FDA Approves First Drug For Spinal Muscular Atrophy

 

Spinal muscular atrophy (SMA), is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. SMA types 1 through 4 all result from a single known cause – a deficiency of a protein called SMN, for “survival of motor neuron.“ Deficiency of SMN protein occurs when a mutation is present in both copies of the SMN1 gene one on each chromosome 5. When SMA symptoms are present at birth or by the age of 6 months, the disease is called type 1 SMA (also called infantile onset or Werdnig-Hoffmann disease). Babies typically have generalized muscle weakness, a weak cry and breathing distress. They often have difficulty swallowing and sucking, and don’t reach the developmental milestone of being able to sit up unassisted. Typically these babies have two copies of the SMN2 gene, one on each chromosome 5. Over half of all new SMA cases are SMA type 1. When SMA has its onset between the ages of 7 and 18 months and before the child can stand or walk independently, it is called type 2 or intermediate SMA. Children with type 2 SMA generally have at least three SMN2 genes. Late-onset SMA (also known as types 3 and 4 SMA, mild SMA, adult-onset SMA and Kugelberg-Welander disease) results in variable levels of weakness. Type 3 SMA has its onset after 18 months, and children can stand and walk independently, although they may require assistance. Type 4 SMA has its onset in adulthood, and people are able to walk during their adult years. People with types 3 or 4 SMA generally have between four and eight SMN2 genes, from which a fair amount of full-length SMN protein can be produced.

 

The FDA has approved Spinraza (nusinersen) for use across the range of SMA patients. Spinraza is the first drug approved to treat children and adults with SMA, is administered by injection into the fluid surrounding the spinal cord. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.

 

The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible. A total of 82 of the 121 treated patients were eligible for this analysis. Results showed that 40% of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did. Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.

 

The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.

 

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The sponsor is also receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.

 

Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.

 

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Under the Weather  –  Recipes Resume Next Week

 

 

From Our Table to Yours !

 

Bon Appetit!

 

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International research team presents findings from frozen ‘climate archive’ of Antarctica

Date:January 5, 2017Source:University of BonnSummary:About 15,000 years ago, the ocean around Antarctica has seen an abrupt sea level rise of several meters. It could happen again.

 

Iceberg in the southeastern Weddell Sea region.
Credit: Photo: Dr. Michael Weber

 

 

About 15,000 years ago, the ocean around Antarctica has seen an abrupt sea level rise of several meters. It could happen again. An international team of scientists with the participation of the University of Bonn is now reporting its findings in the magazine Scientific Reports.

University of Bonn’s climate researcher Michael E. Weber is a member of the study group. He says, “The changes that are currently taking place in a disturbing manner resemble those 14,700 years ago.” At that time, changes in atmospheric-oceanic circulation led to a stratification in the ocean with a cold layer at the surface and a warm layer below. Under such conditions, ice sheets melt more strongly than when the surrounding ocean is thoroughly mixed. This is exactly what is presently happening around the Antarctic.

The main author of the study, the Australian climate researcher Chris Fogwill from the Climate Change Research Center in Sydney, explains the process as follows: “The reason for the layering is that global warming in parts of Antarctica is causing land based ice to melt, adding massive amounts of freshwater to the ocean surface. At the same time as the surface is cooling, the deeper ocean is warming, which has already accelerated the decline of glaciers in the Amundsen Sea Embayment.” It appears global warming is replicating conditions that, in the past, triggered significant shifts in the stability of the Antarctic ice sheet.

To investigate the climate changes of the past, the scientists are studying drill cores from the eternal ice. Layer by layer, this frozen “climate archive” reveals its secrets to the experts. In previous studies, the scientists had found evidence of eight massive melting events in deep sea sediments around the Antarctic, which occurred at the transition from the last ice age to the present warm period. Co-author Dr. Weber from the Steinmann Institute of the University of Bonn says: “The largest melt occurred 14,700 years ago. During this time the Antarctic contributed to a sea level rise of at least three meters within a few centuries.”

The present discovery is the first direct evidence from the Antarctic continent which confirms the assumed models. The research team used isotopic analyzes of ice cores from the Weddell Sea region, which now flows into the ocean about a quarter of the Antarctic melt.

