Daily Archives: June 29, 2017

Gene Editing Reverses Huntington’s in Mouse Study – Bioscience Technology

Posted: June 29, 2017 at 11:50 pm

While still early, a new study reports that the disease process and motor symptoms of Huntingtons disease were reversed using CRISPR/Cas9 gene editing methods in mouse models.

The new findings spark hope for future treatments in humans, though much more work to test long-term effects and safety are needed.

Huntingtons is a progressive inherited disease that occurs when a mutant copy of the huntingtin (HTT) gene is inherited from one parent. This leads the production of a toxic protein (mutant huntingtin or mHTT) that that causes brain cells to die and triggers a degenerative process. As time goes on people experience symptoms such as uncontrolled movements, slurred speech, cognitive decline and mood swings.

Researchers led by Su Yang, Ph.D. of Emory University and Renbao Chang, Ph.D., of the Institute of Genetics and Developmental Biology at the Chinese Academy of Sciences, showed in previous work that stopping production of healthy or mutated HTT protein doesnt cause neurological problems or hurt cells in mice older than four months, so they hypothesized that shutting off both copies of the gene could be safe and potentially reverse early signs of the disease.

In the mouse model used, the animals had one human mutant huntingtin gene in place of one of the mouse huntingtin genes and motor problems as well as aggregated mutant huntingtin could be observed by the age of 9 months.

For the study, the team used a gene therapy method based on AAV (adeno-associated virus) to deliver CRISPR/Cas9-guided enzymes into brain cells. They injected millions of viral vectors into the striatum region of the mouse brains, which is the area that controls motor skills. Neurons received either a short guide RNA sequence to mark for the removal of the HTT genes repeats or a Cas9 enzyme to snip out the repeats, effectively knocking out both healthy and abnormal copies of the HTT gene, and stopping the production of HTT protein.

Three weeks later, the team observed a dramatic decrease in aggregated mutant huntingtin in the striatum. The findings indicate that brain cells have the ability to heal themselves if the genetic source of the toxic proteins is removed, the scientists said.

CRISPR/Cas9 injections were repeated in a dozen 9-month old mice and similar protein-clearing results were observed.

Mice that received the CRISPR/Cas9 injections significantly improved on tests of balance, muscle coordination, and grip strength compared to control Huntingtons mice. However they did not improve to the level of healthy control mice.

Interestingly, how well motor skills improved related to the level of toxic protein that was cleared from the striatum.

One issue with CRISPR/Cas9 that has been reported is unintended mutations resulting from off-target editing. However, the NIH-funded team reported that the gene editing occurred primarily around their target sequences and there was not significant genomic edits in other potential off-target genes.

While this early study is promising, the long-term effects and safety of injecting AAV in the brain to express CRISPR/Cas9 still needs to be thoroughly tested before translating this method to patients, senior author Xiao-Jiang Li, M.D., Ph.D., distinguished professor of human genetics at Emory, said.

The findings were published in The Journal of Clinical Investigation.

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Researchers identify new mechanism for keeping DNA protein in line – Phys.Org

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June 29, 2017 Shown is the crystal structure of the FEN1 protein bound to its target DNA. Researchers found that single-stranded flaps are threaded through a tunnel in FEN1. The unexpected inversion of the threaded flap, guided by phosphate steering, keeps the phosphodiester bonds facing away from the metals that could inadvertently shred them. Credit: Susan Tsutakawa/Berkeley Lab

The actions of a protein used for DNA replication and repair are guided by electrostatic forces known as phosphate steering, a finding that not only reveals key details about a vital process in healthy cells, but provides new directions for cancer treatment research.

The findings, published this week in the journal Nature Communications, focus on an enzyme called flap endonuclease 1, or FEN1. Using a combination of crystallographic, biochemical, and genetic analyses, researchers at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) showed that phosphate steering kept FEN1 in line and working properly.

