are in the early stages of peritoneal mesothelioma due to the intensity of the surgery. The procedure lasts about ten hours.

This study referenced another analysis from 2015 where more than 1000 mesothelioma patients were analyzed for their survival rate after surgery and chemotherapy. The results predicted an improved survival rate of about five years and an additional five years if the patient received both surgery and chemotherapy.

According to the report, peritoneal mesothelioma makes up one-fourth of mesothelioma cases worldwide and difficult to detect early. Therefore, cytoreductive surgery is usually a form of palliative treatment. However, the 2015 study did mention that the increase in cytoreductive surgeries with chemotherapy have led to a more-improved prognosis.

If you think you may have been exposed to asbestos at any point in your lifetime, then it is important to get frequent checkups for mesothelioma. Catching peritoneal mesothelioma early can make a major difference in prognosis. You can also talk to someone about receiving compensation for the medical bills.

Peritoneal Mesothelioma is still a difficult form of cancer to treat, but cytoreductive surgery can improve the quality of life for many patients and result in a substantially longer prognosis.

Read the full study here.

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New Study Shows that Surgery Can Improve Prognosis in Patients with Peritoneal Mesothelioma - MesoWatch

Evolutionary theory of economic decisions | Stanford News – Stanford University News

Making decisions in the face of uncertainty has never been easy. But the global pandemic has raised the stakes for many previously mundane choices: how to travel, where to get food, when to send kids back to school.

A decision to keep a mixed herd of highly productive goats and drought tolerant camels may help a household survive rare but severe water shortages, even if it doesnt maximize long-term accumulation of wealth. (Image credit: iStock)

Understanding how humans have made high-stakes decisions over evolutionary time may help to explain our choices in the present day including our tendency to veer from the preferences predicted by economic models, according to a new study from scholars at Stanford University and the Santa Fe Institute.

Rather than starting with utility the happiness or value I get out of making my decision now lets think about how the brain was constructed over evolutionary history, said study co-author James Holland Jones, a biological anthropologist at Stanfords School of Earth, Energy & Environmental Sciences (Stanford Earth). The research was published in the journal Evolutionary Human Sciences.

The pairs proposal adds a new perspective to long-running scholarly debates over why practices designed to improve the standard of living among subsistence populations dont take hold, such as the seemingly slow adoption of new farming technologies among poor, small-scale farmers, and more recently, the unwillingness of the poorest poor to adopt microfinance and other development schemes.

There is an inclination to think of the poorest people as being natural entrepreneurs because they have nothing to lose economically, Jones explained. However, the evolutionary logic we employ suggests that the poorest poor have everything to lose and are, in fact, closer to losing it than better-off people. Our model predicts that very poor people would be especially risk-averse.

It also points to the weakness of lean systems in the face of uncommon but severe threats, such as the coronavirus. One of the things were seeing right now is a world that has been optimized for efficiency and is extremely vulnerable to risk, he said. If you scale back organizations to keep them running at a mean level thats high, and you dont have a lot of slack, when a crisis hits youre in trouble.

According to the theory of expected utility, a staple of modern economics, people should always carefully weigh the likelihood of an event along with the prizes or consequences that would accrue from our decision and then choose the option with the highest average payoff. Of course, we rarely calculate these averages in practice, as behavioral economists have long recognized. Yet an assumption that our brains will behave as if we made decisions this way maximizing personal gain at every turn is still baked into many public and economic policies.

We might expect evolutionary systems to mirror markets, with organisms that act rationally out-competing those not behaving rationally, said Jones, an associate professor of Earth system science at Stanford Earth and a senior fellow at the Stanford Woods Institute for the Environment. The catch is that you cant outcompete something if youre extinct.

In addition to influencing policy, business and financial markets, theories of how we make decisions have filtered into popular culture through books like Nudge and Thinking Fast and Slow. However, they tend to deal poorly with choices that humans have faced for the vast majority of their history on Earth namely, those shaped not by market forces, but by environmental variables like temperature or rainfall. In this context, boom times cant compensate for a single lethal bust. Just one bad heat wave, drought, cold snap or flood can leave a household hungry or worse. Variance is what drives you to extinction, Jones said.

As a result, when it comes to preferences that evolve by natural selection, he said, we should expect to see people undervalue long shots that could be profitable, play it safe when things look risky and generally overestimate the likelihood of rare bad outcomes.

On the timescale of evolution, the salient outcome of a decision is how it contributes to fitness, meaning the proportion of the population through time that carries your DNA. Unlike utility, fitness is a measure that multiplies over time. If any generation in your lineage has zero offspring in it, its game over, Jones said. It is a general aversion to zeros that leads to pessimism.

At the same time, fitness plays out over such long timescales that it cant directly influence our behavior. The things that do shape our choices day to day are more like utility in that they can rise and fall without bringing catastrophe. Psychological mechanisms, like satiety or sexual gratification, or something like love of your children, can motivate you in the immediate. They promote fitness in the long run, but they are not the thing actually being maximized over time, he said.

Maximizing fitness leads us to be more pessimistic in our economic decisions than utility models predict. The optimal level of pessimism to promote survival depends on the exact universe the organism occupies, the authors write. For example, hunters targeting rare, big game may stand to bring home more calories if they succeed, but their household could go hungry if they fail. Herders have to weigh not only the productivity of their animals, but also their susceptibility to drought and disease.

Any time where you have to avoid zero, pessimism will pay off, because youd rather leave money on the table than run the risk of going extinct, Jones said.

When social distancing restrictions loosen enough to conduct group experiments, Jones and co-author Michael Price, PhD 15, who studies complex systems as a fellow at the Santa Fe Institute, plan to test their theory with games challenging participants to maximize payoffs that multiply over time or that are hidden but associated with some tangible proxy. By formalizing and eventually testing the theory, the researchers write, they hope to stimulate more work on the possible evolutionary foundations of key results from behavioral economics.

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Evolutionary theory of economic decisions | Stanford News - Stanford University News

US Teachers Evolving on Science of Evolution – T.H.E. Journal

Science Education

Asurvey done in 2007 found that only a third of public high schoolbiology teachers were able to present the subject of evolution in away that satisfied national science experts. And 13 percent ofteachers offered creationism as a "valid scientific alternative"to evolution.

Twelveyears later, teaching practices related to evolution are much better,according to arecently published report.The researchers found "substantial reductions" increationist instruction and a "substantial increase" in thetime that high school teachers devote to human evolution and theevolutionary process in general. The findings were published in thejournal Evolution:Education and Outreach.The researchers came from PennState Universityand the NationalCenter for Science Education.

Whythe uptake in more scientifically astute instruction? The researcherspointed to three changes:

Broad adoption of the Next Generation Science Standards or state standards that borrow heavily from NGSS;

Improvements in pre-service teacher education; and

Changing practices of in-service teachers through improved professional development.

Theproject analyzed data from the "Survey of American ScienceTeachers" which was done between February and May 2019. Whilethe survey included both high school and middle school samples, thisreport relied on high school responses, in particular.

Inboth surveys more than 95 percent of high school biology teachersreported covering evolution to some degree. But there was a 60percent increase in the average number of class hours devoted tohuman evolution in the 2019 survey, an increase from 4.1 hours to 7.7hours.

Also,there was "considerable movement" in how teachers respondedto a question asking them whether they "emphasize the broadconsensus that evolution is a fact, even as scientists disagree aboutthe specific mechanisms through which evolution occurred." Theshare of teachers who disagreed with that statement declined from 22percent to 13 percent, and the percentage who agreed grew from 74percent to 79 percent. Those who "strongly agreed" rosefrom 30 percent to 47 percent.

Theproportion of teachers who reported discussing creationism andintelligent design in classes dropped from 23 percent to 14 percent.And where it was discussed, the researchers pointed out, "someteachers may raise the topic of creationism in the context ofexplaining why it is not scientific." To understand responsesbetter, the survey included two additional questions:

"I emphasize that intelligent design is a valid, scientific alternative to Darwinian explanations for the origin of species"; and

"I emphasize that many reputable scientists view creationism or intelligent design as valid alternatives to Darwinian theory."

Thenumber of teachers disagreeing with the first statement rose from 32percent to 58 percent, a change "largely driven by a sharp dropin the number of teachers who declined to answer this question,"from 53 percent to 29 percent. And there was a big increase "inthe percentage of teachers strongly disagreeing with each statement."The researchers interpreted that to mean that "more teachers areconfident in their acceptance of evolution and rejection ofcreationism."

Continued here:

US Teachers Evolving on Science of Evolution - T.H.E. Journal

Minnesota Football: The evolution of the slot cornerback – The Daily Gopher

What is a slot cornerback?

First of all, it is important to establish that under defensive coordinator Joe Rossi the Gopher defense has operated out of a base 4-2-5 formation. That means four defensive linemen, two linebackers, and five defensive backs. Here is a typical look:

Fresno State is in a four wide receiver set, so the Gophers have Coney Durr and Terell Smith as their outside corners, with Chris Williamson in at slot corner on the wide side of the field and safety Jordan Howden providing help over the top. Antoine Winfield Jr. is playing center field as the free safety. Thomas Barber and Kamal Martin are your linebackers, with the more athletic Martin split out to cover the inside receiver on the short side of the hash. The four defensive linemen are Winston DeLattiboudere, Micah Dew-Treadway, Sam Renner, and Carter Coughlin.