Through a combination with ice sheet and climate modeling, the isotopic data show that the waters around the Antarctic were heavily layered at the time of the melting events, so that the ice sheets melted at a faster rate. “The big question is whether the ice sheet will react to these changing ocean conditions as rapidly as it did 14,700 years ago,” says co-author Nick Golledge from the Antarctic Research Center in Wellington, New Zealand.


Story Source:

Materials provided by University of Bonn. Note: Content may be edited for style and length.


Journal Reference:

  1. C. J. Fogwill, C. S. M. Turney, N. R. Golledge, D. M. Etheridge, M. Rubino, D. P. Thornton, A. Baker, J. Woodward, K. Winter, T. D. van Ommen, A. D. Moy, M. A. J. Curran, S. M. Davies, M. E. Weber, M. I. Bird, N. C. Munksgaard, L. Menviel, C. M. Rootes, B. Ellis, H. Millman, J. Vohra, A. Rivera, A. Cooper. Antarctic ice sheet discharge driven by atmosphere-ocean feedbacks at the Last Glacial Termination. Scientific Reports, 2017; 7: 39979 DOI: 10.1038/srep39979

 

Source: University of Bonn. “Climate change could trigger strong sea level rise: International research team presents findings from frozen ‘climate archive’ of Antarctica.” ScienceDaily. ScienceDaily, 5 January 2017. <www.sciencedaily.com/releases/2017/01/170105123158.htm>.

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Date:
January 4, 2017

Source:
University of Nottingham

Summary:
A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk.

 

Spider silk and spider are shown.
Credit: The University of Nottingham

 

 

A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk.

After five years’ work an interdisciplinary team of scientists at The University of Nottingham has developed a technique to produce chemically functionalised spider silk that can be tailored to applications used in drug delivery, regenerative medicine and wound healing.

The Nottingham research team has shown for the first time how ‘click-chemistry’ can be used to attach molecules, such as antibiotics or fluorescent dyes, to artificially produced spider silk synthesised by E.coli bacteria. The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) is published today in the online journal Advanced Materials.

The chosen molecules can be ‘clicked’ into place in soluble silk protein before it has been turned into fibres, or after the fibres have been formed. This means that the process can be easily controlled and more than one type of molecule can be used to ‘decorate’ individual silk strands.

Nottingham breakthrough

In a laboratory in the Centre of Biomolecular Sciences, Professor Neil Thomas from the School of Chemistry in collaboration with Dr Sara Goodacre from the School of Life Sciences, has led a team of BBSRC DTP-funded PhD students starting with David Harvey who was then joined by Victor Tudorica, Leah Ashley and Tom Coekin. They have developed and diversified this new approach to functionalising ‘recombinant’ — artificial — spider silk with a wide range of small molecules.

They have shown that when these ‘silk’ fibres are ‘decorated’ with the antibiotic levofloxacin it is slowly released from the silk, retaining its anti-bacterial activity for at least five days.

Neil Thomas, a Professor of Medicinal and Biological Chemistry, said: “Our technique allows the rapid generation of biocompatible, mono or multi-functionalised silk structures for use in a wide range of applications. These will be particularly useful in the fields of tissue engineering and biomedicine.”

Remarkable qualities of spider silk

Spider silk is strong, biocompatible and biodegradable. It is a protein-based material that does not appear to cause a strong immune, allergic or inflammatory reaction. With the recent development of recombinant spider silk, the race has been on to find ways of harnessing its remarkable qualities.

The Nottingham research team has shown that their technique can be used to create a biodegradable mesh which can do two jobs at once. It can replace the extra cellular matrix that our own cells generate, to accelerate growth of the new tissue. It can also be used for the slow release of antibiotics.

Professor Thomas said: “There is the possibility of using the silk in advanced dressings for the treatment of slow-healing wounds such as diabetic ulcers. Using our technique infection could be prevented over weeks or months by the controlled release of antibiotics. At the same time tissue regeneration is accelerated by silk fibres functioning as a temporary scaffold before being biodegraded.”

The medicinal properties of spider silk recognised for centuries.

