Daily Archives: April 3, 2020

Changes are coming at the Red Lake Mine Complex with a new boss in charge.

Australias Evolution Mining calls the northwestern Ontario operation an undercapitalized asset and intends to spend a significant amount of money on exploration to find more high-grade gold.

The Sydney-based gold miner finalized its acquisition of the complex with Newmont on March 31.

Evolution announced in late November it was acquiring the Red Lake Gold Complexin a US$475 million.

The deal is structured to enable Newmont to receive $375 million cash and a $100-million contingent payment where Evolution will pay Newmont $20 million for each one million ounces of new gold resources, staggered over a 15-year period.

The Red Lake operation has a 13-year mine life and, according to Evolution, there is outstanding exploration potential to grow the resource base in a geological environment that they are quite familiar with.

Their strategy is recapitalize the asset to reduce operational costs and spent money on development and exploration over the next three years.

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Part of the transformation program has already started with changes on the personnel side.

The mine general manager has been replaced and the search is on for a successor. The site leadership team has been reduced from 12 to 7 people.

Evolution expects to announce more changes shortly with regards to the broader workforce.

Beginning in February, Evolution began a complete overhaul of the approach toward exploration.

To build on Red Lakes history of high-grade discoveries, Evolution is consolidating all their inherited geological data for their 460-square-kilometre property.

The goal is amalgamate the 130 individual block models into a more simplified model using Evolutions methodology. The geology and exploration teams are being combined under one manager.

This will set things up for 2021 when plans will be in place to rapidly scale up drilling.

Next years exploration drilling budget is estimated to be $20 million to $25 million (Australian dollars).

Up to eight underground drill rigs will be utilized with a stated objective of finding high-grade gold across their entire land holdings.

Currently, there are four rigs operating underground doing definition and grade control drilling. Results should be out in the March 2020 quarterly report.

Evolution also expects to accelerate mine development to more than 1,000 metres per month by next December, up from an average of 668 metres from last December.

The company said their executive team has spent considerable time in Red Lake to start planning their turnaround strategy.

Among the key takeaways from their tour was a high level of confidence that there was more gold to be discovered, a belief that there are places to cut costs, and very positive engagement with workers who know that change is necessary for the operations long-term future.

In a statement, Evolutions executive chair Jake Klein said in starting their search to acquire a Canadian operation in 2017, Red Lake was identified as having the most upside.

The driver for our interest was both the outstanding potential for the discovery of new, high grade mineralization and clear turnaround opportunity to restore it to being a safe, efficient, long life, low cost operation."

The company reports there have not been any positive tests of COVID-19 among its employees or contractors on site.

All fly-in/fly-out traffic has ceased but only 10 per cent of the Red Lake workforce has unable to work due to travel restrictions. That doesnt seem to have impacted production or mine development work, Evolution said.

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Evolution Mining puts its Red Lake turnaround strategy in motion - Northern Ontario Business

As molecular biologist Douglas Axe recalls, the Greek philosopher Gorgias (born about 483 BC) spent a lifetime pondering the nature of existence. At last he arrived at a firm conclusion: Nothing exists. In a presentation at the 2020 Dallas Conference on Science & Faith, Dr. Axe used Gorgias to illustrate his point that expertise does not necessarily drive you in the right direction. Sometimes it does the exact opposite. How could that be? Watch now and find out:

The controversy about Darwinian evolution is often framed as a matter of credentials. We must listen to the experts! Please precious experts, tell us what to think!

When Dr. Axe was planning his book, Undeniable: How Biology Confirms Our Intuition That Life Is Designed, he considered doing as other scientists have done: distill a lot of technical literature down for a lay audience. But he ultimately decided that that was to play into the hands of those atheists and materialists he was arguing against. They would simply tell his lay readers that the readers were in no position to judge even an ultimate question like this the origins of life and must instead docilely confirm the majority or consensus view of people holding PhDs in the correct fields. As Axe says here, I firmly believe you dont need a PhD to decide whether we are cosmic accidents or not.

Axe tells some of his own personal story, which I did not know. As a high school student he dissected frogs in biology class and found that uninspiring. It wasnt until college at U.C. Berkley and grad school at Caltech that he came to appreciate the wonders of life at the molecular level. He realized, This is engineering, remarkable engineering, far beyond anything humans can do.

But he explains why, even without his background as a professional scientist, we all already know what we need to know to decide whether life reflects intelligent purpose. This is an affirming and liberating message.

Looking for more great content in contrast to all the negativity everywhere else in the media and online? We have been releasing videos from Discovery Institutes January event in Dallas. Come back next Wednesday for Stephen Meyer on The Return of the God Hypothesis.

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Evolution and the Experts A Liberating Message from Molecular Biologist Doug Axe - Discovery Institute

(Inside Science) Imagine putting your hand in a pile of poop. It stinks and squishes. What do you do next?

Most likely, you'll scrub that hand with plenty of soap and you don't need public health officials or a germ theory of disease to tell you that's the right thing to do. But when you touch the handrail on an escalator, it's much harder to remember that you could be picking up coronavirus germs.

Humans have instincts that have evolved over millions of years to steer them away from infectious diseases. In some ways, these psychological adaptations collectively dubbed "the behavioral immune system" are helping us fight the COVID-19 pandemic. In other ways, they're failing us. And some experts warn that if we're not careful, our pandemic-heightened instincts could turn us into more bigoted, less compassionate people.

For most of human history, infectious diseases probably killed more people than anything else, said Joshua Ackerman, a social psychologist at the University of Michigan in Ann Arbor. The need to defeat viruses, bacteria and other parasites has shaped well-known elements of the immune system such as antibodies and white blood cells.

But the traditional immune system can only respond once a parasite is inside our bodies. By that time, the invader may already have caused damage, and to destroy it, the body must fight a messy and expensive war.

