The Week That Wasn’t: Cold Cure, Sickle Cell, Polluted Placenta – Medscape

This week you may have read headlines about a protein that's key to defeating the common cold, an Alabama man cured of a genetic disease, or pollution particles reaching the placenta. Here's why you didn't see those stories covered by Medscape Medical News.

Two teams of California researchers are making headway toward the ever-elusive cure for the common cold. The trick, it seems, is not altering the virus but altering the human cells they infect.

Research teams from Stanford and the University of California, San Francisco, found that the enzyme SETD3 is critical to viral replication. In human cell lines lacking SETD3, replication of enteroviruses was reduced 100- to 1000-fold, depending on the cell type. The researchers attempted to infect the cells with multiple types of enterovirus, including poliovirus and three types of rhinovirus, none of which were able to thrive without SETD3.

"Our results reveal a crucial role of a host protein in viral pathogenesis, and suggest targeting SETD3 as a potential mechanism for controlling viral infections," the authors write in an article published in Nature Microbiology.

This study provides a mechanistic foundation for further drug research, not yet a cure for the common cold. Scientists will need to find a way to block the part of SETD3 the virus needs without hindering the enzyme from performing its other cellular functions. Such a drug could treat the common cold and a host of other enteroviral infections, but since it doesn't yet exist, this is not must-read news for a busy clinician.

After 2 years of gene therapy at the National Institutes of Health, Lynndrick Holmes, a 29-year-old Mobile, Alabama, native born with sickle cell anemia, has been declared sickle cell free, according to news reports. He's one of seven participants in a clinical trial by bluebird bio, a Cambridge, Massachusetts, biotech firm, that finished in February. The therapy, LentiGlobin, involves removing and editing patients' stem cells using a lentiviral vector to produce an engineered form of hemoglobin (HbAT87Q) instead of the problematic S-hemoglobin.

Although Holmes' improvement illustrates the exciting promise of gene therapy for patients with sickle cell, it will take years of monitoring a large group of patients to confirm LentiGlobin as an efficacious, long-term treatment. Clinical trials are ongoing. We decided not to cover an early result from a study that involved one patient and that has not been peer reviewed for publication in the medical literature.

A new study published in Nature Communications reported that soot inhaled by people who are pregnant can make its way into but maybe not across the placenta. Research has previously connected air pollution to adverse birth outcomes, including premature birth. In this study, Belgian researchers used a scanning technique called femtosecond pulsed illumination to illuminate black carbon in placenta samples and quantify it.

They analyzed 20 samples: 10 placentas from mothers exposed to high levels of pollution, and 10 from mothers exposed to lower levels of pollution. The researchers found that higher exposure to black carbon during pregnancy corresponded to higher concentrations of black carbon in the placenta. Besides the small sample size, the study didn't show any evidence that black carbon crosses the placenta or affects the fetus. Although the study introduces an interesting methodology, it doesn't change how clinicians should counsel pregnant women, so we decided not to cover it.

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The Week That Wasn't: Cold Cure, Sickle Cell, Polluted Placenta - Medscape

Bluebird Bio reveals further encouraging data for CALD gene therapy – PMLiVE

Last year, Bluebird Bio claimed anFDA breakthrough designation for its Lenti-D gene therapy for cerebral adrenoleukodystrophy (CALD) it has now revealed additional data to support a fast-track approval.

The updated results from the biotechs phase 2/3 Starbeam study were revealed at the European Paediatric Neurology Society (EPNS) congress in Athens, Greece.

CALD is caused by progressive destruction of the myelin sheath that surrounds nerves responsible for thinking and muscle control, resulting in a relentless deterioration that typically leads to a vegetative state or death within a few years of diagnosis. The condition mostly affects young males, with the majority of patients dying before the age of ten.

The only current treatment for the disease is stem cell transplant, but it carries a significant risk from the high-dose chemotherapy used to prepare patients for the procedure. Other potential complications include graft-versus-host (GvHD) disease, when the transplanted cells recognise the recipients cells as foreign and attack them.

Bluebird's treatment works by extracting patients' stem cells and modifying them with Lenti-D. They are then infused back into the patient, where they thenhave the potential to develop into multiple cell types that can produce a functional version of the ALD protein that is lacking in CALD.

Of the patient population involved in the study, as of 25 April 2019, 15 had completed the trial and are enrolled in a long-term follow-up study, 14 are currently still on-study, and three are no longer on-study.