The medicinal properties of spider silk have been recognised for centuries but not clearly understood. The Greeks and Romans treated wounded soldiers with spider webs to stop bleeding. It is said that soldiers would use a combination of honey and vinegar to clean deep wounds and then cover the whole thing with balled-up spider webs.

There is even a mention in Shakespeare’s Midsummer Night’s Dream: “I shall desire you of more acquaintance, good master cobweb,” the character ‘Bottom’ said. “If I cut my finger, I shall make bold of you.”

‘I think we could make that!’

The idea came together at a discipline bridging university ‘sandpit’ meeting five years ago. Dr Goodacre says her chance meeting at that event with Professor Thomas proved to be one of the most productive afternoons of her career.

Dr Goodacre, who heads up the SpiderLab in the School of Life Sciences, said: “I got up at that meeting and showed the audience a picture of some spider silk. I said ‘I want to understand how this silk works, and then make some.’

“At the end of the session Neil came up to me and said ‘I think my group could make that.’ He also suggested that there might be more interesting ‘tweaks’ one could make so that the silk could be ‘decorated’ with different, useful, compounds either permanently or which could be released over time due to a change in the acidity of the environment.”

The approach required the production of the silk proteins in a bacterium where an amino acid not normally found in proteins was included. This amino acid contained an azide group which is widely used in ‘click’ reactions that only occur at that position in the protein. It was an approach that no-one had used before with spider silk — but the big question was — would it work?

Dr Goodacre said: “It was the start of a fascinating adventure that saw a postdoc undertake a very preliminary study to construct the synthetic silks. He was a former SpiderLab PhD student who had previously worked with our tarantulas. Thanks to his ground work we showed we could produce the silk proteins in bacteria. We were then joined by David Harvey, a new PhD student, who not only made the silk fibres, incorporating the unusual amino acid, but also decorated it and demonstrated its antibiotic activity. He has since extended those first ideas far beyond what we had thought might be possible.”

David Harvey’s work is described in this paper but Professor Thomas and Dr Goodacre say this is just the start. There are other joint SpiderLab/Thomas lab students working on uses for this technology in the hope of developing it further.

David Harvey, the lead author on this their first paper, has just been awarded his PhD and is now a postdoctoral researcher on a BBSRC follow-on grant so is still at the heart of the research. His current work is focused on driving the functionalised spider silk technology towards commercial application in wound healing and tissue regeneration.

Where will we be in 5 years’ time?

Dr Goodacre said: “It is likely that this paper is just the start of a very exciting range of studies using the new spider silk material. Some of the future work will also be supported by other, neat ideas from the world of spiders and their silk, which the SpiderLab is currently trying to unravel.”


Story Source:

Materials provided by University of Nottingham. Note: Content may be edited for style and length.


Journal Reference:

  1. David Harvey, Philip Bardelang, Sara L. Goodacre, Alan Cockayne, Neil R. Thomas. Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using “Click” Chemistry. Advanced Materials, 2016; 1604245 DOI: 10.1002/adma.201604245

 

Source: University of Nottingham. “Antibiotic spider silk for drug delivery, regenerative medicine and wound healing.” ScienceDaily. ScienceDaily, 4 January 2017. <www.sciencedaily.com/releases/2017/01/170104103533.htm>.

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Research results present a new strategy for measuring the impact of zinc on health

Date:
January 3, 2017

Source:
Children’s Hospital & Research Center Oakland

Summary:
A new study shows that a modest 4 milligrams of extra zinc a day in the diet can have a profound, positive impact on cellular health that helps fight infections and diseases. This amount of zinc is equivalent to what biofortified crops like zinc rice and zinc wheat can add to the diet of vulnerable, nutrient deficient populations.

 

Collage of products containing zinc.
Credit: © Africa Studio / Fotolia

 

 

A new study by researchers from the UCSF Benioff Children’s Hospital Research Institute (CHORI) shows that a modest 4 milligrams of extra zinc a day in the diet can have a profound, positive impact on cellular health that helps fight infections and diseases. This amount of zinc is equivalent to what biofortified crops like zinc rice and zinc wheat can add to the diet of vulnerable, nutrient deficient populations.