"FEN1, like many DNA replication and repair proteins, have paradoxical roles relevant to cancer," said study lead author Susan Tsutakawa, a biochemist at Berkeley Lab's Molecular Biophysics and Integrated Bioimaging Division. "A mistake by FEN1 could damage the DNA, leading to the development of cancer. On the other side, many cancers need replication and repair proteins to survive and to repair DNA damaged from cancer treatments. New evidence shows that phosphate steering helps ensure that FEN1 behaves as it should to prevent genome instability."

During the process of replication, double-stranded DNA unzips to expose the nucleotides along its two separate strands. In that process, flaps of single-stranded DNA are created. The job of FEN1 is to remove those flaps by positioning metal catalysts so that they can break down the phosphodiester bonds that make up the backbone of nucleic acid strands. This cleavage action occurs in the duplex DNA near the junction with the single-stranded flap.

Flaps that remain uncleaved can lead to toxic DNA damage that either kill the cell or cause extensive mutations. For example, trinucleotide repeat expansions, a mutation associated with disorders such as Huntington's disease and fragile X syndrome, are characterized by the failure of FEN1 to cut off the excess strand.

"What had been unclear before our study was how FEN1 was able to identify its exact target while preventing the indiscriminate cutting of single-stranded flaps," said Tsutakawa. "There must be a way for this protein to not shred similar targets, such as single-stranded RNA or DNA. Getting that right is critical."

Tsutakawa worked with corresponding author John Tainer, Berkeley Lab research scientist and a professor at the University of Texas, at the Advanced Light Source, a DOE Office of Science User Facility that produces extremely bright X-ray beams suitable for solving the atomic structure of protein and DNA complexes. Using X-ray crystallography, they were able to get a molecular-level view of the FEN1 protein structure.

They determined that the single-stranded flap threaded through a small hole formed by the FEN1 protein. The size of the hole serves as an extra check that FEN1 is binding the correct target. However, they surprisingly found that the single-stranded flap is inverted such that the more vulnerable part of the DNA, the phosphodiester backbone, faces away from the metal catalysts, thereby reducing the chance of inadvertent incision.

The inversion is guided by a positively charged region in FEN1 that stabilizes the upside-down position and steers the negatively charged phosphodiester of the single-stranded DNA through the FEN1 tunnel.

"These metals are like scissors and will cut any DNA near them," said Tsutakawa. "The positively charged region in FEN1 acts like a magnet, pulling the flap away from these metals and protecting the flap from being cut. This is how FEN1 avoids cutting single-stranded DNA or RNA."

"This phosphate steering is a previously unknown mechanism for controlling the specificity of FEN1," she added. "Cancer cells need FEN proteins to replicate, so understanding how FEN1 works could help provide targets for research into treatments down the line."

Explore further: Enzyme follows a two-step verification system before cutting and repairing DNA damage

More information: Susan E. Tsutakawa et al, Phosphate steering by Flap Endonuclease 1 promotes 5-flap specificity and incision to prevent genome instability, Nature Communications (2017). DOI: 10.1038/ncomms15855

Microscopes that reveal the hidden complexities of life down to the nanoscale level have shown in exquisite detail how an enzyme involved in DNA repair works its molecular magic.

An international team of scientists has discovered how compounds block flap endonuclease 1 (FEN1) - a crucial enzyme class in the DNA damage response and potential target for cancer treatment.

(PhysOrg.com) -- An enzyme essential for DNA replication and repair in humans works in a way that might be exploited as anti-cancer therapy, say researchers at The Scripps Research Institute and Lawrence Berkeley National ...

Breaks in DNA can cause chromosome rearrangements, abnormalities linked to cancer. Now Yale scientists have identified how the molecule DNA2 helps begin the complex process of repairing these breaks.

Almost all life on Earth is based on DNA being copied, or replicated. Now for the first time scientists have been able to watch the replication of a single DNA molecule, with some surprising findings. For one thing, there's ...

Cancer is caused by the growth of an abnormal cell which harbours DNA mutations, "copy errors" occurring during the DNA replication process. If these errors do take place quite regularly without having any damaging effect ...

Photosynthesis is one of the most complicated and important processesresponsible for kick-starting Earth's food chain. While we have modeled its more-than-100 major steps, scientists are still discovering the purpose of ...