The primary efficacy endpoint of the study is the number of patients who are alive and free of MFDs at month 24 MFDS are the six severe disabilities commonly attributed to CALD, which have the most severe effect on a patients ability to function independently.

The study demonstrated that of those patients who have or would reach 24 months of followup and complete the study, 88% continue to be MFD-free and alive. The 14 patients currently on study have less than 24 months of follow-up and have so far shown no evidence of MFDs.

Out of the 32 treated patients, three did not or will not meet the primary efficacy endpoint, two patients withdrew from the study and one experienced rapid disease progression early, which lead to MFDs and death.

The primary safety endpoint the number of patients experiencing GvHD by month 24 was also met. According to Bluebird, no events of acute or chronic GvHD were reported posttreatment and there were no reports of graft failure, cases of insertional oncogenesis or replication competent lentivirus. There were three adverse events potentially related to treatment of Lenti-D, but these resolved using standard measures.

Lenti-D is Bluebirds lead gene therapy programme,but the company has also made significant progress with its Celgene-partnered CAR-T cancer immunotherapy programme, reporting dramatic responses with its multiple myeloma candidatebb2121 last December.

It also received approval for its gene therapy Zynteglo earlier this year. The one-time gene therapy has been approved for patients 12 years and older with transfusion-dependent -thalassaemia (TDT), and has been shown in a series of small studies to free a majority of patients from the need to have regular blood transfusions.

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Bluebird Bio reveals further encouraging data for CALD gene therapy - PMLiVE

Rays’ Tommy Pham: Hampered by multiple injuries – CBSSports.com

Pham, who went 0-for-5 in Tuesday's loss to the Dodgers, is significantly hampered by hand and elbow injuries that would sideline him were the Rays not in the playoff hunt, Marc Topkin of the Tampa Bay Times reports. "He wants to be out there, we want him out there, we've got to continue a do a good job of managing his workload, the treatment and rehab everything,'' manager Kevin Cash said.

The veteran outfielder says his right hand issue, which he originally sustained Aug. 9 while sliding, has shown some improvement of late but still leaves him at less than full strength. Meanwhile, his elbow problem has officially been diagnosed as a flexor strain, and Pham is planning to address it with platelet-rich plasma injections and stem cell treatments this offseason. In a testament to his toughness, Pham has remained a viable contributor during the most critical time of the season, as he was hitting .340 with one home run and eight RBI over the 13 games prior to Tuesday's blanking.

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Rays' Tommy Pham: Hampered by multiple injuries - CBSSports.com

Kourtney Kardashian Got Scalp Injections For A Bald Spot – Glamour UK

With the return of their reality show, Keeping Up with the Kardashians, now on Season 17, the drama levels are as high as ever. The latest kerfuffle is all about the eldest Kardashian sibling, Kourtney and her hair, or in this case, lack of.

It seems a high ponytail that Kourtney wore at an event in New York was so tight it ended up pulling and leaving her with a bald spot on the top of her head.

The highlight of the episode came from her sister, Kim Kardashian, commenting on Kourtneys growing bald spot. Oh my god, Im afraid for your life, reacts Kim.

Kourtney later went on to see Beverly Hills Plastic Surgeon, Dr Jason Diamond, to help her out. Today Im getting PRP (platelet-rich plasma), which is where they take your blood and spin it and they use your plasma and they inject it in my head for my hair to grow back, she said.

The treatments intentions are focused on rebuilding, and so its a great option as hair loss remedies go. The functions of PRP include: "helping repair blood vessels, promote cell growth and wound healing, and stimulate collagen production," according to medical centre, The Cleveland Clinic.

PRP treatment for hair loss is on the rise, and is actually a lot simpler than you might think. The plasma is directly injected into the patients hair follicles in a process that takes no more than 10 minutes, according to Jeffrey Rapaport, MD, FAAD, a board-certified dermatologist in private practice in New Jersey in the USA.

Since the procedure involves only minimal discomfort, patients typically do not require any numbing or downtime following therapy he says. Youll start to see improvements after 2-3 months.

Its the quick and effective treatment for hair loss and like Kourtney, it could possibly be the avenue to take for you.