The study, published in the American Journal of Clinical Nutrition, was led by CHORI Senior Scientist Janet King, PhD. King and her team are the first to show that a modest increase in dietary zinc reduces oxidative stress and damage to DNA.

“We were pleasantly surprised to see that just a small increase in dietary zinc can have such a significant impact on how metabolism is carried out throughout the body,” says King. “These results present a new strategy for measuring the impact of zinc on health and reinforce the evidence that food-based interventions can improve micronutrient deficiencies worldwide.”

Zinc is ubiquitous in our body and facilitates many functions that are essential for preserving life. It plays a vital role in maintaining optimal childhood growth, and in ensuring a healthy immune system. Zinc also helps limit inflammation and oxidative stress in our body, which are associated with the onset of chronic cardiovascular diseases and cancers.

Around much of the world, many households eat polished white rice or highly refined wheat or maize flours, which provide energy but do not provide enough essential micronutrients such as zinc. Zinc is an essential part of nearly 3,000 different proteins, and it impacts how these proteins regulate every cell in our body. In the absence of sufficient zinc, our ability to repair everyday wear and tear on our DNA is compromised.

In the randomized, controlled, six-week study the scientists measured the impact of zinc on human metabolism by counting DNA strand breaks. They used the parameter of DNA damage to examine the influence of a moderate amount of zinc on healthy living. This was a novel approach, different from the commonly used method of looking at zinc in the blood or using stunting and morbidity for assessing zinc status.

According to King, these results are relevant to the planning and evaluation of food-based solutions for mitigating the impact of hidden hunger and malnutrition. King believes that biofortification can be a sustainable, long-term solution to zinc deficiency.


Story Source:

Materials provided by Children’s Hospital & Research Center Oakland. Note: Content may be edited for style and length.


Journal Reference:

  1. Sarah J Zyba, Swapna V Shenvi, David W Killilea, Tai C Holland, Elijah Kim, Adrian Moy, Barbara Sutherland, Virginia Gildengorin, Mark K Shigenaga, Janet C King. A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations. The American Journal of Clinical Nutrition, 2016; ajcn135327 DOI: 10.3945/ajcn.116.135327

 

Source: Children’s Hospital & Research Center Oakland. “Zinc eaten at levels found in biofortified crops reduces ‘wear and tear’ on DNA: Research results present a new strategy for measuring the impact of zinc on health.” ScienceDaily. ScienceDaily, 3 January 2017. <www.sciencedaily.com/releases/2017/01/170103084620.htm>.

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Dysregulated cellular response to estrogen and progesterone suspected

Date:
January 3, 2017

Source:
NIH/National Institute of Mental Health

Summary:
Researchers have discovered molecular mechanisms that may underlie a woman’s susceptibility to disabling irritability, sadness, and anxiety in the days leading up to her menstrual period. In women with premenstrual dysphoric disorder (PMDD), they found dysregulated expression in a sex hormone-responsive gene complex which adds to evidence that PMDD is a disorder of cellular response to estrogen and progesterone.

 

Expression of the ESC/E(Z) gene network was found to be systematically disturbed in PMDD.
Credit: Peter Schmidt, M.D., NIMH., David Goldman, M.D., NIAAA

 

 

National Institutes of Health (NIH) researchers have discovered molecular mechanisms that may underlie a woman’s susceptibility to disabling irritability, sadness, and anxiety in the days leading up to her menstrual period. Such premenstrual dysphoric disorder (PMDD) affects 2 to 5 percent of women of reproductive age, whereas less severe premenstrual syndrome (PMS) is much more common.

“We found dysregulated expression in a suspect gene complex which adds to evidence that PMDD is a disorder of cellular response to estrogen and progesterone,” explained Peter Schmidt, M.D. of the NIH’s National Institute of Mental Health, Behavioral Endocrinology Branch. “Learning more about the role of this gene complex holds hope for improved treatment of such prevalent reproductive endocrine-related mood disorders.”

Schmidt, David Goldman, M.D., of the NIH’s National Institute on Alcohol Abuse and Alcoholism, and colleagues, report on their findings January 3, 2017 in the journal Molecular Psychiatry.