Whether or not society shakes its addiction to oil and gasoline will depend on a number of profound environmental, geopolitical and societal factors.

The actions of a protein used for DNA replication and repair are guided by electrostatic forces known as phosphate steering, a finding that not only reveals key details about a vital process in healthy cells, but provides ...

Worker and queen honeybees exposed to field realistic levels of neonicotinoids die sooner, reducing the health of the entire colony, a new study led by York University biologists has found.

If aliens sent an exploratory mission to Earth, one of the first things they'd noticeafter the fluffy white clouds and blue oceans of our water worldwould be the way vegetation grades from exuberance at the equator ...

Researchers from the Centre for Ecology & Hydrology (CEH) publish results of a large-scale, field-realistic experiment to assess neonicotinoid impacts on honeybees and wild bees across Europe, in the peer-review journal Science ...

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Horse Tale: Oriental Stallions Dominate Horse DNA, Gene Study Shows – NBCNews.com

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A Lipizzan stallion named Conversano Sessana, born in 2001.The Y sequence that is needed as a template to detect variants in any horse is generated from a stallion of this breed. Spanische Hofreitschule Wien

A group of researchers led by Barbara Wallner of the Institute of Animal Breeding and Genetics in Vienna, Austria sampled the genes of 52 modern horses representing 21 different breeds for their study. They included the famous white dancing Lipizzaners, quarter horses, cobs, Thoroughbreds and Arabians.

The team focused on the male specific

The findings were startling. Most of the horses in common use descend from just two lineages, the Arabian lineage from the Arabian Peninsula and the Turkoman lineage from the steppes of Central Asia, also widely known as "Oriental" among horse breeders, as reported in the Journal of Current Biology.

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"Apart from stallion lines in Northern European breeds, all stallion lines detected in other modern breeds derive from more recently introduced Oriental ancestors," Wallner said.

Its not surprising that a few studs would have a large number of progeny. Females can have one or two foals a year, while males can sire many.

It seems medieval horse breeders made great use of a few very strong specimens, Wallner said, breeding them with local mares.

The qualities they were looking for are still the same qualities people still admire today.

They wanted them because they were beautiful. They wanted them to be faster and stronger and lighter, Wallner told NBC News.

Related:

Theres plenty of history about horse breeding and its no secret that Arabian stallions were desired and shipped long distances for breeding.

Of particular importance was the trend to import stallions from foreign studs to improve local herds. In central Europe, this practice started in the 16th century with the popularity of Spanish and Neapolitan stallions. Until the end of the 18th century, the Central European horse population was shaped by the introduction of Oriental stallions, they wrote.

A person riding a Lipizzan stallion. They perform in the Spanish Riding School in Vienna. Spanische Hofreitschule Wien

Wallners study shows just how few male lines ended up surviving the process.

Other research has looked at mitochondrial DNA, which females pass down virtually unchanged to their children. This collection of DNA is particularly diverse in horses, demonstrating that many, many mares are ancestors of modern horses.

Now Wallner wants to collect DNA from the remains of ancient horses to see if she can determine when wild horse were first domesticated, and where.

Similar recent studies have shown the surprising

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Newly identified small RNA fragments defend the genome when it’s … – Phys.Org

Posted: at 11:49 pm

June 29, 2017 A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself. Credit: Vossman/ Wikipedia

Our genomes are minefields, studded with potentially damaging DNA sequences over which hundreds of thousands of sentries stand guard. These sentries, called epigenetic marks, attach to the double helix at such spots and prevent the underlying DNA sequences from springing into destructive action.

About half the human genome is composed of these damaging sequences. They are places where ancient viruses and parasitic elements called transposons and retrotransposons have incorporated themselves over the long course of evolution. It's astonishing, then, to consider that during two of the most crucial processes in the life cycle, the sentries are removed, leaving the genome naked. The defenders are quickly welcomed back, but only after an interval in which the epigenetic slate is wiped clean.