When possible, it's better to avoid catching a disease in the first place. So evolution has crafted a parallel immune system in our minds, and at its core is disgust. That "ew" feeling is part of what motivated our ancestors to avoid likely sources of infection such as feces, vomit and rotting food.

"We don't even need to visually detect these things. They're some of the most aversive smells that we can experience," said Joshua Tybur, an evolutionary psychologist at Vrije University Amsterdam.

While it's hard to know whether other species experience disgust the way we do, it seems clear that our behavioral immune system has origins older than humanity. Jane Goodall observed chimpanzees shunning other chimps that had polio. Bonobos, sheep, horses and kangaroos all avoid food that has feces on it. Caribbean spiny lobsters are normally highly social, but they avoid sharing dens with other lobsters that are sick.

In some ways, a person with no sense of disgust might face similar handicaps to someone who can't feel pain, said Tybur. There are conditions that make people unable to feel pain, and they often lead to serious health consequences as people accumulate injuries and infections.

"We often take for granted how kind of naturally and intuitively we move ourselves away from reliable pathogen risks even without thinking, 'Oh, there might be a pathogen in there,'" said Tybur.

Now, that ancient psychological system is confronting a modern threat: a pandemic that travels on airplanes and sweeps through cities that are home to millions. Governments are encouraging or mandating that people stay home, where there's less possibility of encountering the virus. When people do go out, they're supposed to avoid touching their faces, wash their hands frequently, and keep their distance from others. But people are struggling to comply.

Part of the problem may be that for most of human history, people lived in small hunter-gatherer bands of a few dozen people. Our ancestors would never have encountered things that thousands of people touched in the same day, said Tybur. We haven't yet evolved instincts that such things are dangerous, and without that disgust reflex, it's easy to forget.

The story is more complicated when it comes to direct contact with other people. Humans already have an instinct for social distancing, noted Tybur. For contrast, think of dogs.

"When they see another dog, they will often run over and go mouth-to-mouth contact, they'll go mouth-to-[rear] contact, with a complete stranger," said Tybur. "For humans that would be unthinkable."

Humans like to keep a buffer between themselves and others, and the size of that buffer depends on the relationship. Between sexual partners, it's essentially zero; with strangers, it is much larger. The more intimate a relationship, the more comfortable people are with things like hugging and drinking from the same glass.

According to frameworks developed by Tybur as well as Debra Lieberman and colleagues at the University of Miami in Florida, people's brains calibrate their levels of disgust based on the "social value" they place on another person. People subconsciously compute things like how much they want to have sex with someone, what kind of friendship and support that person can offer, and whether they are genetically related. At the same time, they evaluate how likely the person is to give them a disease.

For example, if you encounter a stranger who smells bad or has bloody sores on their face, you will probably feel some level of disgust, but that reaction will be tamped down if it's your own child. And you may be fine with sitting next to a stranger on the bus, but unless you found them extremely sexy, you'd likely recoil at the idea of sticking your tongue in their mouth.

Now, people are being told to increase the buffer between themselves and others past where they feel it should be, said Tybur. He speculates that greeting rituals such as hugs, handshakes and cheek kisses may have developed in part because they demonstrate how highly we value people.

"When we shake someone's hand or when we give someone a hug, we might be advertising to that person that they're important enough to us that we're willing to take that pathogen risk," he said.

If that's true, it's no wonder that social distancing is hard. Talk show hosts may mock alternative greeting practices like touching elbows or feet (behavior changes that, for many, have gone from seeming overly cautious to grossly inadequate in the past few weeks). But to Lieberman, it makes perfect sense why people would want to bump elbows. It's to signal how much they care.

"They're just grabbing for straws in order to kind of figure out 'how do I show people this value,'" she said.

So if our sense of disgust isn't doing what we need it to, can we deliberately manipulate it to help us through this crisis? Perhaps, said Lieberman at least when it comes to hand-washing and disinfecting surfaces. A 2009 study found that when posters and educational videos about hand sanitation included disgusting images such as a poop sandwich, people were more likely to actually wash their hands.

In the last few weeks, news reports and public service announcements have been full of pictures that make the COVID-19 virus look "pretty," noted Lieberman. Icky images might make more of an impression. But, she warned, officials should be cautious about using disgust to encourage social distancing, as that would involve painting other people as disgusting.

"That's potentially dangerous because disgust has a nefarious relationship with morality," she said.

Many studies have shown links between the behavioral immune system and phenomena such as xenophobia, discrimination and willingness to trust others. For example, one study by Lene Aare at Aarhus University in Denmark found that people who are more sensitive to disgust tend to have lower levels of "generalized social trust," a measure of how much you believe others will look out for your best interests and avoid deliberately harming you. People who have low social trust also tend to be less willing to do things, like recycling, that benefit society as a whole.

People who view disease-related images are less likely to support immigration, especially when the immigrants are from different races and cultures. Several studies have suggested that when people's behavioral immune systems are triggered by images or articles related to infectious disease, they become more biased against groups including the elderly, the obese, foreigners and the disabled.

Such effects are modest and not always consistent, and researchers interpret them in a variety of ways. Nevertheless, it's enough to convince some experts that manipulating disgust could be playing with fire.

Renata Schiavo, a senior lecturer at Columbia University Mailman School of Public Health in New York, doesn't support using disgust in any public health messaging, even to promote hand-washing. The research on disgust in public health campaigns has mostly focused on hand-washing after people use the bathroom or before eating, she noted. It's not clear what effect such methods would have in a pandemic, when people must wash their hands far more often and in other circumstances. And given that this crisis is already inspiring fear and bigotry, Schiavo views disgust as too dangerous a tool.

"This virus is not Chinese. It's not European. It's not American. But there have been a number of populations that are unfortunately experiencing an increase in discrimination," she said. "While I know the intentions of using disgust are good, I don't know if we know enough about how to [address] people's emotions and biases."