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Kourtney Kardashian Got Scalp Injections For A Bald Spot - Glamour UK

Bell, Marte hope to return before season’s end – MLB.com

PITTSBURGH -- The Pirates havent given up hope that theyll see first baseman Josh Bell and center fielder Starling Marte on the field before the regular season ends. More than anything, thats because Bell and Marte -- two of the Bucs best players this year -- wont give up on

PITTSBURGH -- The Pirates havent given up hope that theyll see first baseman Josh Bell and center fielder Starling Marte on the field before the regular season ends. More than anything, thats because Bell and Marte -- two of the Bucs best players this year -- wont give up on the idea of playing again in 2019.

Pirates director of sports medicine Todd Tomczyk said on Wednesday that both players are hoping to return next week. Neither will play Wednesday or Thursday against the Mariners, and neither is likely to play this weekend in Milwaukee.

But there is still a chance that Bell (left groin strain) and/or Marte (sprained left wrist) could return during the Pirates final homestand beginning Tuesday against the Cubs and Reds. Bell, who is three homers shy of 40, has been sidelined since playing in Friday's game at Wrigley Field.

Josh is a competitor. He wants to finish strong. He wants to add to this career year for himself, Tomczyk said. At the same time, we as an organization, we as a medical staff, need to do whats best for Josh both short- and long-term.

Marte has been able to serve as a pinch-runner, and it may be possible for him to play defense. But he's not started a game since Sept. 8. Marte has tried to test his wrist, within reason, by progressing from range-of-motion work to strength exercises to gripping a bat.

Starling wants to be out there. He wants to compete, Tomczyk said. But what makes sense for them, both short- and long-term?

Catcher Jacob Stallings (back spasms) hasnt started since last Thursday, but he could return soon, Tomczyk said. Stallings went through a pregame workout on Wednesday to assess his availability off the bench.

Trainers room

Tomczyk provided updates on several rehabbing players who were previously ruled out for the season.

Right-handers Chad Kuhl and Edgar Santana, nearing the end of their year-long Tommy John rehabs, have each thrown a live batting practice session in Bradenton, Fla. Within the next 10 days, they hope to pitch a simulated game or two before beginning a relatively normal offseason routine. Both are expected to be ready for Spring Training.

Right fielder Gregory Polanco (left shoulder inflammation) has had two of his three scheduled platelet-rich plasma injections. He will receive another injection next week then remain with the Pirates for the final week of the season.

Reliever Nick Burdi (neurogenic thoracic outlet syndrome) had surgery last week to clear fascial tissue irritating a nerve in his right forearm. He wont throw for six to eight weeks, Tomczyk said, but Burdi should have a normal offseason as long as hes ready to throw in late December or early January.

Outfielder Jason Martin (dislocated left shoulder) has begun strengthening exercises at his home.

Right-hander Jameson Taillon, who is out until 2021 after undergoing Tommy John surgery, will be able to remove his post-surgical brace in the coming days before beginning formal physical therapy.

Awards season

The Pittsburgh chapter of the Baseball Writers' Association of America announced its annual awards on Wednesday afternoon. Bell received the Roberto Clemente Award as the Pirates MVP. Left-hander Steven Brault received the Chuck Tanner Award, given to the player who is most cooperative with the media.

The Pirates on Wednesday named Class A Greensboro first baseman Mason Martin their Minor League Player of the Year and right-hander James Marvel, who is currently in Pittsburghs six-man rotation, their Minor League Pitcher of the Year.

Adam Berry has covered the Pirates for MLB.com since 2015. Follow him on Twitter and Facebook and read his blog.

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Bell, Marte hope to return before season's end - MLB.com

Global Stem Cell Therapy Market Analysis and Forecast, 2019-2029: Focus on Treatment Type, Cell Source, Indication,11 Countries’ Data, and Competitive…

DUBLIN, Sept. 20, 2019 /PRNewswire/ -- The "Global Stem Cell Therapy Market: Focus on Treatment Type, Cell Source, Indication,11 Countries' Data, and Competitive Landscape - Analysis and Forecast, 2019-2029" report has been added to ResearchAndMarkets.com's offering.

Research and Markets Logo

Key Questions Answered in this Report:

The Global Stem Cell Therapy Industry Analysis projects the market to grow at a significant CAGR of 27.99% during the forecast period, 2019-2029.

The global stem cell therapy market growth has been primarily attributed to the major drivers in this market such as the increasing prevalence of chronic diseases, rising number of clinical trials for cell-based therapy, steady investment, and consolidation in the regenerative medicine market, and favorable regulatory environment.