“This is a big moment for women’s health, because it establishes that women with PMDD have an intrinsic difference in their molecular apparatus for response to sex hormones — not just emotional behaviors they should be able to voluntarily control,” said Goldman.

By the late 1990s, the NIMH team had demonstrated that women who regularly experience mood disorder symptoms just prior to their periods were abnormally sensitive to normal changes in sex hormones — even though their hormone levels were normal. But the cause remained a mystery.

In women with PMDD, experimentally turning off estrogen and progesterone eliminated PMDD symptoms, while experimentally adding back the hormones triggered the re-emergence of symptoms. This confirmed that they had a biologically-based behavioral sensitivity to the hormones that might be reflected in molecular differences detectable in their cells.

Following up on clues — including the fact that PMS is 56 percent heritable — the NIH researchers studied the genetic control of gene expression in cultured white blood cell lines from women with PMDD and controls. These cells express many of the same genes expressed in brain cells — potentially providing a window into genetically-influenced differences in molecular responses to sex hormones.

An analysis of all gene transcription in the cultured cell lines turned up a large gene complex in which gene expression differed conspicuously in cells from patients compared to controls. Notably, this ESC/E(Z) (Extra Sex Combs/Enhancer of Zeste) gene complex regulates epigenetic mechanisms that govern the transcription of genes into proteins in response to the environment — including sex hormones and stressors.

More than half of the ESC/E(Z) genes were over-expressed in PMDD patients’ cells, compared to cells from controls. But paradoxically, protein expression of four key genes was decreased in cells from women with PMDD. In addition, progesterone boosted expression of several of these genes in controls, while estrogen decreased expression in cell lines derived from PMDD patients. This suggested dysregulated cellular response to the hormones in PMDD.

“For the first time, we now have cellular evidence of abnormal signaling in cells derived from women with PMDD, and a plausible biological cause for their abnormal behavioral sensitivity to estrogen and progesterone,” explained Schmidt.

Using cutting edge “disease in a dish” technologies, the researchers are now following up the leads discovered in blood cell lines in neurons induced from stem cells derived from the blood of PMDD patients — in hopes of gaining a more direct window into the ESC/E(Z) complex’s role in the brain.


Story Source:

Materials provided by NIH/National Institute of Mental Health. Note: Content may be edited for style and length.


Journal Reference:

  1. N Dubey, J F Hoffman, K Schuebel, Q Yuan, P E Martinez, L K Nieman, D R Rubinow, P J Schmidt, D Goldman. The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Molecular Psychiatry, 2017; DOI: 10.1038/mp.2016.229

 

Source: NIH/National Institute of Mental Health. “Sex hormone-sensitive gene complex linked to premenstrual mood disorder: Dysregulated cellular response to estrogen and progesterone suspected.” ScienceDaily. ScienceDaily, 3 January 2017. <www.sciencedaily.com/releases/2017/01/170103084608.htm>.

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Research challenges prevalent views that brain enlargement and dental reduction co-evolved

Date:
January 2, 2017

Source:
George Washington University

Summary:
A new study found that whereas brain size evolved at different rates for different species, especially during the evolution of Homo, the genus that includes humans, chewing teeth tended to evolve at more similar rates. The finding suggests that our brains and teeth did not evolve in lock step and were likely influenced by different ecological and behavioral factors.

 

This is a 3-D reconstruction of a modern human cranium showing the teeth and endocranial cast.
Credit: George Washington University

 

 

A new study from the George Washington University’s Center for the Advanced Study of Human Paleobiology (CASHP) found that whereas brain size evolved at different rates for different species, especially during the evolution of Homo, the genus that includes humans, chewing teeth tended to evolve at more similar rates. The finding suggests that our brains and teeth did not evolve in lock step and were likely influenced by different ecological and behavioral factors.

This research challenges the classically accepted view that reduction of tooth size in hominins is linked with having a larger brain. The reasoning is that larger brains allowed hominins to start making stone tools and that the use of these tools reduced the need to have such large chewing teeth. But recent studies by other authors found that hominins had larger brains before chewing teeth became smaller, and they made and used stone tools when brains were still quite small, which challenges this relationship.