Today in Cell, a team from Cold Spring Harbor Laboratory (CSHL) describes its discovery of what might be considered emergency replacements for the sentries, shock troops pressed into service across the genome only during these curiously undefended moments. Specifically, these defenders are protecting the genome in mammalian embryos, at the very early point in their development before they are implanted in the wall of the maternal uterus.

The preimplantation embryo is one of two normal settings in which epigenetic marks are wiped clean before being reinscribed. The other setting is a step in the formation of germline cells - sperm and eggswhich have temporary defenders already known to biology, so-called piwi-interacting RNAs (piRNAs). The research published today, led by first author Andrea Schorn, a postdoctoral investigator in the lab of Rob Martienssen, demonstrates that another species of small RNA performs an analogous genome-defending role in preimplantation embryos during an interval of epigenetic reprogramming. Dr. Martienssen is a CSHL Professor and HHMI-Gordon and Betty Moore Foundation investigator.

The newly identified defenders come in two varieties - RNA fragments consisting of 18 and 22 nucleotides. These RNA fragments, Dr. Schorn discovered, are perfect complements of sequences in retrotransposons that must be engaged in order for the genomic parasites to be activated.

This fact led to the discovery. Schorn scrutinized the contents of mouse embryonic stem cells and found many free-floating RNA fragments 18 nucleotides in length. Computer analysis revealed that their sequences perfectly matched sequences within transfer RNAs. tRNAs are ubiquitous, and are involved in the synthesis of proteins. It has been known for decades that tRNAs are hijacked by long terminal repeat (LTR)-retrotransposons, a portion of their sequence docking at a primer binding site (PBS) and initiating a process that activates the genomic parasite.

"Knowing that LTR retrotransposons need tRNAs to replicate, it was very tempting to believe that these 18-nucleotide tRNA fragments we were seeing in preimplantation embryonic stem cells could interfere with that process," says Schorn. "We think the cell is deliberately chopping up full-length tRNAs into smaller fragments precisely because both tRNAs and the fragments cut from them recognize the PBS. This means the small, tRNA-derived fragments would be able to occupy that site and inhibit retrotransposon replication and mobility," Martienssen explains.

The implications, Martienssen says, are potentially profound. This appears to tell us one way in which the genomes of mammals have tolerated vast numbers of transposons and other parasitic elements, even during periods when the genome is wiped clean of repressive epigenetic marks. "It's plausible that this is a very ancient mechanism that cells have found to not only inhibit retrotransposons but help in protection against viruses as well," Martienssen says.

Explore further: Newly identified small-RNA pathway defends genome against the enemy within

More information: "LTR-Retrotransposon Control by tRNA-Derived Small RNAs" appears online in Cell June 29, 2017.

Journal reference: Cell

Provided by: Cold Spring Harbor Laboratory

Reproductive cells, such as an egg and sperm, join to form stem cells that can mature into any tissue type. But how do reproductive cells arise? We humans are born with all of the reproductive cells that we will ever produce. ...

In plant pollen grains, sperm cells, which carry the genetic material to be passed on to progeny, are cocooned within larger "companion" cells that are called pollen vegetative cells. These companions provide sperm with ...

During embryonic development in humans and other mammals, sperm and egg cells are essentially wiped clean of chemical modifications to DNA called epigenetic marks. They are then held in reserve to await fertilization.

Transfer RNAs (tRNAs) are ancient molecules and indispensable components of all living cells - they are found in all three kingdoms of life i.e., in archaea, bacteria and eukaryotes. In a cell, they are part of the machinery ...

Rotifers are tough, microscopic organisms highly resistant to radiation and repeated cycles of dehydration and rehydration. Now Irina Arkhipova, Irina Yushenova, and Fernando Rodriguez of the Marine Biological Laboratory ...

Much like cancer cells, plant cells grown for a long time outside of their normal milieu, in culture dishes, have highly unstable genomes. Changes in gene activity, or how genes are "expressed," help cells cope with challenging ...

Photosynthesis is one of the most complicated and important processesresponsible for kick-starting Earth's food chain. While we have modeled its more-than-100 major steps, scientists are still discovering the purpose of ...