The market is expected to grow at a significant growth rate due to the opportunities that lie within its domain, which include product approvals, declining product price, and increasing adoption rate.

However, there are significant challenges which are restraining the market growth. High treatment cost, the exorbitant cost required for set up, and ethical considerations related to the use of embryonic stem cells are the challenges faced by the market.

Key Topics Covered:

Executive Summary

1 Product Definition

2 Scope of the Work2.1 Overview: Report Scope2.2 Segmentation of the Global Stem Cell Therapy Market2.3 Assumptions and Limitations2.4 Key Questions Answered in the Report2.5 Base Year and Forecast Period

3 Research Methodology3.1 Overview: Report Methodology

4 Global Stem Cell Therapy Market4.1 Market Overview4.2 Introduction of Stem Cell Therapy4.3 Application of Stem Cells in Different Therapeutic Areas4.4 Market Dynamics4.5 Global Market Scenario4.6 Assumptions and Limitations

5 Competitive Landscape5.1 Overview5.2 Key Developments and Strategies5.2.1 Collaborations, and Partnerships5.2.2 Approvals and Clinical Studies5.2.3 Funding5.2.4 Business Expansions5.2.5 Product Launches and Developments5.2.6 Mergers and Acquisitions5.2.7 Others5.3 Market Share Analysis

6 Industry Insights6.1 Regulatory Scenario6.2 Regulatory Designations6.3 Expedited Designation Vs. Traditional Approval Timelines:6.4 Regulatory Challenges:

7 Global Stem Cell Therapy Market (by Treatment Type)7.1 Overview7.2 Key Trends of the Global Stem Cell Therapy Market (by Treatment Type)7.3 Autologous Treatment7.4 Allogenic Treatment

8 Global Stem Cell Therapy Market (by Cell Source)8.1 Overview8.2 Key Trends of the Global Stem Cell Therapy Market (by Cell Source)8.3 Bone Marrow and Peripheral Blood8.4 Adipose Tissue8.5 Placenta and Umbilical Cord8.6 Embryo8.7 Others

9 Global Stem Cell Therapy Market (by Indication)9.1 Overview9.2 Key Trends of the Global Stem Cell Therapy Market (by Indication)9.3 Orthopaedic and Dental9.4 Wounds and Injuries9.5 Cardiology and Neurology9.6 Immunology and Inflammatory9.7 Oncology and Metabolism9.8 Others

10 Global Stem Cell Therapy Market (by Region)10.1 Overview10.2 North America10.2.1 Overview10.2.2 U.S.10.2.3 Canada10.3 Europe10.3.1 Overview10.3.2 Germany10.3.3 U.K.10.3.4 France10.3.5 Italy10.3.6 Rest-of-Europe10.4 Asia-Pacific10.4.1 Overview10.4.2 Japan10.4.3 Australia10.4.4 China10.4.5 South Korea10.4.6 India10.4.7 Rest-of-Asia-Pacific10.5 Rest-of-the-World10.5.1 Overview10.5.2 Middle East and Africa10.5.3 Latin America

11 Company Profiles

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For more information about this report visit https://www.researchandmarkets.com/r/nyrlw5

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

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4 Stocks to Focus on Global Biotechnology Reagents Market – Yahoo Finance

Advancement in the field of biotechnology along with growing need of reagents in drug testing and stem cell research is pushing demand for biotechnology reagents worldwide. Therefore it would be prudent to take a look at a couple of stocks operating in the segment that are poised to gain from the trend.

Promising Growth for Biotechnology Reagents

The global biotechnology reagents market is poised for impressive growth, according to a reportby research firm Research and Markets. Increasing research on stem cells is a major factor pushing this industry. Per the research firm, the industry is set to witness a compound annual growth rate of about 9% during the forecast period 2019-2023.

Trends Driving Demand for Reagents

The biotechnology sector has been doing remarkably well this year, despite the lackluster performance by the broader healthcare sector. In fact, the SPDR S&P Biotech ETF (XBI) has outperformed the broader Health Care Select Sector SPDR Fund (XLV) on a year-to-date basis. The former has increased 15.2% while the latter has only moved 6.2% higher.

The increasing use of biotechnology reagents is a prominent reason behind the significant growth of the biotechnology sector. Reagents are a crucial element in the area of drug discovery and these have high demand in research, therapeutics and commercial applications.