The new study evaluates this issue by measuring and comparing the rates at which teeth and brains have evolved along the different branches of the human evolutionary tree.

“The findings of the study indicate that simple causal relationships between the evolution of brain size, tool use and tooth size are unlikely to hold true when considering the complex scenarios of hominin evolution and the extended time periods during which evolutionary change has occurred,” said Aida Gómez-Robles, lead author of the paper and a postdoctoral scientist at GW’s CASHP.

To conduct the research, Dr. Gómez-Robles and her colleagues analyzed eight different hominin species. The researchers identified fast-evolving species by comparing differences between groups with those obtained when simulating evolution at a constant rate across all lineages, and they found clear differences between tooth evolution and brain evolution. If the classical view proposing co-evolution between brains and teeth is correct, they expected to see a close correspondence between species evolving at a fast rate for both traits. The differences they observed indicate that diverse and unrelated factors influenced the evolution of teeth and brains.

“Once something becomes conventional wisdom, in no time at all it becomes dogma,” said Bernard Wood, university professor of human origins at GW and a co-author of the paper. “The co-evolution of brains and teeth was on a fast-track to dogma status, but we caught it in the nick of time.”

The research published Jan. 2 in the Proceedings of the National Academy of Sciences.


Story Source:

Materials provided by George Washington University. Note: Content may be edited for style and length.

 

Source: George Washington University. “Evolution of brain and tooth size were not linked in humans: Research challenges prevalent views that brain enlargement and dental reduction co-evolved.” ScienceDaily. ScienceDaily, 2 January 2017. <www.sciencedaily.com/releases/2017/01/170102155013.htm>.

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Implications also for understanding Zika virus-caused microencephaly

Date:
December 29, 2016

Source:
Whitehead Institute for Biomedical Research

Summary:
Researchers provide insight into a specific gene pathway that appears to regulate the growth, structure, and organization of the human cortex. They also demonstrate that 3-D human cerebral organoids can be effective in modeling the molecular, cellular, and anatomical processes of human brain development. And they suggest a new path for identifying the cells affected by Zika virus.

 

360 degree imaging of human brain organoids using lightsheet microscope, showing smooth appearance of normal organoid (left) and surface folding in PTEN mutant organoid (right) — as well as the mutant organoid’s large size.
Credit: Yun Li and Julien Muffat

 

 

One of the most significant ways in which the human brain is unique is the size and structure of the cerebral cortex. But what drives the growth of the human cortex, likely the foundation for our unique intellectual abilities?

In research published in the journal Cell Stem Cell — in a study entitled, Induction of expansion and folding in human cerebral organoids — researchers at Whitehead Institute provide insight into a specific gene pathway that appears to regulate the growth, structure, and organization of the human cortex. They also demonstrate that 3D human cerebral organoids — miniature, lab-grown versions of specific brain structures — can be effective in modeling the molecular, cellular, and anatomical processes of human brain development. And they suggest a new path for identifying the cells affected by Zika virus.

“We found that increased proliferation of neural progenitor cells (NPs) induces expansion of cortical tissue and cortical folding in human cerebral organoids,” says Yun Li, a lead author of study and post-doctoral researcher at Whitehead Institute. “Further, we determined that deleting the PTEN gene allows increased growth factor signaling in the cell, unleashing its growth potential, and stimulating proliferation.”

These findings lend support to the notion that an increase in the proliferative potential of NPs contributes to the expansion of the human cerebral neocortex, and the emergence of surface folding.

With normal NPs, the human organoid developed into relatively small cell clusters with smooth surface appearance, displaying some features of very early development of a human cortex. However, deleting PTEN allowed the progenitor population to continue expanding and delayed their differentiation into specific kinds of neurons — both key features of the developing human cortex. “Because the PTEN mutant NPs experienced more rounds of division and retained their progenitor state for an extended period, the organoids grew significantly larger and had substantially folded cortical tissue,” explains Julien Muffat, also a lead author and post-doctoral researcher at Whitehead Institute.