Whether or not society shakes its addiction to oil and gasoline will depend on a number of profound environmental, geopolitical and societal factors.

The actions of a protein used for DNA replication and repair are guided by electrostatic forces known as phosphate steering, a finding that not only reveals key details about a vital process in healthy cells, but provides ...

Worker and queen honeybees exposed to field realistic levels of neonicotinoids die sooner, reducing the health of the entire colony, a new study led by York University biologists has found.

If aliens sent an exploratory mission to Earth, one of the first things they'd noticeafter the fluffy white clouds and blue oceans of our water worldwould be the way vegetation grades from exuberance at the equator ...

Researchers from the Centre for Ecology & Hydrology (CEH) publish results of a large-scale, field-realistic experiment to assess neonicotinoid impacts on honeybees and wild bees across Europe, in the peer-review journal Science ...

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Gene Testing for Most Effective Drugs Could Help Save Lives – NBCNews.com

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Gene Testing for Most Effective Drugs Could Help Save Lives
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Gene Testing for Most Effective Drugs Could Help Save Lives. Thu, Jun 29. An apparent breakthrough in the field of personalized medicine: people can now test their genetic profiles to see how they might process a variety of drugs from pain relievers to ...

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Gene Medicine Therapy Market Growth Analysis, Share, Demand by Regions, Types and Analysis of Key Players … – MilTech

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In the end Gene Medicine TherapyMarket report provides the main region, market conditions with the product price, profit, capacity, production, supply, demand and market growth rateand forecast etc. Gene Medicine TherapyMarket report also Present new project SWOT analysis, investment feasibility analysis, and investment return analysis.

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Gene Medicine Therapy Market Growth Analysis, Share, Demand by Regions, Types and Analysis of Key Players ... - MilTech

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Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art … – Dove Medical Press

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Marco Solmi,1,2 Andrea Murru,3 Isabella Pacchiarotti,3 Juan Undurraga,4,5 Nicola Veronese,2,6 Michele Fornaro,7,8 Brendon Stubbs,2,911 Francesco Monaco,2 Eduard Vieta,3 Mary V Seeman,12 Christoph U Correll,13,14 Andr F Carvalho2,15

1Neuroscience Department, University of Padua, 2Institute for Clinical Research and Education in Medicine, Padua, Italy; 3Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clnic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 4Department of Psychiatry, Faculty of Medicine, Clnica Alemana Universidad del Desarrollo, 5Early Intervention Program, J. Horwitz Psychiatric Institute, Santiago, Chile; 6National Research Council, Ageing Section, Padua, 7Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University Federico II, Naples, Italy; 8New York State Psychiatric Institute, Columbia University, New York, NY, USA; 9Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 10Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, 11Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK; 12Institute of Medical Science, Toronto, ON, Canada; 13Department of Psychiatry Research, Zucker Hillside Hospital, Northwell Health, Glen Oaks, 14Department of Psychiatry and Molecular Medicine Hempstead, Hofstra Northwell School of Medicine, Hempstead, NY, USA; 15Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Cear, Fortaleza, Cear, Brazil

Abstract: Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole,ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the behavioral toxicity conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. Keywords: antipsychotics, side effects, tolerability, safety, psychosis, psychiatry

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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’50s musical lightens up Bolingbrook summer stage – Chicago Tribune

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Sandwiched between a dense Tennessee Williams play and an ultra-spooky Halloween thriller comes a laugh-a-minute summer musical.

Bolingbrook's Theatre-on-the-Hill is staging "How to Succeed in Business Without Really Trying" July 7-23 at the Bolingbrook Performing Art Center's outdoor stage. Performances are at 8 p.m. Fridays and Saturdays and 7 p.m. Sundays.

The troupe staged "A Streetcar Named Desire" in the spring and this fall plans to do an immersive stage adaptation of "Night of the Living Dead."

Theatre-on-the-Hill President Michael Fudala is directing the musical, which features a score by score by Frank Loesser of "Guys and Dolls" fame. Loesser is a hero of Fudala's, he said.