Why the 4-2-5? The formation, which is also referred to as the nickel defense, was championed in the 21st century as the answer to the spread offense. TCU head coach Gary Patterson is perhaps the schemes most renowned innovator, having originally utilized it to counter power running teams before evolving it to defend the prolific up-tempo offenses of the Big 12.

I wont get too much into the weeds on the nuances of the 4-2-5 Google Gary Patterson, 4-2-5 for ample supplemental reading but the foundational tenet of the scheme is to flood the field with speed. Athleticism is emphasized over size, even at defensive end, where fleet-footed outside linebackers have been converted into undersized rush ends who can cause problems for slower offensive tackles. Its an aggressive style of defense, one in which the goal is to use mismatches up front to generate pressure, attack gaps, and spill the ball to the perimeter.

The proliferation of the 4-2-5 has seen the role of the nickelback evolve from backup third cornerback to one of the most versatile defenders in modern football. Today, slot corners need be able to blitz the quarterback as pass rushers, step up in the run game as linebackers, and hold their own in coverage as defensive backs. Thats a lot to ask of one player.

Chris Williamson, a transfer from Florida, made the slot corner position his home in his two seasons at Minnesota. He became such a critical part of the Gophers defense that I am more concerned about how Joe Rossi will replace his production than I am about filling the shoes of All-American safety Antoine Winfield Jr.

Seriously.

One of the challenges of playing slot corner is that the slot receiver position is no longer relegated to lesser pass catchers. Teams top targets in the passing game are lining up inside more than ever before. That puts a lot of pressure on slot corners, who are already in a precarious position due to their alignment. They dont have the benefit of using the sideline as leverage or squeezing receivers into the boundary. Slot corners have to play both an inside and outside release. With more area to cover, one false step could spell doom.

Which brings me to a fourth down play against Penn State. On 4th and Goal at the 5, the Nittany Lions lined up in trips formation with three wide receivers on the wide side of the field, and KJ Hamler was in the slot with tight end Pat Freiermuth. Freiermuth ran a slant to try and disrupt the defenders in coverage as Hamler ran a fade to the corner of the end zone. But Williamson reads the route, breaks on Hamlers hip, turns his head, and bats the ball out of bounds.

But as I mentioned previously, pass coverage is only one part of the position.

The slot cornerback also needs to be able to play close to the line of scrimmage, almost functioning as a third linebacker at times. Not every nickel corner who can hold their own in pass coverage is also a reliable tackler. You have to be physical and able to make tackles in space.

Williamson and Justus Harris were relied upon heavily against Georgia Southern last season, both operating out of the slot corner position but playing near the line of scrimmage to help stifle the Eagles option offense in run support. The pair helped limit Georgia Southern to 123 rushing yards (well below their season average of 253.2 yards per game).

Here, Williamson comes in from across the formation to drop the ball carrier for a minimal gain on third down after Thomas Barber whiffs on the tackle.

Last but not least, rushing the passer. On this second down play against Fresno State, Joe Rossi gets creative. DeLattiboudere takes the right tackle upfield and Thomas Barber blitzes, occupying both the right guard and the running back in pass protection. Williamson, sprinting in from his slot corner position, runs through an opening so big that he never even breaks stride en route to the sack. Coughlin is following close behind, ready to take a crack at the quarterback if Williamson cant finish the play, but he requires no such assistance.

Senior Justus Harris is the most experienced slot corner on the roster, but his game action has been limited mostly to special teams. Redshirt freshman Solomon Brown and incoming freshman Jalen Glaze are both expected to compete with Harris at slot corner, but the lack of a clear successor to Williamson is a concern. Williamson was an unsung hero of the defense last season, and replacing his production will be no small task.

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Minnesota Football: The evolution of the slot cornerback - The Daily Gopher

Rapid and robust evolution of collateral sensitivity in Pseudomonas aeruginosa antibiotic-resistant mutants – Science Advances

INTRODUCTION

Antibiotic effectiveness, currently compromised by the spread of antibiotic resistance (AR), requires not only innovation but also conservation, which may allow for improved use of current antibiotics (1). For this conservation, understanding of the trade-offs associated with AR acquisitionsuch as increased susceptibility to a second drug after use of the first, a phenomenon first described in the 1950s as collateral sensitivity (2)might be particularly relevant. Various studies have been undertaken trying to exploit the evolutionary constraint imposed by collateral sensitivity patterns (3, 4), such as combinatory therapy (5, 6) or alternating collaterally susceptible drug pairs (79).

Despite progress in study of the collateral sensitivity phenomenon, some questions remain to be answered. In particular, there is still only limited information on the evolutionary conservation of collateral sensitivity patterns, not only between different species (10, 11) but also within different members from the same species (1215). In the case of Pseudomonas aeruginosa, some studies have revealed that isolates of this pathogen obtained from patients with chronic infections and treated with distinct antibiotic classes present convergence in their collateral sensitivity phenotypes (9), while others have described major differences in the collateral sensitivity patterns associated with the acquisition of resistance to one antibiotic between replicates of the same strain of P. aeruginosa evolving in parallel (13). These discrepancies may lie in the degree of reproducibility of the evolutionary pathways leading to AR. In this respect, it is known that the type of resistance mutations present in a given genetic background may be restricted because of epistatic interactions (10, 1621) and that the cumulative acquisition of AR mutations in different loci reduces the variety of pathways, leading to AR (22, 23). Since contingency may be relevant not only for AR evolution but also for the acquired collateral sensitivity phenotype (24), knowing the degree of conservation of collateral sensitivity patterns associated with the use of a specific drug in different genetic backgrounds, particularly in the case of mutants already presenting a phenotype of AR, is of special interest.

In a previous study, we observed that P. aeruginosa PA14 populations experimentally evolved in the presence of ceftazidime displayed a robust collateral sensitivity to amikacin (25), as a consequence of selection of large chromosomal deletions upon 1 day of adaptive laboratory evolution (ALE) (25). The chromosomal deletions included hmgA, which encodes an enzyme whose lack of activity leads to the hyperproduction of the brown pigment pyomelanin (26); galU, whose inactivation reduces ceftazidime susceptibility (27); and mexXY, which encodes a multidrug resistance (MDR) efflux pump that contributes to P. aeruginosa intrinsic aminoglycosides resistance (28). Up to 13% of patients with cystic fibrosis (CF) are infected by P. aeruginosa pyomelanin-producing mutants (29) that, in agreement with the phenotype of the mutants selected after ALEs, are also hypersusceptible to aminoglycosides (30). Although the fact that pyomelanin increases resistance to oxidative stress and favors bacterial persistence in chronic lung infections (26) has been considered the most likely explanation for in vivo selection of those mutants, this genetic event has also been reported in different strains of P. aeruginosa subjected to ALE in the presence of other -lactams (3134). Therefore, it remains to be established whether these deletions are selected by the antibiotic treatment or merely represent an adaptation to the lung environment of patients with CF (35), as was previously proposed (34, 35). Even further, it remains to be answered whether these deletions are selected upon ceftazidime treatment in different genetic backgrounds of P. aeruginosa, in particular, in mutants resistant to other antibiotics; or on the contrary, whether the evolutionary robustness of this genetic event, and of its phenotypic effects, is limited. In this study, by constructing a set of resistant mutants previously identified in different ALE experiments of P. aeruginosa PA14 (16, 36) in the presence of antibiotics, and by submitting them, as well as the wild-type PA14 strain, to ALE in the presence of ceftazidime, we have determined the robustness of an early event of ceftazidime resistance evolution that is associated with collateral sensitivity to tobramycin. Further, by the recreation of heterogeneous pyomelanogenic populations belonging to each genetic background and the alternation of tobramycin with ceftazidime, we found that driving evolution toward hypersusceptibility to the first drug is generally feasible, at least in the genetic backgrounds analyzed. This finding supports the possibility of rationally designing treatments based on collateral sensitivity convergence in P. aeruginosa.

As mentioned above, the conservation of collateral sensitivity to a given drug within different genetic backgrounds of a species may be contingent on the degree of conservation of the evolutionary routes toward resistance to the first drug used for selection. We and others have reported the early selection of large chromosomal deletions that contain genes encoding the intrinsic aminoglycosides resistance efflux pump MexXY (28), when ALE experiments in the presence of different -lactams, including ceftazidime (31), piperacillin (32), or meropenem (33, 34), were performed. These data suggest that this genetic event could be one of the first evolutionary steps in the evolution of P. aeruginosa toward -lactam resistance. However, since these studies were limited to a single wild-type genetic background, it remained to be analyzed whether a similar evolutionary pattern could be followed by P. aeruginosa PA14 strains presenting different genetic backgrounds, in particular, different antibiotic-resistant mutants. That being so, collateral sensitivity to aminoglycosides, such as tobramycin, a drug that forms part of usual therapy regimens against P. aeruginosa (37), would also be conserved.