In contrast, they found that while PTEN deletion in mouse cells does create a somewhat larger than normal organoid, it does not lead to significant NP expansion or to folding. “Previous studies have suggested that abnormal variation in PTEN expression may play an important role in driving brain development conditions leading to syndromes such as Autism Spectrum Disorders,” says Rudolf Jaenisch, Founding Member of Whitehead Institute and senior author of the study. “Our findings suggest that the PTEN pathway is also an important mechanism for controlling brain-structure differences observed between species.”

The Whitehead investigators chose to focus on the PTEN gene because it had previously been shown to have some function in cortical development and to have a role in regulating progenitor cells of various lineages. Notably PTEN loss-of-function mutations have been associated with human macrocephaly.

In this study, deletion of the PTEN gene increased activation of the PI3K-AKT pathway and thereby enhanced AKT activity in the human NPs comprising the 3D human cerebral organoids; it promoted cell cycle re-entry and transiently delayed neuronal differentiation, resulting in a marked expansion of the radial glia and intermediate progenitor population. Validating the molecular mechanism at work with PTEN, the investigators used pharmacological AKT inhibitors to reverse the effect of the PTEN deletion. They also found that they could regulate the degree of expansion and folding by tuning the strength of AKT signaling — with reduced signaling resulting in smaller and smooth organoids, and increased signaling producing larger and more folded organoids.

Finally, the researchers utilized the 3D human cerebral organoid system to show that infection with Zika virus impairs cortical growth and folding. In the organoids, Zika infection at the onset of surface folding (day 19 of development) led to widespread apoptosis; and, ten days later, it had severely hampered organoid growth and surface folding. Zika infection of 4-week-old organoids, showed that PTEN mutant organoids were much more susceptible to infection than normal control organoids; notably, they showed increased apoptosis and decreased proliferation of progenitor cells.

“Although not an original goal of our study, we have demonstrated that 3D human cortical organoids can be very effective for Zika modeling — better enabling researchers to observe how human brain tissue reacts to the infection and to test potential treatments,” Li says.


Story Source:

Materials provided by Whitehead Institute for Biomedical Research. Note: Content may be edited for style and length.


Journal Reference:

  1. Yun Li, Julien Muffat, Attya Omer, Irene Bosch, Madeline A. Lancaster, Mriganka Sur, Lee Gehrke, Juergen A. Knoblich, Rudolf Jaenisch. Induction of Expansion and Folding in Human Cerebral Organoids. Cell Stem Cell, 2016; DOI: 10.1016/j.stem.2016.11.017

 

Source: Whitehead Institute for Biomedical Research. “Scientists engineer gene pathway to grow brain organoids with surface folding: Implications also for understanding Zika virus-caused microencephaly.” ScienceDaily. ScienceDaily, 29 December 2016. <www.sciencedaily.com/releases/2016/12/161229141842.htm>.

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Process enables creation of mechanical components with functionality, such as surgical pins that change color with strain

Date:
December 26, 2016

Source:
Tufts University

Summary:
Engineers have created a new format of solids made from silk protein that can be preprogrammed with biological, chemical, or optical functions, such as mechanical components that change color with strain, deliver drugs, or respond to light.

 

This image shows examples of engineered 3-D silk constructs.
Credit: Silklab, Department of Biomedical Engineering, School of Engineering, Tufts University

 

 

Tufts University engineers have created a new format of solids made from silk protein that can be preprogrammed with biological, chemical, or optical functions, such as mechanical components that change color with strain, deliver drugs, or respond to light, according to a paper published online this week in Proceedings of the National Academy of Sciences (PNAS).

Using a water-based fabrication method based on protein self-assembly, the researchers generated three-dimensional bulk materials out of silk fibroin, the protein that gives silk its durability. Then they manipulated the bulk materials with water-soluble molecules to create multiple solid forms, from the nano- to the micro-scale, that have embedded, pre-designed functions.

For example, the researchers created a surgical pin that changes color as it nears its mechanical limits and is about to fail, functional screws that can be heated on demand in response to infrared light, and a biocompatible component that enables the sustained release of bioactive agents, such as enzymes.

Although more research is needed, additional applications could include new mechanical components for orthopedics that can be embedded with growth factors or enzymes, a surgical screw that changes color as it reaches its torque limits, hardware such as nuts and bolts that sense and report on the environmental conditions of their surroundings, or household goods that can be remolded or reshaped.