"It is a wonderfully biting satire of big business that is based on a book of the same name that came out in 1952," he said. "It is all over the top, tongue-in-cheek, politically incorrect. This came out in '61 as a stage play, won seven Tony awards, won a Grammy for best album and won the Pulitzer for drama one of only eight musicals ever to win a Pulitzer. And it happens to be, in my humble opinion, probably the funniest musical ever."

It plays off all the stereotypes we "know and love to hate" in the business world, he said.

"It charts the rise of J. Pierrepont Finch, who starts as a window washer and with the help of this handy little book, 'How to Succeed in Business Without Really Trying,' and rises to become the chairman of the board in a very short period of time," he said.

As Chairman of the Board at the World-Wide Wicket Company, Finch's morally-questionable business practices jeopardize not only his career but also his romance with secretary Rosemary Pilkington (Rachel Banda of Bolingbrook and Claire Diamond of Lockport).

Characters include company boss J. B. Biggley (Andrew Philippides of Bolingbrook), Biggley's nephew Bud Frump (Chris Tinoco of Bolingbrook and Kush Soni of Naperville) and Biggley's mistress Hedy LaRue (Melaura Rice of Bolingbrook and Abby Williams of Aurora). Famous songs include "I Believe in You," "Been a Long Day," and "Brotherhood of Man."

"As usual, we have just a phenomenal cast," Fudala said. "I'm always impressed with the level of talent that we have come out, even for the lesser known (musical) I mean, it was really popular in its day, but it's been 50 years. It was re-done in the '90s with Matthew Broderick and there was a revival in 2011 with Daniel Radcliffe as the main character."

He was inspired to do this show by those revivals, particularly by Rob Ashford's choreography and direction, he said.

"I've loved this show forever. I've done it once in the '90s and (while) I don't like to repeat myself, this one is so good," he said. "It has brilliant singing and brilliant dancing. It's really an ensemble piece."

J. Pierrepont Finch is played by Bolingbrook High School sophomore Spencer Avery of Bolingbrook.

"He came to us a few years back when we did 'Spamalot' and he was still in grade school and his level of maturity and understanding of British humor knocked my socks off," Fudala said. "And in the intervening years, he has really matured vocally as well. I can't say enough about the kid. He is destined to go on to bigger things."

Fudala is anxious for audiences to see the musical. It's the perfect cure for any lingering summertime blues, he said.

"I really thought everyone could use a few laughs and this is funny from beginning to end," he said. "Something lighthearted, something you don't have to think too hard about. It's the funniest musical of all time."

Annie Alleman is a freelance writer for the Naperville Sun.

When: July 7-23

Where: Bolingbrook Performing Arts Center 375 W. Briarcliff, Bolingbrook

Tickets: $17

Information: 630-908-2538; facebook.com/Theatre-on-the-Hill-117023365025544/

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ASK DOG LADY: A crated dog may be a happy dog – The Salem News

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Dear Dog Lady,

I love dogs. In fact, I love dogs so much that I don't own one. I have a house with a small yard, and I refuse to get a dog until I have a yard with space for him to enjoy his life. Unfortunately, you and many of your readers seem intent on having a dog whether it's good for the dog or not.

In a recent column, you responded to a woman whose dog was chewing everything in the house. Your advice to her was to keep the dog confined in a crate, in a room or behind a gate.

Consider the quality of life for this dog that nature designed to run and roam free. He will be severely confined inside a crate, or at best in a room, for the vast majority of his day, with at best an hour of exercise walking on a leash. This is a lifestyle we reserve for our worst criminals in solitary confinement.

A: Your well-reasoned letter makes perfect sense for you and your non-existent dog. However, for other people and their real and beloved pets, your prison scenario isnt the case. Many dogs are quite happy to be contained in crates or cages (the politically incorrect term for dog enclosures). These are the animals safe houses for peaceful, solitary confinement. Crates are also effective house-training tools.