Our first objective was to analyze the evolutionary conservation of ceftazidime resistance evolution in different genetic backgrounds, consisting of mutants derived from different P. aeruginosa PA14 ALEs in the presence of antibiotics (see table S1). It has been recently suggested that AR mutations may associate with either robust or variable collateral sensitivity patterns in different genetic backgrounds, depending on whether they lead to target or regulatory alterations, respectively (10). Taking this hypothesis into account and resorting to previous different in-house ALE experiments (16, 36), we constructed a broad spectrum of strains containing single mutations that affect regulatory proteins (NfxB, ParR, or MexZ), nonregulatory proteins (NuoD or OrfN), or simultaneously containing both types of mutations. The mutant containing mutations in nfxB, phoQ, frr, and pmrB was dubbed MDR6, and the mutant containing mutations in fusA, orfN, pmrB, mexZ, gabP, ptsP, and nuoD was dubbed MDR12 (see table S1 for detailed information). The susceptibility of each mutant to different antibiotics, including those of interest in this studytobramycin and ceftazidimeis shown in Table 1.

MICs 2-fold of the MICs for the wild-type PA14 strain are highlighted in bold. TOB, tobramycin; TGC, tigecycline; CAZ, ceftazidime; CIP, ciprofloxacin; IPM, imipenem.

To determine whether chromosomal deletions containing mexXY would be early selected during P. aeruginosa evolution in presence of ceftazidime in the set of mutants mentioned above, as it was the case in the wild-type strain PA14 (25), four biological replicates of each single (nfxB177, parR87, mexZ43, orfN50, and nuoD184) and multiple mutants (MDR6 and MDR12), and the wild-type PA14 strain, were subjected to ALE in presence or absence of ceftazidime (a total of 64 populations) for 3 days. Upon 1 day of experimental evolution, almost every P. aeruginosa population challenged with antibiotic hyperproduced pyomelanin (27 of 32 populations; Fig. 1A). This result is consistent with the presence of deletions that include hmgA, as those described in our previous study, because pyomelanin accumulation is due to the lack of homogentisate 1,2-dioxygenase activity provided by HmgA (26). Since we had previously determined a cause-effect relationship between the presence of chromosomal deletions containing hmgA and mexXY and the hyperproduction of pyomelanin and hypersusceptibility to aminoglycosides, respectively (25), the susceptibility of each final population to tobramycin was analyzed. All the pyomelanogenic populations obtained after the short-term evolution in presence of ceftazidime were resistant to ceftazidime and hypersusceptible to tobramycin, when compared to the parental strain from which they evolved (Fig. 1B and table S2), even when the mutants were originally less susceptible to tobramycin than the wild-type P. aeruginosa PA14 strain. In particular, tobramycin minimal inhibitory concentration (MIC) was reduced by up to 4-fold in PA14, 2.6-fold in nfxB177, 3-fold in parR87, 7.9-fold in orfN50, 6-fold in mexZ43, 5.3-fold in MDR6, and 10.7-fold in MDR12. Consistent with the linkage between pyomelanin production and deletion of a chromosomal region containing mexXY, nonpyomelanogenic populations (parR87, replicate 1; and nuoD184, all replicates) were not tobramycin hypersusceptible (Fig. 1B and table S2). Further analysis of the results from the experimental evolution study has revealed that six of eight genetic backgrounds presented a significantly (P < 0.01 in all cases) reduced MIC to tobramycin, compared to their parental strains, after the ceftazidime short-term evolution. To further analyze whether chromosomal deletions containing mexXY could be associated with the phenotype of hypersusceptibility, every evolved population, as well as their original parental strain, was genotyped (fig. S1A). A 163-bp polymerase chain reaction (PCR) fragment corresponding to mexXY was detected in every parental strain, as well as in nonpyomelanogenic populations (parR87, replicate 1; and nuoD184, all replicates) and in a pyomelanogenic mixed population (PA14, replicate 2). Consistent with the observed increase in tobramycin susceptibility of most evolved populations (table S2), every pyomelanogenic tobramycin-hypersusceptible population lacked mexXY (fig. S1A). Overall, these results suggest that chromosomal deletions containing mexXY are consistently selected at first steps of ceftazidime resistance evolution in P. aeruginosa, at least in the genetic backgrounds analyzed. To further test whether this observation could be conditioned by the number of replicates used during the assay for each genetic background, 32 replicates of one of the mutants (mexZ43) were subjected to evolution under the same conditions used before, in presence or absence of ceftazidime. We observed that upon 1 day of experimental evolution, a high number of mexZ43 populations challenged with antibiotic hyperproduced pyomelanin (28 of 32 populations; Fig. 1D), just 4 of 32 populations did not become pyomelanogenic (Fig. 1D). Although we are aware that there is a space for unpredictability of ceftazidime resistance evolution in the mutants analyzed, the results here described suggest that alternative genetic evolutionary trajectories in ceftazidime resistance evolution may be limited, and that phenotypic convergence toward collateral sensitivity to tobramycin is robust in P. aeruginosa, even in the case of antibiotic-resistant mutants, as those here analyzed (table S1), after ceftazidime treatment (table S2). However, we are fully aware that all mutants described here derive from P. aeruginosa PA14, and the generalization of our results to other strains will require the analysis of the effect of short-term ceftazidime evolution on a broad and diverse set of clinical strains of P. aeruginosa.

(A) Scheme of the resultant phenotype after the evolution of PA14, single (nfxB177, parR87, mexZ43, orfN50, and nuoD184) and multiple (MDR6 and MDR12) mutants, in the presence of CAZ [left part of (A)] or in the absence of antibiotic [LB; right part of (A)] for 3 days (see Materials and Methods). Pyomelanin hyperproduction was observed in 27 of 32 populations evolved in the presence of CAZ (red-colored cells). (B) Diagram showing convergence toward hypersusceptibility to TOB in the different genetic backgrounds and replicates, analyzed after short-term evolution on CAZ. In all cases, acquisition of a pyomelanogenic phenotype is associated with collateral sensitivity to TOB, irrespective of the genetic background of the evolving strain. MIC values of TOB and CAZ are included in table S2. (C) Isolation of pyomelanogenic clones from each 27 pyomelanogenic population [left part of (A); red-colored cells] obtained in the presence of CAZ. As shown in the figure, the early steps of evolution in presence of CAZ of P. aeruginosa, which lead to collateral sensitivity to TOB and pyomelanin production, are conserved among the different antibiotic-resistant mutants analyzed. (D) Pyomelanogenic phenotype of mexZ43 mutant after 1-day evolution in the presence of CAZ or in the absence of antibiotic (LB). Pyomelanin hyperproduction was observed in 28 of 32 populations evolved on CAZ. Photo credits for (C) and (D): Ins Poveda, Centro Nacional de Biotecnologa. Permission for using these images is not required.

We have shown that ceftazidime selects, in the short term, pyomelanogenic mutants presenting collateral sensitivity to tobramycin in P. aeruginosa, at least in the set of resistant mutants analyzed here (table S1). Nevertheless, there is an extensive heterogeneity within populations of P. aeruginosa in the CF lungs (38), frequently including mutants already presenting a pyomelanogenic phenotype (29, 30), which is usually associated with a reduced susceptibility to ceftazidime. Since this heterogeneity might impair the chances of exploiting the observed tobramycin collateral sensitivity associated with the use of ceftazidime in these heterogeneous populations, we tested the possibility of alternating the antibiotics, first, by using tobramycin and then second, ceftazidime, for reducing the chances of pyomelanogenic heterogeneous populations to escape from the antibiotic challenge.