Even without deliberate interventions, the coronavirus crisis is probably ramping up our disease-avoidance instincts, said Anastasia Makhanova, a social psychologist at the University of Arkansas in Fayetteville. Much of Makhanova's research involves measuring how people's attitudes and bodies change when they read articles about disease threats, but that approach is impossible while the pandemic rages.

"Right now everyone is thinking about pathogen threats. So I can't engage in the experimental manipulation of how freaked out people are about getting sick," she said.

On the one hand, activating everyone's disease-avoidance instincts could help prevent the spread of the virus. Indeed, according to preliminary findings from data Makhanova gathered in the second week of March, people with stronger behavioral immune systems may be more likely to abide by recommendations for hand-washing and social distancing.

But we should also be aware that our heightened instincts could have harmful side effects, according to Aare, Makhanova and other experts. For example, those instincts could contribute to discrimination against people of Asian descent.

The instincts and biases our species has evolved don't mean we are doomed to behave badly, said Makhanova. People can correct for their biases if they are aware of them.

"[People] think that just because something's biological, it means we can't change it. But that's not true," she said. "We have a prefrontal cortex. We have self-control."

This article originally appeared on Inside Science.

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Disgust Evolved To Protect Us From Disease. Is It Working? - Discover Magazine

In 1951, movie audiences were introduced to a future classic in The Day The Earth Stood Still. At the start of this black and white film, a flying saucer lands in Washington D.C. and reveals a stoic defender in the robot Gort. This extremely powerful AI capable of turning our military's weapons to dust is entirely under the control of an alien named Klaatu. Throughout most of the film, Gort simply stands guard over the spacecraft while the story unravels elsewhere. By this point in time, audiences had seen such technological advances as radar and the atomic bomb. The concept of controlling an intelligent robot was no longer unimaginable or ludicrous. If anything, it was kind of cool.

The Day the Earth Stood Stilldepicts artificial intelligenceas a guardian that can be controlled and used for good, although this isn't immediately apparent in the plot. It isn't until the end of the film that Gort is given his commands and scoops up his master before departing Earth. The movie demonstrates a wonderfully diverse view of AI in both how it could be used in the right hands and how it would be perceived by its enemies. It's also shown as a device that can be used to achieve goals our fleshy bodies aren't capable of reaching alone but one without character or emotion. It would be more than two decades until the world would be transported to a galaxy far, far away and introduced to the lively robotic antics of two cultural icons.

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The stunning evolution of AI in movies - Looper

Our earliest vertebrate (animals with backbones) ancestors laid eggs, but over millions of years of evolution, some species began to give birth to live young.

There is a traditional dichotomy in vertebrate reproduction: species either lay eggs or have live births. However, as is often the case in biology, things arent as simple as they first appear, and there are a handful of vertebrate animals that do both.

One of these is the three-toed skink (Saiphos equalis). Our recent research suggests the egg-laying S. equalis may currently be in the process of transitioning from egg-laying to giving live birth.

Studying them gives us a unique opportunity to watch evolution in action.

There are two main reproductive strategies in vertebrates.

Animals that lay eggs are called oviparous. For instance, many fish species spawn eggs that are fertilised externally. In other oviparous species, including birds and some lizards and snakes, eggs are fertilised inside the mother, an eggshell is added, and then eggs are laid.

Depending on the species, much or all of the nutrition needed to grow a healthy baby is supplied in the egg yolk.

In contrast, viviparous animals carry embryos internally until they are fully developed. The embryos can rely entirely on yolk for nutrition, or the parents can provide supplementary nutrition, sometimes via a placenta (as in humans).

There is strong evidence that egg-laying is ancestral to live birth, meaning it came first. Many physiological changes were necessary for live birth to have evolved from egg-laying. With this transition, some structures were lost, including the hard outer eggshell. Other mechanisms were gained to ensure embryonic survival within the parent, including the supply of adequate oxygen and water during development.

The evolution of live birth has occurred frequently, including at least 121 times in independent groups of reptiles.

Evolutionary reversals to egg-laying are much rarer, probably because regaining the physiological machinery for producing eggshells would be exceptionally difficult.

Despite the vast differences between egg-laying and live birth, some species can do both. This phenomenon called bimodal reproduction is exceptionally rare. There are more than 6500 species of lizards worldwide, but only three exhibit bimodal reproduction.

Read more: Lizards help us find out which came first: the baby or the egg?

Were lucky enough to have two of these in Australia. Our research group at the University of Sydney studies the bimodally reproductive three-toed skink, in the hope of understanding how live birth evolved.

In northern NSW, the three-toed skink gives birth to live young, but near Sydney, they lay eggs. Even though they reproduce differently, previous research has shown these lizards are a single species.

Even the egg-laying members of the species are odd, as the eggs are retained within the mother for a relatively long time. After being laid, ordinary skink eggs are incubated for at least 35 days before they hatch, but some three-toed skink eggs hatch in as few as five days after being laid.

One female even laid eggs and gave birth to a live baby in the same litter.

Read more: The first known case of eggs plus live birth from one pregnancy in a tiny lizard

Most aspects of an animals development are controlled by its genes, but not every gene is always active. Genes can be expressed (switched on) to different degrees, and gene expression can stop when not needed.

An egg-laying skink uterus undergoes only a couple of genetic changes between being empty and holding an egg.

A live-bearing skink uterus is different. It undergoes thousands of genetic changes to help support the developing baby, including genes that probably help provide oxygen and water, and regulate the mothers immune system to keep the baby safe from immunological attack.

Our research measured changes in gene expression between egg-laying and live-birth in the three-toed skink. We investigated how the expression of all genes in the uterus differed between when the uterus was empty and when it held an egg or embryo.

As expected, live-bearing S. equalis, undergo thousands of genetic changes during pregnancy to produce a healthy baby.

But surprisingly, when we looked at the uterus of the egg-laying S. equalis, we found these also undergo thousands of genetic changes, many of which are similar to those in their live-bearing counterparts.