This is why biotechnology reagents have attracted heavy investments in research and development lately and will continue to do so. In fact, reagents have a rather broad spectrum of application in stem cell research. These are used as biomarkers to visualize cell and tissue lines.

Stem cell research is growing by leaps and bounds, thanks to its many benefits that include treatment of an array of diseases. Therefore with the rise in stem cell research, demand for reagents is poised to rise as well.

Our Choices

We have therefore chosen four stocks that are revolutionizing the global biotechnology reagents market which investors could consider in their portfolio. All of these stocks carry a Zacks Rank #2 (Buy) or 3 (Hold).

Agilent Technologies, Inc. A is an analytical laboratory instrument manufacturing company. The companys Dako brand offers high-quality reagents, diagnostic antibodies, instruments and software solutions that assist in the treatment of cancer patients.

Agilent Technologies carries a Zacks Rank #2. The companys stock price has outperformed the Zacks Electronics - Testing Equipmentmarket on an annualized basis (+10.4% vs +0.6%). The Zacks Consensus Estimate for its current-year earnings has risen 1% over the past 60 days. You can seethe complete list of todays Zacks #1 Rank stocks here.

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Danaher Corporation DHR is a conglomerate and manufacturer of medical products. The companys life sciences wing offers sophisticated equipment for biological research.

Danaher carries a Zacks Rank #2. The companys stock price has already outperformed the Zacks Diversified Operationsmarket on a year-to-date basis (+34.9% vs -5.2%). The Zacks Consensus Estimate for its current-year earnings has risen 0.2% over the past 60 days.

Thermo Fisher Scientific Inc.TMO is a manufacturer of analytical instruments, equipment and reagents.

Thermo Fisher Scientific carries a Zacks Rank #3. The companys stock price has outperformed the Zacks Medical - Instrumentsmarket on a year-to-date basis (+21.3% vs -5.7%). The Zacks Consensus Estimate for its current-year earnings has risen 0.4% over the past 60 days.

General Electric Companys GE life sciences wing operates in the cell and gene therapy industry. The company offers end-to-end solutions that include software and equipment that drive uniformity to dependable reagents.

General Electric carries a Zacks Rank #3. The stock price has outperformed the Zacks Diversified Operationsmarket on a year-to-date basis (+24.5% vs +20.3%). The Zacks Consensus Estimate for its current-year earnings has risen 1.6% over the past 60 days.

Just Released: Zacks 7 Best Stocks for Today

Experts extracted 7 stocks from the list of 220 Zacks Rank #1 Strong Buys that has beaten the market more than 2X over with a stunning average gain of +24.6% per year.

These 7 were selected because of their superior potential for immediate breakout.

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Want the latest recommendations from Zacks Investment Research? Today, you can download 7 Best Stocks for the Next 30 Days. Click to get this free reportDanaher Corporation (DHR) : Free Stock Analysis ReportGeneral Electric Company (GE) : Free Stock Analysis ReportThermo Fisher Scientific Inc. (TMO) : Free Stock Analysis ReportAgilent Technologies, Inc. (A) : Free Stock Analysis ReportTo read this article on Zacks.com click here.Zacks Investment Research

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4 Stocks to Focus on Global Biotechnology Reagents Market - Yahoo Finance

Editing Muscle Stem Cells with CRISPR Treats Mouse Model of Muscular Dystrophy – DocWire News

A research team from the University of Missouri School of Medicine has recently used CRISPR to edit a genetic mutation that contributes to Duchenne muscular dystrophy (DMD). This rare and debilitating genetic disorder is characterized by loss of muscle mass and physical impairment. By using this powerful gene-editing technology, these MU School of Medicine researchers have successfully treated mouse models of the disease. This work was published this summer in the journal Molecular Therapy.

Those with DMD possess a specific mutation that hinders the production of the dystrophin protein, which contributes to the structural integrity of muscle tissue. In the absence of this protein, the muscle cells weaken and eventually die. Pediatric patients with the condition often lose their ability to walk and can even lose the function of muscles that are essential for respiration and heart contractions.