The strategy would consist of three stages: A first step on tobramycin may force extinction of the ceftazidime-resistant (tobramycin-hypersusceptible) part of the populations, a second step on ceftazidime may drive evolution toward tobramycin hypersusceptibility, and then the extinction of the tobramycin-hypersusceptible cells after switching back to tobramycin (Fig. 2) would be expected. Although this strategy would be also potentially applicable to populations not resistant to ceftazidime, being reduced to a first step on ceftazidime followed by a second one on tobramycin, we decided to analyze its effectiveness in a more complex situation of clinical relevance, as it is the case of heterogeneous pyomelanogenic populations. In particular, diverse populations derived from the set of mutants were analyzed in this work (see table S1). To that end, we isolated a pyomelanogenic clone from each of the 27 pyomelanogenic populations obtained after ceftazidime short-term evolution (Fig. 1A). To note here that although the original clones from which these populations were derived belonged to a diverse set of genetic backgrounds, consisting of antibiotic-resistant mutants that contain mutations in regulatory, nonregulatory, or both types of proteins (Table 1 and table S1), all the isolated clones that hyperproduced pyomelanin (Fig. 1C) were significantly (P < 0.001 in all cases) more susceptible to tobramycin than their respective parental strain (table S3), and lacked mexXY (fig. S1B). Then, we recreated a total of 27 heterogeneous pyomelanogenic populations by mixing each of the 27 pyomelanogenic clones with its respective parental strain in a 1:1 ratio. The heterogeneous populations were dubbed PA14 +1 to +4, nfxB177 +1 to +4, parR87 +2 to +4, mexZ43 +1 to +4, orfN50 +1 to +4, MDR6 +1 to +4, and MDR12 +1 to +4. These populations were first subjected to tobramycin short-term evolution for 3 days (see Materials and Methods), and the capacity of these populations to either evolve toward tobramycin resistance or to go extinct was analyzed (Fig. 3). Since pyomelanogenic clones are less susceptible to ceftazidime (i.e., >256 g/ml in all the parR87 clones; see b data in table S4) than the parental strain from which they evolved (1 g/ml in parR87; see a data in table S4), ceftazidime MIC values were used to verify the extinction of the pyomelanogenic part of each population. After 3 days of evolution in the presence of tobramycin, the ceftazidime MICs for every population (i.e., 1 g/ml in parR87 heterogeneous populations; see the First step (TOB) data in table S4) were close to the ceftazidime MIC for the parental strain [compare First Step (TOB) to the a and b MIC data in table S4]. These data support that the pyomelanogenic part of every population is extinct after the first step of sequential evolution. To further confirm the extinction of the pyomelanogenic clones, the phenotype (green/yellow versus brown color) of 20 clones from each of the 27 populations, a total of 540 clones, were isolated and grown in liquid medium (brown color is poorly appreciated in colonies) to detect any escape of ceftazidime-resistant cells from tobramycin treatment. As shown in Fig. 3B, none of the clones produced pyomelanin, confirming the extinction of the pyomelanogenic part of every population, a fact that was previously hinted by the ceftazidime MIC values of the resultant populations (see table S4). Besides that, each resultant population presented an increased tobramycin MIC, up to 48-fold, depending on the genetic background and replicate (table S4).

Evolution of a heterogeneous population containing a pyomelanogenic (CAZ resistant) subpopulation starts when TOB is added at time zero (t0). In the presence of TOB, there is an extinction of TOB-hypersusceptible pyomelanogenic mutants (red-colored cells) and TOB becomes ineffective (t1). Then, treatment is switched to CAZ, and TOB-resistant cells (contoured gray-colored cells) become TOB-hypersusceptible (t2). Treatment would be switched back to TOB, resulting in the elimination of TOB-hypersusceptible cells (t3). This strategy would also be potentially applicable to initial populations not resistant to CAZ (t1), being reduced to a first step on CAZ (leading to t2), followed by a second step on TOB (resulting in t3).

(A) Diagram showing the evolution of heterogeneous populations (dubbed +1, +2, +3, and +4) containing each parental strain: PA14, nfxB177, parR87, mexZ43, orfN50, MDR6, or MDR12 and four individual pyomelanogenic clones belonging to the same genetic background, during first step of sequential evolution in the presence of TOB (left) and second step in the presence of CAZ (right), for 6 days (see Materials and Methods). In the case of parR87, only three pyomelanogenic clones from independent CAZ-evolved populations (see Fig. 1, A and C) could be isolated. Hypersusceptibility to TOB (contoured and noncontoured red-colored cells) is observed in 23 of 27 populations (see table S4), and pyomelanin production (noncontoured red-colored cells) is observed in 17 of 27 populations. (B) Analysis of extinction of the pyomelanogenic part of the heterogeneous pyomelanogenic populations after a first step of sequential evolution in the presence of TOB [(A) section, left]. The phenotype (color) of 20 clones isolated from each heterogeneous population, after 3 days of TOB evolution, was observed in liquid medium and compared with the color (brown) of each pyomelanogenic parental strain (upper left corner of each plate). In agreement with data shown in table S4, which points to the extinction of pyomelanogenic populations by comparison of CAZ MIC value of each heterogeneous population with the ones of their parental strains and pyomelanogenic clones, the color of the 540 clones analyzed indicated that pyomelanogenic clones were extinct after first step of sequential evolution on TOB. Photo credits for (B): Fernando Sanz-Garca, Centro Nacional de Biotecnologa.

At this point, we specifically focused on the switch from tobramycin to ceftazidime, the second step of the sequential evolution (Fig. 2). Although we had observed conservation of tobramycin collateral sensitivity after evolution in presence of ceftazidime within the analyzed set of mutants of P. aeruginosa (Fig. 1 and table S2), a critical point would be to determine whether this genetic event would also be selected by ceftazidime in the tobramycin-resistant mutants obtained after the first step of evolution of the populations in the presence of tobramycin. Hence, we switched the selective pressure from tobramycin to ceftazidime (see Materials and Methods). As shown in Fig. 3, 17 of 27 populations hyperproduced pyomelanin. A second critical point emerged here: The degree of sensitization to tobramycin of highly resistant mutants to the said antibiotic was uncertain. To determine whether these populations presented an increased susceptibility to tobramycin, as it was observed in the wild-type PA14 background and in most of mutants analyzed in this work (Fig. 1 and table S2), the tobramycin MIC was determined in all the evolved populations. Twenty-three of 27 populations presented an important increase in their sensitivity to tobramycin after switching the selective pressure from tobramycin to ceftazidime, reducing the MIC by up to 128-fold in PA14, 48-fold in nfxB177, 21-fold in parR87, 96-fold in orfN50, 43-fold in mexZ43, 4-fold in MDR6, and 11-fold in MDR12 (Fig. 4 and table S4). This analysis revealed that five of seven heterogeneous pyomelanogenic populations presented a substantially reduced MIC to tobramycin after the second step of sequential evolution on ceftazidime (table S4). These results suggest that it could be possible to exploit the tobramycin collateral sensitivity associated with the use of ceftazidime by switching back selective pressure to tobramycin, although there may be some limitations depending on the genetic background. This was the case of the multiple resistant mutants MDR6 and MDR12, which did not present a relevant reduction in tobramycin MIC after the switch to ceftazidime.

Evolution of TOB MICs (g/ml) of heterogeneous pyomelanogenic populations after sequential evolution on TOB/CAZ (see Fig. 3). Each plot shows the TOB MIC values for a parental strain (PA14, parR87, orfN50, nfxB177, mexZ43, MDR6, or MDR12), indicated as t0 in the x axis, and for four heterogeneous pyomelanogenic populations (represented as black circles) after first evolution on TOB (indicated as TOB in the x axis), followed by second evolution on CAZ (indicated as CAZ in the x axis). Only three heterogeneous pyomelanogenic populations of parR87 were analyzed. TOB MICs decreased after switching from TOB to CAZ by up to 128-fold in PA14, 48-fold in nfxB177, 21-fold in parR87, 96-fold in orfN50, 43-fold in mexZ43, 4-fold in MDR6, and 11-fold in MDR12. MIC values are shown in table S4.

The fact that some populations were hypersusceptible to tobramycin, even without having suffered chromosomal deletions containing mexXY (6 of 27 populations; Fig. 3 and fig. S1C) or being mixed populations (4 of 27 populations; Fig. 3 and fig. S1C), indicates that reciprocal collateral sensitivity between ceftazidime and tobramycin may occur even in the absence of these deletions, a feature that remains to be explored in detail. Overall, our results indicate that this strategy could potentially be applicable from complex situations similar to the ones explored in the current work (heterogeneous pyomelanogenic ceftazidime-resistant populations) to other ones (populations not resistant to ceftazidime).

We have recently described that P. aeruginosa replicate populations subjected to ribosome-targeting antibiotics may present common changes in the susceptibility to other antibiotics, besides those used along selection (16, 36). However, important differences have been described in the collateral sensitivity phenotype among replicate populations of the same P. aeruginosa strain adapted to one antibiotic (13). We have recently reported that a loss-of-function mutant of P. aeruginosa PA14, differing from its parental strain in the activity of just one regulator, not directly linked to AR, presents different patterns of collateral sensitivity and cross-resistance phenotype when it acquires resistance to ribosome-targeting antibiotics (16). Since historical contingency may restrict the evolution of collateral sensitivity and cross-resistance phenotypic outcomes, we wondered whether the populations obtained after tobramycin and ceftazidime sequential evolution, besides presenting a convergent hypersusceptibility to tobramycin, may converge toward the phenotypes of cross-resistance or collateral sensitivity to antibiotics found in other structural families. To address this question, the MICs of a set of antibiotics were determined for the 27 populations. A general pattern of cross-resistance to aztreonam, imipenem, and chloramphenicol, as well as significant collateral sensitivity to fosfomycin, tobramycin, and tetracycline, was observed (P < 0.0001 in all cases) (Fig. 5 and table S5). Since the combination fosfomycin-tobramycin has been found to be synergistic against biofilms of CF P. aeruginosa strains (39) and against P. aeruginosa PAO1 in anaerobic environments (40), we propose that the switch back to tobramycin (Fig. 2) could also be replaced, if necessary, by the combination fosfomycin-tobramycin. To analyze the relative efficacy of the two possible options, we subjected the resultant populations obtained after tobramycin/ceftazidime sequential evolution to ALE in either tobramycin or the combination fosfomycin-tobramycin, applying twice the MIC of each parental strain. We observed that 8 of 27 populations were able to escape from the switch back to tobramycin (orfN50 +3, mexZ43 +2 and +3, MDR6 +1 and +3, and MDR12 +2 to +4). This result agrees with the fact that although most of the populations (23 of 27) presented an important reduction in the tobramycin MIC after sequential evolution on tobramycin and ceftazidime, by up to 128-fold in PA14, 48-fold in nfxB177, 21-fold in parR87, 96-fold in orfN50, 43-fold in mexZ43, 4-fold in MDR6, and 11-fold in MDR12 (Fig. 4), tobramycin MIC values were close to those of parental strains. None of the populations survived the combination fosfomycin-tobramycin, possibly due to the synergistic effect of these antibiotics (39). We therefore propose that use of the fosfomycin-tobramycin combination is more effective than switching back to tobramycin after that treatment.