Some of the most important genetic changes in gene expression in egg-laying S. equalis allow embryos to develop within the mother for a long time. These genes also seem to allow the uterus to remodel to accommodate a growing embryo, and drive the same kinds of functions required for the embryonic development in live-birthing three-toed skinks.

Our findings are important because they demonstrate that egg-laying three-toed skinks are an evolutionary intermediate between true egg-laying and live birth.

We now know that uterine gene expression in egg-laying S. equalis mirrors live-bearing skinks much more closely than true egg-laying skinks. These results may explain why its possible for a female three-toed skink to lay eggs and give birth to a live baby in a single pregnancy.

The similarities in gene expression between egg-laying and live-bearing three-toed skink uteri might also mean reversals from live birth back to egg-laying could be be easier than previously thought. However, this may be restricted to species in which live-birth has evolved recently, such as the three-toed skink.

Read more: Why we're not giving up the search for mainland Australia's 'first extinct lizard'

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This lizard lays eggs and gives live birth. We think it's undergoing a major evolutionary transition - The Conversation AU

IoT platforms are creating advanced data pipes between connected assets and the data center or cloud

Today, IoT solutions and platforms that are enabling users to derive more value from connected devices have become more popular.

The Road ahead for Data Analytics and Business Intelligence

Primarily, the IoT stack is going beyond merely ingesting data to data analytics and management, with a focus on real-time analysis and autonomous AI capacities. Enterprises are finding more advanced ways to apply IoT for better and more profitable outcomes. IoT platforms have evolved to use standard open-source protocols and components. Now enterprises are primarily focusing on resolving business problems such as predictive maintenance or usage of smart devices to streamline business operations.

Platforms focus on similar things, but early attempts at the creation of highly discrete solutions around specific use cases in place of broad platforms, have been successful. That means more vendors offer more choices for customers, to broaden the chances for success. Clearly, IoT platforms actually sit at the heart of value creation in the IoT.

The new IoT deployments drive the market growth along with the scaling up of existing implementations. The platform concept is definitely more inclusive, and precise use cases and patterns mean apps are being built to simplify processes. With thousands of vendors in the mix, firms cant be going after all individual pieces of the stack. They need to compare and differentiate to grow in this competitive market environment.

Whatever vendor path customers take, data analytics should be the driving force behind all the new IoT projects. Analytics will remain one of the most crucial components of any valuable IoT use case. The main point of gathering the data is to make valuable interpretation and sense out of the data.

The new analytics applications are focused on real-time analytics and data collection that can be utilized to train predictive algorithms. Data interpretation to identify and pick out patterns is vital to ensure business success. A lot of valuable IoT use cases are derived from IoT data, decoding it, and using machine learning and AI to go ahead.

IoT platforms are capable of making autonomous decisions, supporting unique use cases within IoT. The market has enough data available to build good machine learning models, IoT being such a vast sensing and reactionary system. Another crucial aspect of IoT success is the ability to manage devices in a scalable manner and deploy services and apps accordingly.The lines of businesses within organizations are pushing hard on rapidly using services and extracting value from the collected data. The pace is accelerating.

Innodisk Unveils Security-optimized AIoT Solutions

While there is progress in defining use cases, the choices for enterprises are getting more complicated. A clear plan is a must for future-proofing an IoT project and how much if any of the builds should be handled in-house prior to vendor selection.

As for scalability, IDCconfirmed that there would be about41.6 billion connected IoT devices by 2025. IoT is everything thats beyond a PC or mobile device. There are a lot of possibilities that can be overwhelming. But, it can be hard for firms to know where to start as they need to invest in digitization to unlock the advantage of IoT.

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Data Analytics the Force Behind the IoT Evolution - EnterpriseTalk

For almost as long as men had tried to fly, they had dreamed of taking off from water.

The French had an awful lot to do with the earliest days of conventional flight and they were also at the very birth of seaplanes.

Alphonse Penaud, who in the 1800s advanced theories about wing shapes, airplanes, helicopters and the like, would also file the first patent for a flying machine with a boat hull beneath it.

This was in 1876 and several attempts and near-disasters would occur before March 28 1910.

On that date, another Frenchman, Henri Fabre, flew the first successful powered seaplane and aviation history entered a thrilling new phase.

He did so in the Gnome Omega-powered hydravion, a trimaran floatplane, and his feat inspired many others who later relied on Fabres designs for similar machines of their own.

In just two years, Monaco hosted the first hydro-airplane competition, with Fabres inventions up against machines from other big names of the time such as Glenn Curtiss, an American, his compatriot Alphonse Tellier and Anglo-French aviator Henry Farman.

That same year, 1912, the first day of August saw the very first scheduled seaplane passenger flight, from Aix-les-Bains in Frances south-east Savoie department.

The five-seater was such a success that the French Navy ordered its first floating plane the same year. Suddenly, everyone who was anyone had to have the latest thing, a plane that could take off from water rather than dry land.

Just weeks after Fabres breakthrough, American Glenn L. Martin had set time and distance records after flying his homemade seaplane in California, but Fabre had been first and would always be the name in the history books.

Thats not to take anything away from Gabriel Voisin, who five years previously had landed his towed kite glider with floats on the River Seine, but Fabres feat was amazing for its time.

Even today, while the majority of us have been on a passenger plane, few have had the unique thrill of taking off from or landing on water in a seaplane.

Britain, however, was not terribly far behind our Gallic cousins in the race to fly from a watery take-off.

English duo Captain Edward Wakefield and Oscar Gnosspelius had used Englands largest lake at Windermere to test the feasibility of flight from water in 1908.

Large crowds got very excited but ultimately deflated as each attempt geared up but then failed to see their craft rise to the skies.

When they eventually ordered a machine like Fabres, it did take off, in 1911, although it soon crashed into the lake again.

With a more helpful wind, though, subsequent flights did much better and they got to 50 feet before making a nice turn and a perfect landing on the watery surface.

The crowds were beside themselves with excitement, as were the men behind the whole thing seaplanes were going to be much more than a flash in the pan.