In my response to the woman whose dog chewed everything, you might have also seen the sharp finger wag at the woman who had not properly trained her dog. We humans are responsible for our dogs success. We train them to live with us. We are the dunces if they flunk. Through their domesticated natures, dogs want to please us by fitting in. We should not fail them.

You are to be complimented for deciding your lifestyle cannot support a dog. You have thought it all out and you have made a good decision for you. Others would naturally disagree.

Dear Dog Lady,

All but one of my/our six dogs had been lucky happenings. I found one without having had to search. The latest, a rescue, was a dear but had health problems and the veterinarian couldnt help. I wonder where to begin looking for another? Now that I am old, I hope to find a small animal I will be able to lift without pain, and one that is more couch potato than border collie. Do you advise local shelters? National searches via the web? Newspaper ads? Theres luck, of course.

A: Local shelters are a good place to start, especially if you visit first and tell the staff about the sort of dog you seek. I love your description of more couch potato than border collie, which describes your ideal pet succinctly. If you make a connection with a shelter, perhaps make a donation, they will keep your request in mind. Naturally, theres always luck. Dogs come into peoples lives in the strangest and most wonderful ways. Keep your eyes open. Your heart sounds ready.

Monica Collins offers advice on pets, life and love. Ask a question or make a comment at askdoglady@gmail.com.

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Wikipedia Against Censorship – Harvard Magazine

Posted: at 11:45 pm

If you tried to search for Emma Watsons Wikpedia page in Iran in 2013, you wouldnt have been able to find it; the article was one of 963 blocked by the government. This tidbit about the Harry Potter actress is found in a 2013 University of Pennsylvaniareport on Irans censorship of Wikipedia. Researchers at Harvards Berkman Klein Center for Internet & Society recently built on this publication by analyzing censorship of the site in 15 countries since 2014. In a report published in May, they found that censorship of Wikipedia has declined since then due to the sites new security measures.

In fact, they discovered that only three countries blocked access to parts of Wikipedia during the duration of the study: China and Uzbekistan were blocking the Chinese- and Uzbek-language versions of Wikipedia (read more coverage of censorship in China, and its use of fake social media posts to influence public opinion). Thailand had once blocked the Yiddish versionmost likely a weird misconfiguration, says Justin Clark, a software developer at the center and the principal author of the report. They derived their results partly by analyzing data from the Wikimedia Foundation (Wikipedias parent organization) that showed when people load Wikipedia articles, and partly from 41 servers located in different countries around the world that tried to load Wikipedia and could determine if the website was blocked.

Clark says there are multiple reasons for the changing levels of censorship. The first is Wikipedias transition from HTTP to HTTPS. HTTP (hypertext transfer protocol) guides the way a websites data is sent to a browser. Because the connection is unencrypted, however, other people can intercept that connection and see the data being sent. In HTTPS, the s stands for secure; the major difference between the two protocols is that HTTPS encrypts the data being communicated.

Wikipedias transition affected the way countries could block access, Clark explains. With HTTP, a country could block an individual Wikipedia article. But with HTTPS, the country needs to choose between blocking every article or none. Countries are choosing the latter. As the report states: Russia once again blacklisted Wikipedia over a single cannabis-related article, but the ban was reversed less than 24 hours later.

Monitoring censorship of Wikipedia matters because Wikipedia is one of the most prominent, and most important, sites out there, says Rob Faris, the research director at the center, who also worked on the report. How countries treat Wikipedia, he continues, is indicative of how important Internet freedom is not only to them, but also to the rest of the world. Clark adds that understanding the information controls imposed on the Internet is important for allowing an informed citizenry to emerge.

As the first complete empirical deep dive into incidents of the blocking of Wikipedia projects around the world, Faris says, the report will inform future research as other investigators follow its methods. He also notes that accessing Wikipedia server data is novel. Such research paves the way for examining global Internet outages, Clark says, especially those deliberately caused by countries during elections or protests. He adds that after the study concluded, China blocked access to Wikipedia in additional languages spoken there, and Turkey in all languages, so the Berkman Klein Center will continue to monitor Wikipedia around the world.

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Wikipedia Against Censorship - Harvard Magazine

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