Collateral sensitivity and cross-resistance to antibiotics from different structural families were analyzed in the 27 populations obtained after sequential evolution. A population is classified as susceptible or resistant when there was an MIC change with respect to the parental strain value. Triangles indicate antibiotics where a predominant change toward resistance (red) or susceptibility (green) with respect to the parental strain was observed. Thickness of the triangle depends on the percentage of conservation of said phenotype. MIC values (g/ml) are included in table S5. AMK, amikacin; ATM, aztreonam; FOF, fosfomycin; ERY, erythromycin; CHL, chloramphenicol; LEV, levofloxacin; TET, tetracycline.

Bacterial evolution is known to be one of the main causes of the current AR problem; but in-depth analysis of this evolution could also help to tackle this issue through the exploitation of the evolutionary trade-offs (as collateral sensitivity) associated with AR acquisition (2, 4). However, the feasibility of this approach requires the collateral sensitivity phenotypes of different resistant mutants to be robust and reproducible (41). In this study, we describe the robustness of collateral sensitivity to tobramycin associated with the short-term use of ceftazidime in an array of P. aeruginosa antibiotic-resistant mutants, chosen on the basis of their differences both in resistance phenotype and in the functions affected by the mutations that they harbor. We propose that the observed evolutionary trade-offs could be exploited for treating both clonal and heterogeneous pyomelanogenic infections. Patients with CF are usually infected by heterogeneous P. aeruginosa populations (38) that include pyomelanogenic mutants (29, 30), which frequently present resistance to -lactams, a feature that could compromise the use of ceftazidime. However, we have found that it is possible to drive the extinction of the pyomelanogenic mutants, first, by using tobramycin and then second, by driving the evolution of the remaining population toward tobramycin hypersusceptibility, using ceftazidime. A bottleneck for the application of this strategy would be the durability over time of tobramycin hypersusceptibility. However, it is important to highlight that the populations obtained after tobramycin/ceftazidime alternation present also collateral sensitivity to fosfomycin. We observed that it is possible to replace the switch back to tobramycin by a fosfomycin-tobramycin combination, which results in higher efficacy. These results point to the possibility of exploiting specific evolutionary trade-offs for tackling the problem of AR. However, we are aware that a detailed analysis determining the degree of conservation of the short-term ceftazidime resistance evolution in a broad and diverse set of clinical strains of P. aeruginosa would be required. Overall, our results and those of others, previously described (41) suggest that the analysis of phenotypic convergence and, in particular, the aspects that deal with the collateral sensitivity of P. aeruginosa AR mutants, is an important step forward in the rational design of therapeutic approaches capable of reducing the AR burden.

Bacteria were grown in LB at 37C, with shaking at 250 rpm in glass tubes. MICs of ceftazidime, aztreonam, imipenem, tobramycin, amikacin, tigecycline, tetracycline, ciprofloxacin, levofloxacin, chloramphenicol, fosfomycin, and erythromycin were determined at 37C in Mueller-Hinton (MH) agar, using E-test strips (MIC Test Strip, Liofilchem).

Four single mutants of P. aeruginosa (nfxB177, parR87, mexZ43, and nuoD184) were constructed by inserting each mutant allele (table S1) by homologous recombination into the wild-type PA14, while the orfN50 single mutant was previously obtained (16). Mutant alleles were obtained by PCR from previous in-house evolved populations (16, 36), leaving approximately 500 bp upstream and downstream the corresponding single-nucleotide polymorphism, using the oligonucleotides described in table S6. PCR products containing Hind III restriction sites were cloned into the Hind IIIdigested and dephosphorylated pEX18Ap vector (42) and then introduced by transformation into the conjugative Escherichia coli S17-1 strain. Subsequently, conjugation and mutant selection were performed, as described elsewhere (42), using carbenicillin (350 g/ml) and 10% sucrose. In all cases, the presence of the mutations was confirmed by Sanger sequencing. To obtain mutants containing multiple mutations, 10 independent resistant clones from end point evolved populations (16) on tobramycin or tigecycline were selected and mutations confirmed by Sanger sequencing. From them, two multiple mutants (table S1), tobramycin or tigecycline resistant, respectively, were chosen. The mutant allele of lasR was replaced by homologous recombination with that of the wild type in the two selected clones, using the above-described strategy and oligonucleotides encompassed in table S6.

Five single mutants, two multiple mutants, and PA14, four replicates of each, were subjected to short-term ALE in presence or absence of ceftazidime, resulting in a total of 64 independent bacterial populations (32 populations grown in presence of ceftazidime and 32 control populations grown without antibiotic). Cultures were grown at 37C and 250 rpm for 3 days. Every day, the cultures were diluted (1/125), adding 8 l of bacteria in 1 ml of fresh LB, either containing or lacking ceftazidime at the concentration that hinders the growth of each P. aeruginosa genetic background under these culture conditions (4 g/ml for PA14, mexZ43, and MDR12; 5 g/ml for nfxB177, orfN50, and MDR6; 3 g/ml for parR87; and 2 g/ml for nuoD184). During the 3 days, the concentration of ceftazidime was maintained. Every replicate population was preserved at 80C at the end of the experimental evolution. In addition, the MIC of the antibiotic used for selection in populations (ceftazidime) and of the one to which ceftazidime evolution gives rise to collateral sensitivity (tobramycin), was determined at 37C in MH agar using E-test strips.

Pyomelanogenic clones were isolated from every individual pyomelanogenic replicate population of each genetic background previously submitted to short-term evolution in the presence of ceftazidime, resulting in a total of 27 pyomelanogenic clones (see above). Overnight bacterial cultures from each pyomelanogenic clone and its parental strain were normalized to an optical density at 600 nm of 4.0 and then mixed in a 1:1 (pyomelanogenic clone:parental strain) ratio, obtaining 27 heterogeneous populations. Cultures were grown at 37C and 250 rpm for 6 days. Every day, during the first 3 days, the cultures were diluted (1/125) in fresh LB containing the tobramycin concentration that hinders the growth of each P. aeruginosa genetic background under these culture conditions (1 g/ml for PA14; 1.5 g/ml for nfxB177, parR87, mexZ43, and MDR6; 4 g/ml for orfN50; and 12 g/ml for MDR12). During the 3 days, the concentration of tobramycin was maintained. At the end of the first step of sequential experimental evolution, every replicate population was preserved at 80C, and the MIC of ceftazidime and tobramycin was determined at 37C in MH agar using E-test strips. The 27 populations were grown, from glycerol stocks, and every day, during the last 3 days, the cultures were diluted (1/125) in fresh LB containing ceftazidime, as described in the above-mentioned section of Material and Methods (see the Short-term ALE in presence of ceftazidime section). Every final population was preserved at 80C at the end of the second step of sequential experimental evolution, and the MIC of tobramycin was determined at 37C in MH agar using E-test strips.

The presence of chromosomal deletions including mexXY in the different genetic backgrounds and their respective evolved populations was analyzed by determining the absence of a 163-bp PCR fragment belonging to mexXY in 2% agarose gel. Primers used for mexXY genotyping are included in table S6.

Data were subjected to pre hoc and post hoc analyses to identify relevant differences, using either analysis of variance (ANOVA), Friedmans, or 2 tests and Dunnetts or Fishers exact test with Hochberg correction, as implemented in R.

Acknowledgments: We thank J. Ramn Valverde, from the Servicio de Computacin Cientfica del CNB, for the helpful discussion and the assistance with the manuscript, and I. Poveda, from the Servicio de Fotografa del CNB, for the photograph support. Funding: This work was supported by the Instituto de Salud Carlos III (grant number RD16/0016/0011), cofinanced by the European Development Regional Fund A Way to Achieve Europe, by grant S2017/BMD-3691 InGEMICS-CM, funded by Comunidad de Madrid (Spain) and European Structural and Investment Funds and by the Spanish Ministry of Economy and Competitivity (BIO2017-83128-R). F.S.-G. is the recipient of a FPU fellowship from MINECO. Author contributions: S.H.-A. participated in the design of the study and performed experimental work, and F.S.-G. performed experimental work. J.L.M. participated in the design of the study. All authors participated in writing the manuscript and approved the submitted version. Competing interests: All authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Rapid and robust evolution of collateral sensitivity in Pseudomonas aeruginosa antibiotic-resistant mutants - Science Advances

The evolution of Extinction Rebellion | Environment – The Guardian

In November 2017, Roger Hallam looked up from his cup of tea in a central London cafe and made a bold prediction. He had been walking me through the principles behind a new air pollution campaign he was organising, which involved small groups of activists blocking some of Londons busiest junctions, when he paused, mid-sentence. Of course, this is just small-scale stuff compared to what is coming, Hallam said. The scale of the ecological crisis is a different thing. It is going to change everything.