By the time of the Balkan Wars in 1913, inevitably, seaplanes were being used to hurt, rather than entertain, the folks below. A Greek seaplane bombed the Turkish fleet.

In the months before the Great War, J Samuel White, of Cowes, Isle of Wight, had built a flying boat.

Also in 1913, there was a collaboration between SE Saunders boatyard in East Cowes and the Sopwith Aviation Company, which produced the so-called Bat Boat, a plane with a laminated hull that could work on water or dry land.

Today, they are known as amphibious aircraft and it was the very first completely British airplane to make six return flights over five miles inside five hours.

Although designers were still struggling to make properly efficient, reliable seaplanes well into the war years, the Royal Navy did get F2, F3 and F5 flying boats in time to use them for patrols and searches for U-boats.

By 1918, they could be towed on lighters, a type of barge, as close as possible to Germanys northern ports before taking off.

This extended their range immensely and some Navy seaplanes engaged with German seaplanes and in the summer of 1918 shot several out of the skies.

Their effectiveness had been so impressive that top brass decided to use them in this way as much as possible. Dazzle-painting was introduced, which was a method in which the planes were hard to spot when they were onboard ships or barges, and the Navy tried to take as many as possible as close to Germany as they could get.

In the Second World War, these magnificent machines proved just as effective and the battleship Bismarck was located by a Catalina from Lough Erne in Northern Ireland.

The wars largest flying boat, however, belonged to the other side.

The Blohm & Voss BV 238 was the heaviest aircraft ever built when it first flew in 1944.

In 1990, Tom Casey took the whole thing to new levels. He flew more than 29,000 miles in 188 days, landing only on water for the first floating plane round-the-world flight.

Many places he visited had never seen planes that could land on water and therefore lacked bases to tell him about weather conditions, but he survived and made history.

These days, most such planes are amphibious and can land on water or dry land. But they continue to thrill us.

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The fascinating evolution of the seaplane - The Sunday Post

Today, with seven commercially approved antibody-drug conjugates (ADCs) on the market and approximately 90 programs in clinical trials, simplifying the complex supply chain to make manufacturing efficient is a necessity. With approximately 70 percent of ADC projects outsourced to contract development and manufacturing organizations (CMDOs),1 a transparent and integrated supply chain is critical for success. Now, this is more important than ever, with more clinical trials with combination therapy expected as more than 200 trials are registered and as ADCs are expected to gain prominence beyond oncology in the areas of anti-infection, anti-inflammatory, cardiovascular diseases and imaging and diagnostic agents.

The typical ADC supply chain is elaborate due to the numerous, specialized processes in their production and the logistical alignment needed between each step. The three main elements of an ADC are:

The benefits of working with established CDMOs on ADC projects are numerous: experience with a variety of constructs and ADC technologies; efficient processes in place for tech transfer and manufacturing; manufacturing expertise, particularly with GMP batches; and understanding of the regulatory pathway for ADCs.

Interspersed with the above manufacturing steps, requisite quality control measuressuch as mAb bioassays and conjugate stability testingcompound an already complicated pathway. Clearly, manufacturers that can simplify this supply chain are doing customers a great service.

Ten years ago, ADC manufacturing took place on a much smaller scale than today. Raw materials, such as mAbs, were only available in clinical rather than commercial-sized batches. Manufacturing was performed as an add-on to other procedures rather than as an optimized, stand-alone process, and few sites were capable of handling high-potency payloads.

Full-length mAbs were humanized IgGs, most often IgG1, conjugated randomly at cysteine or lysine sites, as shown in Figure 1. In these constructs, the payload could bond to the antibody in multiple locations, potentially affecting its activity. With an IgG scaffold containing over 80 lysines,2 conjugation resulted in very heterogeneous ADCs with variable drug-to-antibody ratios (DARs). High DAR species in the final product can impact stability, solubility and cause problems in manufacturing and operations.

To solve the heterogeneity problem, research moved from native IgGs toward site-specific engineered mAbs, including mAbs with engineered cysteines, non-natural amino acids and sequence tagsall of which could be reacted to perform a more homogenous product. The goal was to manipulate the antibody, so it had specific, limited locations where the toxins were to bond. For instance, monoclonal antibodies containing engineered cysteine moieties limit conjugations to positions that do not disturb immunoglobulin folding or assembly or alter antigen binding.3 The structural representation of an ADC made with such an antibody is shown in Figure 2.

Other second-generation developments included modulation of ADC hydrophobicity by using hydrophilic linkers; structure activity relationship (SAR) design relating a molecules structure to function; and enhanced analytical tools such as chromatography. Cytotoxic payloads with greater potency, such as auristatin and maytansine microtube disruptors, also came into play. All these developments helped improve the usefulness of these agents.

More sophisticated, specialized manufacturing techniques and special facilities were also required to handle these powerful toxins safely.

Second-generation linkers had slightly more functionality than earlier linkers. They were also monovalent, but some were cleavable, either enzymatically or via acid exposure inside cells or lysosomes. Examples include linkers based on proteases, hydrazine, polyethylene glycol (PEG) and disulfides. These linkers were expected to help the antibody release the toxin at the right place and the right time and also stabilize the ADC during preparation, storage and systemic circulation.

Todays researchers are exploring additional modes of action and ways to increase activity and specificity. Bi-specific MAbs, both IgG-like and non-IgG-like, contain two dissimilar binding sites. For example, a single ADC may deliver a toxin and activate natural killer cells. One recently constructed agent had four mechanisms of action. Obviously, the conjugation processes and analytics for these agents are non-trivial.

Another up-and-coming technology is utilizing Fabs (antigen-binding fragments) in place of intact mAbs. These are sections of antibodies that include sites for antigen binding and linkage. These Fabs are very stable, may be internalized more readily, are relatively easy to purify, and tend to be less immunogenic than larger ADCs.