Research has shown that CRISPR can be used to edit out the mutation that causes the early death of muscle cells in an animal model, explained senior author Dongsheng Duan, PhD, Margaret Proctor Mulligan Professor in Medical Research in the Department of Molecular Microbiology and Immunology at the MU School of Medicine. However, there is a major concern of relapse because these gene-edited muscle cells wear out over time. If we can correct the mutation in muscle stem cells, then cells regenerated from the edited stem cells will no longer carry the mutation. A one-time treatment of the muscle stem cells with CRISPR could result in continuous dystrophin expression in regenerated muscle cells.

Working alongside other researchers from MU, the National Center for Advancing Translational Sciences, Johns Hopkins School of Medicine and Duke University, Duan aimed to genetically modify muscle stem cells in mice. These scientists first edited the gene using an adeno-associated virus known as AAV9. Being this specific viral strain was recently approved by the FDA in treating spinal muscular atrophy, the researchers saw it as a viable candidate in treating DMD.

We transplanted AAV9 treated muscle into an immune-deficient mouse, said lead author Michael Nance, an MD-PhD program student in Duans lab. The transplanted muscle died first then regenerated from its stem cells. If the stem cells were successfully edited, the regenerated muscle cells should also carry the edited gene.

Upon analyzing the regenerated muscle tissue, the researchers found that its cells contained the edited gene, supporting their reasoning. The team then tested whether the muscle stem cells in mice with DMD could be genetically edited using CRISPR. These findings also supported their hypothesis, with the stem cells in the diseased tissue sustaining these edits and the regenerated cells successfully producing dystrophin.

This finding suggests that CRISPR gene editing may provide a method for lifelong correction of the genetic mutation in DMD and potentially other muscle diseases, explained Duan. Our research shows that CRISPR can be used to effectively edit the stem cells responsible for muscle regeneration. The ability to treat the stem cells that are responsible for maintaining muscle growth may pave the way for a one-time treatment that can provide a source of gene-edited cells throughout a patients life.

Duan and colleagues hope that future research will help this stem cell CRISPR therapy become a revolutionary treatment for children with DMD.

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Editing Muscle Stem Cells with CRISPR Treats Mouse Model of Muscular Dystrophy - DocWire News

Testing chemicals for birth defects using stem cells, not mice – UC Riverside

Researchers at the University of California, Riverside, are part of an ambitious plan at the U.S. Environmental Protection Agency, or EPA, to eliminate animal testing by 2035. Their contribution: developing a way to test whether chemicals cause musculoskeletal birth defects using lab-grown human tissue, not live animals.

Nicole zur Nieden, an associate professor of molecular, cell, and systems biology, and David Volz, an associate professor of environmental toxicology, are both experts on alternatives to regulatory toxicity testing and chemicals policy and regulation. They received $849,811 to grow human stem cells into bone-like tissue to test industrial and environmental chemicals that might interfere with fetal growth.

Birth defects that affect musculoskeletal tissues can be caused by chemical ingredients in pesticides, fungicides, paints, and food additives. Harmful chemicals must be identified through testing in order to be regulated. Currently, this testing is done on live animals, usually rodents such as mice.

The UC Riverside project, led by zur Nieden, will stimulate human pluripotent stem cells, which have the capacity to develop into any sort of cell, with agents that direct them to form bone cells. The cells will pass through the same developmental stages and be subject to the same molecular cues as in a human embryo. The researchers will expose the cells to selected chemicals at critical junctures, then assess them using advanced imaging and next-generation sequencing techniques.

Bone cells can develop through three different pathways. zur Nieden will use chemicals known to affect specific routes of bone development to look for patterns in how the chemicals affect these origins. The patterns will serve as blueprints for testing unknown chemicals. Next, the researchers will test unknown chemicals and compare them to previously compiled libraries of compounds that have already been tested in animals to see how accurate the petri dish, or in vitro, tests are for assessing risk.

A hallmark feature of bone-forming cells is that they make a bony matrix out of little crystals called hydroxyapatite, which eventually form calcium phosphate, the white stuff on the surface of all bones. Cost-saving visual analysis can help identify defects in calcium.

Calcium crystals appear white when viewed with your eyes, said zur Nieden. But when you view the cultures using phase contrast microscopy, it inverts the light so the normal crystals appear black. Abnormal crystals will have more white and shades of gray. You can use an image analysis algorithm to measure the blackness in images to determine if the calcium has formed correctly or not.

Scientists have known for a long time that animals differ from humans in important developmental and physiological ways, and that animal test results are not always reliable for people. Moreover, animal research is expensive and time-consuming, as well as increasingly untenable for ethical reasons. Non-animal alternatives have been in development for nearly 25 years, and some are already standard.