The air pollution campaign, Stop Killing Londoners, had yet to gain traction with politicians or the media, but Hallam didnt seem too concerned. He explained that it was partly being used to road-test civil disobedience tactics. Within a year or so we will have thousands of people on the streets, blocking large parts of central London for days on end, he said. Hundreds will be arrested and the government will be forced to sit down and tell the truth about the climate emergency.

It seemed fanciful at the time. Hallam, a charismatic, committed and sometimes divisive figure, was splitting his time between his organic farm in Wales and Kings College London, where he was researching a PhD about political activism. Earlier that year, he had staged a hunger strike, which led Kings College to divest from fossil fuels. Despite this recent victory, and an air of certainty that would become familiar to those who dealt with him in the months to come, there was still little to suggest Hallams predictions would come to pass almost word for word within 18 months. Nothing he had been involved in before had achieved the kind of impact that he was now prophesying. The movement that would carry out these protests, Extinction Rebellion (XR), didnt yet exist.

Extinction Rebellion, which would be founded a few months later, was the brainchild of a small group of activists, academics and friends, including Hallam, and Gail Bradbrook, a similarly unorthodox environmentalist. The daughter of a coal miner from South Elmsall in Yorkshire, Bradbrook studied for a PhD in molecular biophysics before working on various social justice campaigns, such as tax justice and the Occupy movement. But by 2016, disillusioned by how little political progress these groups had made, Bradbrook came to the conclusion that she was missing vital information about how to bring about meaningful change. There was something else that nagged at her, too an awareness of something deeper inside her that needed addressing. (In conversation, Bradbrook moves easily between detailed analysis of the latest climate science and organisational theory to discussions of spirituality. She often holds prayer sessions before meetings.)

In March 2016, Bradbrook travelled to Costa Rica in search of enlightenment. There, in a story that has become part of XR lore, she took a series of powerful psychedelic drugs. The most fucking terrifying thing I have done in my entire life, she told me later. But I was willing to do it because I needed help. Before the hallucinogenic trip began, she offered up a prayer to be shown the codes for social change. Those words would have a key role to play in the emergence of XR.

A few months after she returned to the UK, Bradbrook met Hallam for the first time. Their initial conversation lasted four hours Hallam complained that he had a headache by the end as they discussed the unfolding environmental crisis, the inability of the current system to even recognise the oncoming chaos, and theories about how to transform politics. As Hallam stood up and prepared to leave, he half-jokingly told Bradbrook that the ideas he had laid out about how to transform society were the codes she needed. The hairs on the back of my neck stood up, Bradbrook said later. It was exactly the phrase I had used during my prayer in Costa Rica.

Over the coming months, Bradbrook and Hallam continued their conversations, along with a loose grouping of like-minded people, who eventually formed Rising Up, a network of activists committed to peaceful civil disobedience. It wasnt until April 2018 that, in Bradbrooks home on a hillside overlooking the Cotswold town of Stroud, the idea of Extinction Rebellion was born. At the Stroud meeting, as it has become known, a core group of about 15 long-time campaigners, activists and academics decided that after years of small-scale political campaigns, about everything from fracking to migrant rights, they were, in Bradbrooks words, ready to go for the big one. As another of those present, Simon Bramwell, who was Bradbrooks partner at the time, recalled later: It was [then] that we decided to go for broke. We decided to throw all of our energy and intelligence at something that could change the planet.

But before such grand aims could be achieved, there were more mundane tasks. Agreeing on a name for the new group turned into a 25-step process that went on for weeks. It was an absolute mission, said Clare Farrell, another XR co-founder, who has a background in sustainable fashion and design. When Extinction Rebellion was first suggested, Farrell recalled that there was quite a bit of disquiet, because some people thought it was too harsh. But eventually it won.

According to Bradbrook, the group quickly realised it needed to appeal beyond what she called the leftist echo chamber. The campaign would aim not only to tap into progressive concerns about social justice and equality, but also traditionally conservative themes such as national security and protecting family. XRs goals were boiled down to three demands of the government: to tell the truth about the climate and ecological emergency; to halt biodiversity loss and commit to net zero emissions by 2025; and to follow the lead of a citizens assembly. A presentation titled Heading for Extinction and What to Do About It was developed, and quickly became known as the talk. It starkly outlined the scale of the crisis and the dire consequences of inaction, as well as XRs belief that if enough ordinary people took to the streets for peaceful civil disobedience, then radical change was possible.

Then came the hard work of building a movement from scratch in just a few months. Farrell remembers that those early meetings had a different atmosphere to other campaigns she had been involved in: It felt to me straight away like a group of people who were serious, who were very interested in how the system works and how to change it. She recalled the excitement of working with experts in so many different fields, from design to science, philosophy and politics. It was the breadth of the collaboration that was really fundamental.

Hallam told me at the time that they did not want it to simply be an online phenomenon, which he feared could flare up and then disappear again just as quickly. Instead, XR needed people to go out into their own communities, explain, recruit and then rebel. From the summer of 2018 onwards, volunteers began touring the country, giving the talk to people gathered in libraries and meeting halls, cafes and universities, pubs and churches. These meetings were sometimes tense affairs, as the scale of the climate crisis was laid out. But there was also a sense of relief among many of those present that their fears about the crisis were being acknowledged, and that they were being told there was something they could do.

On 31 October 2018, XR formally launched its campaign with a Declaration of Rebellion outside the Houses of Parliament. It had been billed as a small, symbolic act that would probably attract a couple of hundred people. In a taste of what was to come, more than 1,000 turned up and took a spontaneous decision to occupy the road outside parliament. The groups first big test came the following month, when it held a day-long demonstration aiming to block five bridges across the Thames in central London. On a beautiful winters day, thousands turned out, blocking the bridges and bringing chaos to central London in the biggest act of peaceful civil disobedience seen in London for decades.

Five months later, in April 2019, came the protest that the group had been working towards since its foundation. Thousands of people occupied key sites across London for almost two weeks. More than 1,000 were arrested for what were peaceful, respectful, sometimes joyful, protests. The arrests were a key part of XRs strategy, which drew particular inspiration from the civil rights movements in the US and Gandhis independence struggle in India. By encouraging as many protesters as possible to get themselves arrested, XRs plan devised chiefly by Hallam was to overwhelm the court system, with the aim of winning support and forcing change.

The protests turned XR into a movement of global significance, with scores of XR groups springing up in cities around the world, as well as in towns and cities across the UK. By the end, XRs representatives were sitting down for talks with senior politicians and ministers in the UK. Supporters and funders many of whom had been sceptical before April showered praise and money on the new movement, and in the weeks that followed, the UK parliament and scores of councils around the country declared a climate emergency. XR had changed the conversation around the crisis. Now it had a big question to answer: what next?

Within XR there was elation about the success of Aprils rebellion, as well as exhaustion and uncertainty about the future. A lot of these people had been involved in lots of would-be uprisings that they had hoped would take off but hadnt, so they were wary of pinning too much hope on this, said Daze Aghaji, a 20-year-old student and an early member of XR Youth, the influential youth wing of the movement. And then, when it did all come together, it was a bit like: Oh, OK what do we do now?

Hundreds of new people had come forward to join the movement in the weeks after the April protests, many of them giving up their jobs to dedicate themselves to XR full-time. This influx boosted XRs organisational capacity, but also brought new ideas about what the group should be, and competing theories about how to achieve the change needed to tackle the climate crisis.

Among the key figures to emerge during the April rebellion was Farhana Yamin. Her experience as a former UN lawyer who had helped draft the Paris agreement and worked on many of the key climate treaties of the past three decades enhanced XRs credibility, and she became one of the groups most convincing public advocates. Over lunch at a north London cafe a few months later, she told me she had joined XR after becoming disillusioned with her world of diplomacy, thinktanks and policymakers. I had been working with people who were not telling the truth about where we are, and are in a state of euphoric, egocentric denial, she told me. When she was asked to join XR, she agreed immediately. I saw [coverage of] the October rebellion, when people laid down and got arrested and Greta was there, and I thought: yes, that is what we need, that is what I want to do. It looked beautiful.

Amid all the praise for XRs achievements up to that point, there had also been some significant criticism. From the left, some argued that XRs beyond politics framing fatally overlooked the role that neoliberal capitalism, driven by the right, played in the ecological crisis exploiting people and natural resources, particularly in the global south, for the benefit of a wealthy minority. There was also growing criticism from black and ethnic minority groups, who said XRs tactic of encouraging mass arrests ignored the reality of police racism, and effectively made the protests the preserve of privileged white people.