Third-generation payloadspotent cytotoxins such as PBDs and tubulysin, which require special facilities and handlingare not that different than second-generation payloads.

The most unexpected aspect of third-generation development is the revolution in the general understanding of what linkers can do. SAR studies show that linkers change antibody properties, including changes in toxicity and pharmacokinetic profiles. It is now known that if a linker is altered, these parameters must be reevaluated.

New linker categories still include cleavable and non-cleavable, but they also encompass entities such as the Fleximer platform, a polyvalent and biodegradable molecule that can carry multiple payloads. Additionally, hydrophilic linker modulation such as pegylation can mask a larger molecule from the immune system and decrease renal clearance to increase longevity in the circulation. This is a very useful concept as PBDs are very hydrophobic and, once conjugated, are prone to aggregation.

Todays complex, multifaceted ADCs place substantial demands on drug developers and manufacturers, and these challenges are compounded by this sense of urgency in a crowded field and need for life-saving therapies:

Established CMDOs in the ADC business will need to keep pace with future technological advances in this fast-growing industry. Companies that will be successful in the bioconjugation space are providing dedicated facilities for high-potency biologicals, establishing platform operations and developing a workforce with the advanced and specialized expertise to meet the expectations of customers and regulatory agencies. Next-generation bioconjugation will not only be challenged by new and novel chemical unit operations, but will also require novel analytical technologies to provide a more granular understanding at the molecular level. Techniques and tools will need to provide answers for the control strategy of complex products and will need to evolve to support sophisticated release strategies for on-line and at-line in-process testing.

Along with comprehensive laboratory services and expert assistance, the following technologies are particularly helpful for successful ADC manufacturing:

SUS technologies add simplicity and are available for all steps throughout the ADC manufacturing process. Having a complete, single-use process in place can make a big difference: no cleaning studies are needed, reducing costs. The components are designed to be scalable. Extractables and leachables documentation is available to meet regulatory requirements. Operator safety is increased, particularly when handling highly potent ingredients. Implementation of single-use reactor along with a full line of single use equipment for all unit operations is expected be the preferred platform of choice for all bioconjugation processes.

The advancement of PAT allows real-time testing during a GMP process to gather rich, real-time data about the physical and chemical parameters during active processes. It can be used to ensure the process is going as planned and it can also be used to monitor trends in process iterations.

Purification strategies have been expanded to include large-scale chromatography and an increased number of constructs have chromatography. The major reasons to integrate chromatography include: to clear lipophilic drugs that are not amenable to TFF clearance; to remove aggregates and to refine conjugated species distribution, as in removing unconjugated mAb; and to ensure the best possible ADC therapeutic index and specificity, an important function since 60% of constructs require this type of purification.

Potential customers are also evaluating services beyond preparation of the materials, such as formulation support and studies to support the regulatory filing.

Ten years ago, ADCs were a relatively simple concept: use an antibody to target a cell and precisely deliver a biologically active agent. Now, the mission is much more complicated. CDMOs with long-range plans for ADC manufacturing are setting up processes to handle challenging supply chains and investing in facilities and processes to ensure efficiency, quality and security for their customers. Companies that can help deliver multiple constructs to enable a well-designed clinical program are providing customers the opportunity to advance in the field at a fast pace. CDMOs are uniquely positioned to see a wide variety of best practices and can provide solutions based on what has been observed in the industry. In addition, as more commercial products enter the market, there is an acute need for companies that understand how to execute late-stage studies to support a filing strategy. The growth of ADCs in the clinical and commercial API space is a testament to the ability of manufacturers to evolve the technologies required to handle complex molecules.

Whether its understanding the structure-activity relationships around the antibody, linker and drug, or managing a complex supply chain, a CDMO with experience should have the skills and tools needed to help ADC developers navigate these challenges.

Sources

Jyothi Swamy is associate director, ADC/bioconjugation contract manufacturing at MilliporeSigma.

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The Evolution Of The ADC Manufacturer - Contract Pharma

Early Topanga Beach residents endured tense times during WW II but had a front row seat for the birth of Californias surf culture. Their experiences were a key chapter in Topangas creative and colorful history.

In 2005, Topanga Messenger editor Susan Chasen and I interviewed the Rusts daughter, Thais (b.1925), about growing up in Lower Topanga. Her memories, many of which we published in the newspaper and re-published in The Topanga Story, presented a vision of our hometown so unfamiliar that it astonished us.

One of Thaiss earliest memories was watching the enormous German Graf Zeppelin fly by Topanga Beach on its 1929 trip around the world. A few years later, the zeppelin would become a symbol of Nazi propaganda and carry the swastika.

Thais also remembered the gambling ships of the 1930s, which would sometimes anchor off Topanga. They had to stay three miles from the coast to avoid U.S. laws.

Holiday fun was had at the annual Webster Christmas Party for the Children of Malibu, a 20-year tradition at Judge John L. Websters Malibu Courthouse that started in 1932, and drew hundreds.

A simpler ritual was collecting honey with painter Laura Way Mathiesen, who kept her bees in a side canyon that doubled as a shooting range for the police.

Thaiss favorite memories were of spending whole summers on the beach with her cousin Marilyn Kays, and neighbors Dick Carhart and Ida Lee Carrillo. Ida Lee was the daughter of Octavio (Ottie) and Bessie Carrillo, the niece of actor Leo Carrillo, and the descendant of one of Californias oldest Spanish families.

We were at the beach probably from eight or nine in the morning til five or six at night. It didnt matter how large the waves were, we just had fun. One day, Marilyn and I went with Ida Lee and her dad to the beach. The three of us got out beyond the waves, not knowing that there was a strong riptide. When we couldnt get back to shore, Ottie called the Santa Monica lifeguards to rescue us. We were picked up just before Sunset Boulevard. We were having a great time, but Ida Lees dad was frantic.

Other swimming options were the bathhouse of Alfred T. Stewart, rebuilt after the 1926 fire, nicknamed The Plunge, and the private swimming pool of actor/Olympian Johnny Weissmuller at Tuna Beach, where the neighborhood kids liked to jump in from the balcony.