To the general public, the EPAs announcement seemed to come out of nowhere, said Volz, whose lab will sequence messenger RNA in chemical-exposed bone cells from zur Niedens lab to look for changes in gene expression. It didnt happen overnight. That train has already left the station.

Volz said the EPAs Science to Achieve Results Program, through which UC Riverside received the new grant, has been funding research on animal alternatives for more than 10 years.

The EPAs plan to end animal testing by 2035 follows up on earlier changes to the Toxic Substances Control Act, or TSCA, enacted in 1976. TSCA authorizes the EPA to regulate chemicals found in consumer products such as cleaning agents, furniture, paint, carpeting, clothing, and other consumer goods. Regulation under TSCA does not apply to chemicals in food, drugs, cosmetics, and pesticides, which are regulated under different laws.

Even after TSCA, thousands of common chemicals used in everything from plastic to sunscreen have never been tested for safety in humans. In 2016, Congress passed the Lautenberg Chemical Safety Act, amending TSCA to close the loophole for industrial chemicals. The law mandated the EPA to evaluate existing chemicals with clear and enforceable deadlines, and to develop risk-based chemical assessments. It promoted the use of non-animal testing methods, a move sought by both industry and animal rights groups.

The new EPA plan introduces an aggressive timeline for ramping up development of non-animal tests that can accurately predict toxicity in humans. Volz said the United States lags behind some other countries around the world, which have already greatly reduced animal testing. He said he interacts with fewer and fewer students interested in research involving animal experiments, and that our culture is shifting toward a desire to reduce animal suffering.

But neither Volz nor zur Nieden are sure animal testing can ever be replaced completely, a position echoed by the EPA memo, which states that after 2035, animal tests will be approved on a case-by-case basis. Some chemicals, for example, are not directly toxic to cells but become toxic after they are metabolized in the body.

If your result is that the chemical does not interfere with a human stem cell developing in a dish, how sure can you be thats not really happening in humans? The best way we have to assess that is an animal experiment, zur Nieden said. At the same time, we want to do this in an appropriate way. We need to think about, is this really necessary? Can we look at the question some other way?

zur Nieden thinks we need a tiered system, with in vitro tests weeding out the most toxic chemicals first, and animal tests used where in vitro tests dont reveal toxicity.

If you cannot fully replace an animal test with an in vitro method, you can at least decrease suffering of the animal. If you think about a highly toxic chemical that has effects on the mom as she is exposed during pregnancy as well as on the developing embryos, if you can use an in vitro test system to find all these strong toxic chemicals, you will not need to test them in an animal, she said.

Previous versions of the test system zur Nieden will use for the new musculoskeletal research have been able to identify embryotoxic chemicals for other tissues, such as heart tissue, with almost 100% accuracy.

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Testing chemicals for birth defects using stem cells, not mice - UC Riverside

Mutant Tau Stiffens Axon Cytoskeleton Near Soma – Alzforum

20 Sep 2019

Changes to the microtubule-binding protein tau cause it to fall off these struts and aggregate, forming neurofibrillary tangles. But is that the reason for tau toxicity? A study in the September 18 Neuron suggests that V337M tau, a variant associated with frontotemporal dementia, causes morphological changes at the base of the axon. Scientists led by Li Gan, then at the Gladstone Institute of Neurological Disease, San Francisco, found that neurons derived from patients with the mutation are hyperexcitable. They had unusually short, unresponsive axon initial segments (AIS), which usually initiate action potentials and steer neuronal plasticity. Gans results suggest that this FTD mutation robs neurons of a mechanism for maintaining electrical homeostasis.

The initiation of axon potential firing has received little attention in neurodegeneration research, said Jrgen Gtz, What I really like about this paper is the use of complementary techniques to mechanistically dissect the effect of FTD mutant tau on neuronal function.

Because many FTD-causing tau mutations occur in the microtubule-binding domain, scientists believed they lead to disease by weakening microtubules (Rossi and Tagliavini, 2015; Hong et al., 1998). However, studies have mostly found that removing tau leaves microtubules intact (Roberson et al., 2007). On the other hand, FTD patients have hyperexcitable neurons, seizures, and highly synchronized neuronal networks (Beagle et al., 2017). Could the mutant protein alter neuronal excitability in some way?