Meanwhile, from the right, critics branded those involved in Extinction Rebellion variously as middle-class layabouts or drug-addled hippies, dangerous killjoys or extremist anarchists. During the April 2019 protests, Daily Mail headlines described the group as a radical far-Left eco-rabble and detailed how the Extinction Rebellion eco-mob plotted chaos in London from vegetarian caf in leafy market town. (XRs critics have left no cliche unmolested, wrote James Butler in the London Review of Books.)

After April, new recruits also had to be fitted into XRs decentralised structure, which includes an organising hub of circles, each with around a dozen or more individuals who focus on particular themes, from actions to finance, legal support to regenerative culture. On top of this, there are around 485 XR groups spread across more than 70 countries, with about 130 in the UK. There are also scores of affiliated groups based around shared identities, such as XR doctors, XR farmers or XR Muslims. People do not formally join XR, and there is no central membership list. Local groups can plan and carry out their own actions as long as they follow XRs 10 core principles and values, including a commitment to non-violence and focusing on systemic problems rather than blaming and shaming individuals.

Although XRs structure aims, as its website says, to build a participatory, decentralised and inclusive movement, some complain that it allows those with the loudest voices often white, middle-class men to dominate. Others complain of endless meetings, labyrinthine decision-making processes, and the sprawling network of WhatsApp groups the organisation has spawned.

According to Ronan McNern, a veteran of the Occupy movement and a key figure in XRs communications operations, the months after the April rebellion were dominated by internal wrangling. On one side were Hallam and his backers, who were pushing for an escalation in provocative direct action to keep the momentum going. They believed that a relatively small group of people, prepared to keep escalating their disruptive, peaceful, direct action could bring about systemic change quickly especially if the elite in the country are in terminal decline, as Hallam regularly insisted. On the other side were people who argued the good will and moral high ground achieved in April should be used to build a broader movement, within the UK and internationally.

An increasingly important voice in those discussions was XR Youth, a semi-autonomous group that had been created at the start of 2019. I felt pretty early on that as a young person I didnt really fit into main XR, said Aghaji. There was so much love of young people, but not in the right way. I would go to some things and everyone would be like, Do social media! Kids love social media! I was like, this is so sweet, but it is not where we need to be. Another founding member of XR Youth, Nils Agger, 26, who was also one of XRs original co-founders, agreed. I had been feeling for a while that there was something missing, there were just not that many people my own age.

From the start, XR Youth wanted to approach the climate crisis from a more international perspective, to highlight the role of activists in the global south, and to change the perception that this was a struggle for the future, rather than for the present. The message, said Aghaji, was save ourselves rather than save our grandchildren.

As the summer went on and internal disputes about XRs future grew more intense, the conflict came to a head over a proposed action to shut down Heathrow airport. Those in favour, including Hallam, wanted to fly drones within the Heathrow exclusion zone in order to bring the airport to a standstill for days. For others in XR, this represented a counterproductive step-change in the level of civil disobedience. They warned that there could be serious safety concerns, and a real risk that the public goodwill built up in April would be lost.

Towards the end of July, after a series of gruelling discussions, events took an unexpected turn. During a key strategy meeting in Stroud attended by Hallam, Bradbrook and other leading figures, there was a sudden commotion at the door. Aghaji, Agger and half a dozen members of XR youth had turned up, unannounced. Bearing cinnamon rolls with We Love You written in icing on top, they occupied the meeting and read out their three demands, one of which was that the Heathrow plans should not go ahead.

At first they were like: What are you doing coming in here demanding things? recalled Aghaji. But we were like: This is literally what you have taught us to do. Agger said it was a strange feeling, as one of XRs founders, to be occupying an XR meeting: It was us trying to make some kind of intervention in the way XR was working. Heathrow was just the tip of the iceberg. Another member of XR Youth made an emotional speech outlining their concerns. It was very emotionally charged, and very teary, Aghaji said. But, she added, it was a turning point.

A few days later, XR abandoned plans for the Heathrow protest and Bradbrook released a statement on behalf of XR, apologising for failing to address adult privilege within the group, and promising to heal the division and hurts between us. In early September, Hallam and a few others went on to attempt to close down Heathrow anyway, under the banner of a new organisation, Heathrow Pause. The protest, which had already drained so much of XRs energy, fell flat. No planes were stopped or delayed. Several participants were arrested, including Hallam who, after breaching bail conditions by returning to the airport after his initial detention, was subsequently remanded in custody.

In the weeks following the Heathrow protests, hundreds of people who had been arrested during the April rebellion began to appear before the courts. Zo Blackler, a journalist turned activist who oversaw the courts process for XR, said it was a reminder of what the movement was really about: We were presented in the media throughout April as being a young persons movement, or a crusties movement, or a white middle-class movement, or whatever it was that that particular newspaper hated about us. But to her, the hearings showed what those attacks had failed to acknowledge. It was an extraordinary experience to be there having that many people come together and read out their statements about why they had done what they had done. It was very moving. People were crying, and it felt very much as if the judges were listening and responding to what they were hearing. (Earlier this year, one judge said: This is going to be my last Extinction Rebellion trial for a little while. I think they only allow us to do so many of these before our sympathies start to overwhelm us.)

As XR headed towards its October Rebellion labelled internally as the difficult second album the euphoria of April had dissipated, but despite the splits and disputes, the movement had continued to grow, boasting hundreds of groups around the world. Less than 12 months after XRs launch, many were confident that the October rebellion would repeat, or even outdo, its previous success.

One crucial reason XR had risen so far so fast was timing. In the decade before it was founded, the climate movement in the UK had been relatively quiet. Before 2008, a vibrant activist network from Climate Camp, which saw protesters come together to carry out civil disobedience against major carbon emitters, to campaigns against the third runway at Heathrow and Kingsnorth power station had forced the climate crisis up the agenda. And these social movements were at least partially responsible for progress at a political level. In 2008, the Labour government brought in the Climate Change Act, the worlds first long-term, legally binding framework for radically reducing emissions, which committed the UK to an 80% emission reduction by 2050. Among many activists, there was at least some hope that the political class was beginning to grasp the enormity of the challenge ahead.

But when the financial crisis hit in 2008, the focus of politics, and protest, changed, as opposition to austerity became the most urgent concern for campaigning groups from Occupy to UK Uncut, the 2011 student protests to the Peoples Assembly. Paolo Gerbaudo, an academic at Kings College London who studies social movements and had been involved in environmental protests at the Copenhagen climate summit in 2009, said that before the financial crash, the climate emergency felt like the challenge of our time, but afterwards, it had largely slipped off the social and political agenda.

The unfolding ecological crisis, however, had not been put on hold. During the 2010s, evidence of climate breakdown rising temperatures, melting ice, failing harvests continued to mount. As the scientific warnings grew ever more dire, there was a deepening feeling among those who were paying attention that traditional environmental campaigning was failing, and that politicians were not delivering with potentially catastrophic consequences. It was into this context that XR emerged.

In the Autumn of 2018, just as XR launched, UN scientists at the Intergovernmental Panel on Climate Change published an unusually stark report, which warned world leaders that we had only 12 years to make radical changes and avoid the most devastating effects of the climate crisis. According to Blackler, the new movement managed to tap into this feeling of frustration and fear by acknowledging the scale of the crisis, and persuading people that collectively they had the power to change things. We gave people something they could come along to and plug into really easily, she said. XRs message was simple: civil disobedience could actually get results. People suddenly understood that although a few million on a march would achieve nothing, if you could get a comparatively small number to do civil disobedience, you can effect change much, much faster.

As XRs October 2019 rebellion approached, the scientific warnings were becoming, if anything, more dire. The school strike movement, led by Greta Thunberg, had mobilised hundreds of thousands of young people around the world, and public figures such as David Attenborough and Pope Francis were lining up to sound the alarm on the climate and ecological emergency. Everything seemed primed for a repeat of Aprils success.

In reality, it proved impossible to recreate the surprise and novelty that defined the earlier protests. Although XR held more sites in October and said it had more people arrested 1,837, compared with 1,138 in April the protests failed to catch the publics imagination in the same way. Actions that would have been headline news just six months earlier such as hundreds of breastfeeding mothers closing down Google HQ were now seen as par for the course by the media. Other factors also counted against XR. The weather was colder, and the days shorter. Police tactics were harsher and the UK was in the midst of Brexit convulsions.

XR was also criticised for tactical missteps. Early in the morning of 17 October, a number of protesters climbed on top of a tube train at Canning Town station in order to disrupt rush-hour services. Commuters reacted with anger, and scuffles broke out, with one protester being dragged from the roof of the train. The incident only lasted a few minutes, but the footage, which was widely shared, was damaging for XR, and highlighted some of the challenges facing the movement. How do you control what actions go ahead in a decentralised structure? Did the decision to carry out the protest highlight the lack of class and racial diversity within XR? Those who had decided to go ahead with the action did not seem to realise that by targeting the tube at that time of day, the people affected would not be bankers or financiers, but working-class Londoners, many on zero-hours contracts. Many observers also expressed bewilderment at the fact that climate protesters had chosen to target public transport at all.