Later, actress Natalie Talmadge lived in the Weissmuller house with her sons Joseph (James) and Robert (Bob). She legally changed their surnames to Talmadge to avoid being reminded of her famous ex-husband, Buster Keaton.

In the early 1940s, actors David Niven and Errol Flynn took over the house, with Bing Crosby and Paulette Goddard living on either side. In the mid-1940s, it became the Las Tunas Isle Motel. Today its a private residence again.

After high school, Thais became engaged to Bob Talmadge, but they broke up before the wedding. During World War II, she spent Friday nights scanning the sky for enemy planes from a lookout tower that was across the street from todays Getty Villa. In the early 1950s, she was briefly married to a second beach resident, Dave Sykes (1926-2009).

However, a third man from the beach was destined to become her life partner, and surprisingly it was Daves younger brother, John (Jack) Sykes (1935-2017), whom she married in 1956.

Jack, Dave, and their sister Beverly were the children of Sherman and Gladys Sykes, who owned a bar called The Glen, in Beverly Glen. It had a reputation for being tough, and Sherman carried a gun that he would sometimes leave out on the table. Their house had a gangplank that led onto the sand. When it was pulled up, it covered the door to keep big waves from splashing in.

Chasen and I simultaneously interviewed Jack, and he shared vivid memories of what Topanga Beach was like during World War II.

By then, the gambling ships had been outlawed, but the Air Force kept an abandoned ship moored off Topanga for target practice. The hills along the coast were full of artillery. It was a common sight to see 100 army vehicles at a time driving down the highway in convoy. At night, drivers kept their headlights off, and a Blackout Warden fined houses where light was visible.

The Coast Guard had a headquarters at Sunset Blvd., and patrolled the coast on foot every evening, passing by Topanga Beach with bayonets and German Shepherds. Sometimes the army closed the beach to play war games.

On either side of the lagoon, machine gun nests were placed on dirt mounds. One was in front of Jacks house.

They dug a big hole in the sand, and had soldiers in there. I would bring them cookies from our house, and my dad got so mad at me. I was taking all our stuff out for these guys to eat.

Contrasting with the wartime grittiness was the glamour of Jacks celebrity neighbors, like actresses Greta Garbo, with whom he took walks, and Shirley Temple, who occasionally asked his dad for a ride to town.

Jack was also surrounded by icons of early California surfing, which included his brother.

[Dave] Sykes was the best surfer I had seen at that time because he lived there and surfed all day, every day. He could just glide and glide. (Joe Quigg, The Archivist: Turning Points, The Surfers Journal, September 19, 2017)

Topanga dweller Sykes finely honed speed lines and turning were years in advance of others. Sykes delighted in [perfectly] planing surfaces and placed 15 layers of hand-rubbed lacquer over his boards creating a hard-shelled outer surface many years before the discovery of fiberglass and resin. (Craig Stecyk, The Surfers Journal)

The Malibu Point was first surfed in September 1927, when it was still a private ranch, by Tom Blake and Sam Reid. We dont know who first surfed Topanga, but it would make sense for Tom and Sam to have tried it before Malibu. Reid is often quoted as saying that there were only six surfboards in the entire United States when he graduated from Santa Monica High School in the early 1920s.

Although Reids count was meant more to give an impression, two of those six surfboards belonged to brothers John E. O. (1915-1990) and Jim Larronde (1917-1989), who had them engraved with their initials in Hawaii and shipped to their parents Topanga Beach vacation house (Johns redwood surfboard is now in the Museum of Ventura County). In the late 1930s, a transition balsa-redwood surfboard was called the Larronde Model. In the late 1940s, John made a 16-minute home surf movie, popularly known as Sweet Sixteen, of trips he took between Malibu and Santa Barbara.

Their father, Pedro Larronde, supposedly built their beach house in 1917, just after the prison camp closed. He may have been given this privilege because his brother John M. Larronde was an executive of the Title Insurance and Trust Company, who owned the land before the Los Angeles Athletic Club (LAAC). Or it may have happened because their grandfather, Pierre, had been the legal guardian of future-Sheriff Eugene Biscailuzs Uncle William, who was also of Basque ancestry.

Pedro was an executive of the Franco-American Baking Company, and a member of the Los Angeles Athletic Club. For some reason, his wife, another Gladys, was forced to move their beach house across the street to Old Malibu Road when the LAAC took ownership in the mid-1920s.

The Larronde house was bulldozed, along with the Rust house and the rest of the neighborhood, when State Parks took ownership in the mid-2000s.

Other early Topanga Beach surfers that Thais and Jack remembered were Don James, Bob Simmons, Ed Fearon, Jack Quigg, Bob Talmadge, Warren Miller, half-brothers Jerry Hanes and Bobby Jacks, Dave Sweet, Matt Kivlin, and twin brothers Corny and Peter Cole.

More than just a random surf pack, this group is actually noted for evolving the sport with their skill, precociousness, and other contributions. James was Californias first dedicated surf photographer; Simmons and Sweet were influential shapers; Miller was an early surf filmmaker who transitioned to ski filming, a passion which he traced back to a freak snowstorm at Topanga Beach.

Many people and businesses change forever because of a simple event. Mine changed on the beach at Topanga Canyon in 1929. It had snowed about an inch the night before and as I walked barefooted in ankle-deep warm ocean water, I stepped out onto the snow and a kind of visceral feeling happened that to this day is impossible for me to explain. (Nostalgia, Idaho Mountain Express, January 22, 2010)

Kivlin was considered to be the best California surfer of his generation, and Kathy (Gidget) Kohner caught her first wave on his board, which led to an explosion in surfings popularity.

The Cole brothers opened a primitive surf shop at the gas station. Peter later moved to Hawaii to become a big-wave rider, and Corny became the art director of Topanga Beachs own Surf Guide magazine.