Plasticity Deficit. In iPSC-derived wild-type neurons (left) the axon initial segment (green) is long initially (top)and shrinks after chronic depolarization with KCl (bottom). In neurons with V337M tau (right), the AIS starts out and remains short. [Courtesy of Sohn et al., 2019.]

To find out, first author Peter Dongmin Sohn and colleagues focused on the AIS. The closest part of the axon to the soma, the AIS contains a high concentration of voltage-gated ion channels and triggers action potentials. It regulates neuronal excitability by lengthening or shrinking in response to less or more activity, respectively. This remodeling relies on a reorganization of the cytoskeleton, in particular ankyrin G. Staining for AnkG revealed that the AIS shrank, making it less excitable, when Sohn and colleagues depolarized wild-type neurons for two days (see image at left). In contrast, in iPSC-derived neurons from a patient with the V337M tau mutation, the AIS was about 20 percent shorter to begin with, and chronic depolarization did not change its length. This suggested the region was less plastic. If the researchers used CRISPR-Cas9 to correct the mutation, then the initial length of the AIS and its plasticity matched that of wild-type cells.

The researchers next compared electrophysiological properties of mutant and control neurons. In culture, neurons carrying mutant tau more often fired in synch, having longer network bursts containing more spikes, than did wild-type neurons. This suggested the mutated tau caused a type of hyper-synchrony. After a two-day depolarization, these neurons fired six times faster, while the rate stayed steady in isogenic controls.

To find out how the mutant tau might be interfering with homeostatic control of neuronal excitability, the authors examined tau binding partners in the AIS. Tau interacts with end-binding protein 3 (EB3), another component of the AIS cytoskeleton (Sayas et al., 2015). EB3 stabilizes the AIS by linking microtubules to AnkG.

Getting a Grip. At left, wild-type tau (blue) binds EB3 (green), which anchors AnkG (yellow) to microtubules (white). To the right, mutant tau (red) binds more tightly to EB3 and clamps it in place, making the AIS rigid and unchanging. [Courtesy of Sohn et al., 2019.]

Sohn and colleagues determined that tau binds EB3 directly, and that V337M tau does so more tightly. In tau V337M neurons, EB3 levels in the AIS were 40 percent higher than in wild-type. Whats more, rather than distributing throughout the AIS cytosol, EB3 gathered just under the plasma membrane, corralling AnkG. In all, the data suggested that through its grip on EB3, tau concentrated the protein in the AIS and immobilized AnkG such that it couldnt respond to electrical activity.

Would removing EB3 rescue plasticity in V337M neurons? Suppressing translation with siRNA, Sohn reduced levels by 80 percent, which restored both the length and plasticity of the AIS. Reducing mutant tau in these neurons by 40 percent had similar effectsEB3 levels shrank in the AIS, and plasticity was restored.

Our study provides a completely different explanation for why tau is toxicnot because it forms aggregates, but because it binds to cytoskeletal proteins important for plasticity and makes rigid structures, Gan, who has since moved to Weill Cornell Medicine, New York, told Alzforum. This is an unexpected aspect of tau pathology. Gan plans to test whether this is true in other FTD mutations, and wonders about tau-induced hyperexcitability in Alzheimers disease, in which tau is not mutated.

This study provides an important demonstration of the utility of human iPSC models to reveal changes in neuroplasticity that may lead to disruption of brain circuitry over the course of disease, wrote Stephen Haggarty, Massachusetts General Hospital, Boston, to Alzforum. [It] provides further validation of therapeutic strategies seeking to reduce expression of pathological forms of tau.

Not all tau mutations work in this manner. In the September 19 Stem Cell Reports, researchers led by Hideyuki Okano of Keio University, Tokyo, report a different effect of the R406W. This mutation lies outside the microtubule-binding domain, but has nevertheless been reported to impede tau binding to those intracellular rails. Also using patient-derived neurons, first author Mari Nakamura and colleagues found that R406W tau mislocalizes to dendrites, as was seen before in cell and animal overexpression models (Thies and Mandelkow, 2007; Jan 2011 news). There it disrupts mitochondrial transport and causes axonal degeneration.

In neither study do the cell models rely on overexpression of the mutant tau protein, thereby overcoming issues often inherent to artificially engineered systems, Haggarty wrote.Gwyneth Dickey Zakaib

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Mutant Tau Stiffens Axon Cytoskeleton Near Soma - Alzforum