The UK general election, which took place a couple of months later, was another flashpoint within XR. The Labour party offered a raft of policies to rapidly decarbonise the economy and invest in sustainable, well-paid, unionised jobs: its so-called green industrial revolution. For many people concerned about the climate crisis, this was a cause worth rallying behind. But during the election campaign, XR to the dismay of both Labour party activists and some inside the movement did not mobilise behind Labours climate offer, preferring instead to target all three main parties with hunger strikes and people dressed in bee costumes under the slogan Bee-yond politics. One irate XR figure called me to express her dismay at the group targeting Labour in the run-up to the election. There are some of us who have been in meetings all day really trying to stop this, she said. It is crazy, depressing, but we lost. It is going ahead.

The clash came down to two competing ideas about XRs ultimate purpose. For some, it was a vehicle to transform the political landscape, making it possible for existing institutions to put forward radical environmental policies. For others, the existing structures were incapable of overseeing the transition needed, and had to be overhauled and replaced. Reflecting on these tensions earlier in the year, one insider told me that XR had reached a point where the founders needed to take a step back: It is the classic startup or founder syndrome, where an organisation reaches a point where the founders need to let go and let something else emerge.

At the start of 2020, following Labours general election defeat and the relative letdown of its most recent rebellion, XR found itself at a crossroads. There was concern about the direction of travel, about how well we have managed to decentralise, Bradbrook told me. People [were] getting cross with each other and finger-pointing.

In February, XR released a new strategy document that appeared to move away from occupying and holding sites for days on end, instead emphasising targeted civil disobedience in cities around the country. Plans were announced for a rolling rebellion that would take place in London in May, targeting the underlying causes of the climate and ecological emergency government, media and finance.

Just a few weeks later, as the coronavirus pandemic began sweeping across the UK, the prospect of mass demonstrations receded and XRs plans had to be put on hold. The groups finances had been in a parlous state since October, and they had been hoping for an influx of donations during the May demonstrations. When they were cancelled, XR was forced to scale back its headquarters in London and stop all living allowance payments that had previously supported volunteers in need.

The crisis also had a profound impact on the movement in other ways, according to Blackler. There was a certain point when I remember thinking, Everyone in the country is thinking about their own mortality all the time, and it was such a strange moment, she said. But that is what we need people to be doing to be thinking about these big, existential issues and the mortality of our world.

For many environmentalists, the political response to the devastating pandemic had redrawn the boundaries of the possible. Things that they had repeatedly been told were naive or impossible such as shutting down swathes of the global economy overnight, and trillion-dollar investment packages were suddenly happening. Last year, when XR unveiled its demand for zero carbon by 2025, it was widely criticised as unrealistic. Now, such demands seemed less outlandish. The Overton window has been smashed wide open, Bradbrook told me.

Over the summer, this sense of political possibility grew, as Black Lives Matter protests exploded around the world and millions of people took to the streets to demand fundamental changes to policing and the end of structural racism. According to Blackler, the crises of 2020 have underscored the fact that climate change, structural inequality and racism all have the same root, and that is our global financial system. The protests also refocused attention on the existing criticism of XR from black and ethnic minority groups. On 1 July, XR put out a statement apologising for its previous mistakes: We recognise now that our tactic of arrest has made it easier for people of privilege to participate and that our behaviours and attitudes fed into the system of white supremacy. Were sorry this recognition comes so late.

The BLM protests had created space for XR to have really hard but crucial conversations, said Aghaji. It is a time of maturing. XR fucks up so often because we became way too big too quickly, and none of us foresaw that happening. Now, especially with Covid-19, we have had time to look at ourselves.

In July, XR announced plans for its next rebellion, which will begin on 1 September, when activists plan to peacefully disrupt parliament until the government agrees to debate the groups three demands. In its statement, XR identified an intersection of global crises including climate breakdown, Covid-19, racial injustice and economic inequality as symptoms of a toxic economic system propped up by corrupt politicians that is driving us to extinction. Aghaji saw the statement as further proof that XR was learning to play team sports. She said there were ongoing conversations between XR and multiple movements, and was optimistic about what those new relationships would create during Septembers rebellion.

A few weeks later, in a sign that perhaps a more consensual approach was gaining the upper hand in XR, the group announced that Hallam whom Bradbrook had previously described as XRs biggest asset and worst liability no longer had a formal role with the group. In a statement posted to Facebook on 28 July, Hallam stated that he would be devoting himself to a new direct action organisation/anti-political party, Beyond Politics. I believe immediate high level direct action is a right and duty of all citizens to bring down this genocidal government and those liberal institutions which passively stand by as the greatest crime in human history is taking place, he wrote. Earlier that month, Beyond Politics had targeted the headquarters of several NGOs including Greenpeace and Amnesty, pouring paint over walls and floors and handing over letters demanding they write to their members, urging them to rise up against the government. Meanwhile, XR groups have continued to stage smaller protests, including opposition to HS2 and a demonstration at the British Grand Prix on 2 August during which four protesters were arrested.

Speaking at the beginning of the year, back at her home in Stroud where XR was launched, Bradbrook was reluctant to speculate about the future. There is just arrogance in even having an opinion, she said. But after a pause, she began to imagine a couple of scenarios: one dystopian, one utopian. In the first, humanity destroys itself, and perhaps the universe learns something from that. In the second, a truly global citizens assembly is established, humanity reunites, and we use the sort of energy that has previously been used in a war to go into a rapid healing situation. It is all possible.

She paused again, before adding: I cant think of anything else I would rather do with my life. It is such an honour to try. What else can we all do?

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The evolution of Extinction Rebellion | Environment - The Guardian

The Evolution Of Shea Theodore Is Complete – SinBin.vegas

Alex Ovechkins office is in the circle on the power play. Patrice Bergerons is at the faceoff dot. Tom Wilsons is in the penalty box. Now Shea Theodore officially staked claim to his new office after an incredible display of passing during the round-robin.

In the 3rd period of last nights round-robin game against the Avalanche, Theodore found himself in a familiar place with the puck. He surveyed the ice, picked out Marchessault, and fired a 100+ foot pass, tape-to-tape to #81 which set up the go-ahead penalty shot.

It was kind of a broken play because Nate was coming out of the box. He was in the zone and he decided to change. Shea had perfect position and it was an unreal pass. -Jonathan Marchessault

Youll have to use your imagination to fill in just how incredible this pass is, but here it is.

That was just one of Theodores many brilliant passes from that very spot. Here are two more from the same game. (There are a few others from the rest of the round-robin, but three gifs in the same article is already a little overwhelming.)

At this point, thats pretty much what we expect from Shea. -Marchessault

But Theodores brilliance throughout the entire round-robin goes well beyond just stretch passes from his newly minted office. Posting four points on two goals and two assists plus an assist on the penalty shot goal, he was Vegas most dangerous offensive weapon behind the $9.5 million man, Mark Stone. Shea averaged 24 minutes a game playing against three of the best lines in the league, he recorded 11 shots on goal during the three-game stretch and was on the ice for seven Vegas goals, tied with William Karlsson for the most of any Golden Knight.

He has the ability to raise his level depending on the moment and how important the game is and I thought you saw that tonight. -Pete DeBoer

Theodores growth as a player with the Golden Knights has been tremendous since he was first acquired at the Expansion Draft. After coming from Anaheim where he competed in 20 playoff games as a rookie, Theodore didnt even make the Golden Knights roster out of the initial training camp. (Theres a strong argument to be made that this was expansion team roster management, but it happened nonetheless.)

He put up 29 points in his first season in Vegas while playing just over 20 minutes a night in a slightly sheltered role. In the playoffs, he was able to tally 10 points in 20 games but had a tough series against Washington which left a sour taste heading into year two. Prior to that season, he held out of camp looking for a long-term deal, which he eventually got, but is starting to look like an incredible bargain for the Golden Knights.

The evolution of his game continued earning a bit more ice time and mustering up 37 points in 79 games in 2018-19. Then in the playoff series against the Sharks, he posted seven assists and eight points and laid the groundwork for what weve seen this year. 46 points total, 18 in 22 games under DeBoer, and an increased defensive role has seen Theodore unseat Nate Schmidt as the Golden Knights clear #1 defenseman.

Tonight, he was elite. I think this guy is going to be in the Norris conversation for years to come here. -DeBoer

Shea was good the first year with us but his game where its at right now, when you talk about top 10 defensemen in the league he has to be up there. Hes improved so much since the beginning of the Golden Knights and his game this year was unbelievable. Hes definitely a big part of our offense. -Marchessault

Theodore has become a household name to any and all Golden Knights fans, but the hockey world as a whole still hasnt quite caught on.

Thats about to change though as the Golden Knights prepare for what they hope to be a deep playoff run. If they go as far as everyone in Vegas hopes, not only is he probably going to become a star in the eyes of the many more hockey fans, but hes got a real shot finding his name inscribed on the Conn Smythe trophy along the way.

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The Evolution Of Shea Theodore Is Complete - SinBin.vegas