World War II interrupted the lives of many of these young surfers but offered unexpected opportunities for the Rust women. Thais followed her mom into the aerospace field, getting her first job at Douglas Aircraft. She went on to work at the RAND Corporation and the Planning Research Corporation.

Jack was too young to fight in World War II but embarked on a military career anyway when he came of age. He then worked as a plumber and eventually started his own company. Jack and Thais raised two daughters, Lisa and Lori, and retired in Orange, CA.

Thais will be 95 on April 5, 2020.

Pablo Capra is a former Lower Topanga resident, and continues to preserve the history of that neighborhood on his website, http://www.brasstackspress.com, and as a board member of the Topanga Historical Society, http://www.topangahistoricalsociety.org.

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The Original Topanga Beach Generation Helped Shape the Evolution of Southern California Surf Culture - M'Online

Personal and social hygiene awareness has increased exponentially, with a growing scepticism of what and what is not clean.

Whether we are at our workplace, attending leisure facilities or travelling for business or pleasure, we all now have a heightened awareness of how we interact and will now expect and demand a higher level of service from providers that takes cognisance of the perceived risks as a result of this. Put simply, COVID19 will change the way we work, how we live and how and where we travel.

Image credit: Room to Breathe

Few markets have felt the full force of this pandemic more than the hospitality sector. It has decimated trade, scattered the labour force and threatened the very existence of the supply chain. Travellers, holiday makers and businesspeople alike will now become even more difficult to satisfy and will seek to be given as much reassurance as possible.

A single night stay becomes your biggest issue as each and every night your new customer requires that peace of mind that your room is as safe as possible for them to stay in. Failure to address these new concerns could result in the long-term repeat visitor more likely to go somewhere else next time.

By taking steps to show your commitment to your customers health and wellbeing is now, more than ever, of paramount importance.

Image credit: Room to Breathe

Capturing this feeling of assured safety every time must be seen as the focal point for Customer Satisfaction.

What can be done?

So what can the hospitality sector do to insulate itself from the aftershock of COVID19 and prepare for the inevitable increase in customer demands? What can be done to provide that peace of mind that is desired?

Is carrying out the same cleaning protocols more frequently by an already stretched housekeeping department going to provide the reassurance required? In a word, no.

By taking steps to show your commitment to your customers health and wellbeing is now, more than ever, of paramount importance.

Image credit: Room to Breathe

A cleaner solution

A new approach to a new problem must be the way forward. It needs to address the worries and concerns of your customers but must, just as importantly, be cost effective. Imagine the cost of a deep clean between every guest. This is neither practical nor affordable.

This is where Room to Breathe comes into its own. By providing a room that can demonstrate continuous and permanent self-cleaning provision, you can provide customers with an unrivalled level of service and commitment to their needs and concerns.

Room to Breathe also kills 99.99 per cent of viruses and bacteria, including coronaviruses.

Originally developed to provide safe, clean accommodation for the millions of travellers who have a hypersensitivity to various toxins, pathogens and allergens, Room to Breathe also kills 99.99 per cent of viruses and bacteria, including coronaviruses (incl. influenza, SARS, MERS).

Step One deep clean

An initial industrial air purge followed by a combination of steam cleaning above 40, ultra-low-penetration air (UPLA) vacuuming and the application of our unique decontamination fluid which is deadly to pathogens (but is safe to all higher living organisms) is fogged into the area ensuring every surface coated.

Additionally, by using innovative UV technology we can rid mattresses, pillows and soft furnishings of undesirable micro-organisms within seconds.

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Step Two Anti-microbial coating

Once the area has been decontaminated, our antimicrobial coating BioTouch, will be is applied. The BioTouch formula bonds to a clean surface and when viruses and bacteria land on the protected surface, the cellular structure is ruptured (not poisoned) and becomes defunct.

The only way BioTouch can be removed is by it being chipped off. Where there is a risk of this, on door handles, light switches for example, we can easily reapply to maintain the coatings efficiency.

Step three Bedding and soft furnishings

Using our own unique formula, Protextsolution provides a layer of invisible protection which permanently interrupts the life cycle of dust mites and bed bugs.

Our method avoids the use of toxins so whilst lethal to bugs and mites does not pose a risk to the client.This is also applied to all fabrics and soft furnishings.

Step Four continuous air sanification.

Installing filterless air sanifiers provides the final level of protection. Using technology originally developed by NASA, our sanifiers seek out contaminants and pathogens within the air and on surfaces and neutralise them.

By applying this four step process, we not only eradicate 99.99 per cent of viruses and bacteria, we also provide a continuous level of protection in between our Deep Clean processes.

Certification

On completion certification is provided and displayed either outside or within the room to provide that peace of mind to Customers and employees alike.

A Room Information Pack is provided for guests to simply explain the RTB system, providing that peace of mind. In order to maintain the certification, Steps One and Two are carried out every four months in accordance with our terms and conditions.

On-site training is also provided to Housekeeping staff in order to ensure the efficacy of the RTB system is maintained. This is no more onerous to staff and in fact will simplify their cleaning protocols.

Cost

Based on an occupancy of 72 per cent, our cost model demonstrates that a ROI of 100 per centcan be achieved in the first year with a surcharge of just 15 per night per room.

We truly believe Room to Breathe is the next step in the evolution of the hospitality market. Our processes not only provide protection from unseen pathogens but are also proven to improve cognitive function, enable better quality of sleep and promote overall wellbeing.

So whether you are wanting ensure the highest level of protection for your customers or are looking to capture the untapped market for those travellers with intolerances or allergies then Room to Breathe could well be the answer.

Room to Breathe is one of our recommended suppliers. To keep up to date with their news, click here. And, if you are interested in becoming one of our recommended suppliers, please email Katy Phillips byclicking here.

Main image credit: Room to Breathe

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FEATURE: COVID19 pandemic is forcing an evolution in wellness Hotel Designs - Hotel Designs