Silk’s unique crystalline structure makes it one of nature’s toughest materials. Fibroin, an insoluble protein found in silk, has a remarkable ability to protect other materials while being fully biocompatible and biodegradable.

“The ability to embed functional elements in biopolymers, control their self-assembly, and modify their ultimate form creates significant opportunities for bio-inspired fabrication of high-performing multifunctional materials,” said senior and corresponding study author Fiorenzo G. Omenetto, Ph.D. Omenetto is the Frank C. Doble Professor in the Department of Biomedical Engineering at Tufts University’s School of Engineering and also has an appointment in the Department of Physics in the School of Arts and Sciences.


Story Source:

Materials provided by Tufts University. Note: Content may be edited for style and length.


Journal Reference:

  1. Benedetto Marelli, Nereus Patel, Thomas Duggan, Giovanni Perotto, Elijah Shirman, David L. Kaplan, and Fiorenzo G. Omenetto. Directed self-assembly of silk fibroin into bulk materials: Programming function into mechanical forms from the nano- to macroscale. PNAS, 2016 DOI: 10.1073/pnas.1612063114

 

Source: Tufts University. “Engineers create programmable silk-based materials with embedded, pre-designed functions: Process enables creation of mechanical components with functionality, such as surgical pins that change color with strain.” ScienceDaily. ScienceDaily, 26 December 2016. <www.sciencedaily.com/releases/2016/12/161226211244.htm>.

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Date:
December 26, 2016

Source:
University of Queen Mary London

Summary:
Researchers have successfully decoded the genetic sequence of the ash tree, to help the fight against the fungal disease, ash dieback. Tens of millions of ash trees across Europe are dying from the Hymenoscyphus fraxinea fungus – the most visible signs that a tree is infected with ash dieback fungus are cankers on the bark and dying leaves.

 

A young ash tree dying from ash dieback fungal disease. The disease has the potential to wipe out 90 per cent of the European ash tree population, which is one of the most common trees in Britain.
Credit: Image courtesy of University of Queen Mary London

 

 

Researchers at Queen Mary University of London (QMUL) have successfully decoded the genetic sequence of the ash tree, to help the fight against the fungal disease, ash dieback.

Tens of millions of ash trees across Europe are dying from the Hymenoscyphus fraxinea fungus — the most visible signs that a tree is infected with ash dieback fungus are cankers on the bark and dying leaves.

Project leader Dr Richard Buggs from QMUL’s School of Biological and Chemical Sciences said: “This ash tree genome sequence lays the foundations for accelerated breeding of ash trees with resistance to ash dieback.

A small percentage of ash trees in Denmark show some resistance to the fungus and the reference genome is the first step towards identifying the genes that confer this resistance.

The ash tree genome also contains some surprises. Up to quarter of its genes are unique to ash. Known as orphan genes, they were not found in ten other plants whose genomes have been sequenced.

Dr Buggs added: “Orphan genes present a fascinating evolutionary conundrum as we have no idea how they evolved.”

This research is published today in the journal Nature. It involved a collaboration between scientists at: QMUL, the Earlham Institute, Royal Botanic Gardens Kew, University of York, University of Exeter, University of Warwick, Earth Trust, University of Oxford, Forest Research, Teagasc, John Innes Centre, and National Institute of Agricultural Botany.

The reference genome from QMUL was used by scientists at University of York who discovered genes that are associated with greater resistance to ash dieback. They have used these to predict the occurrence of more resistant trees in parts of the UK not yet affected by the disease, which is spreading rapidly.

The genome sequence will also help efforts to combat the beetle Emerald Ash Borer, which has killed hundreds of millions of ash trees in North America.

Ash trees have a huge significance in culture and society — they are one of the most common trees in Britain and over 1,000 species, from wildflowers to butterflies, rely on its ecosystem for shelter or sustenance. Ash timber has been used for years for making tools and sport handles, for example hammers and hockey sticks, and is used often for furniture.

The work was funded by NERC, BBSRC, Defra, ESRC, the Forestry Commission, the Scottish Government, Marie Sklodowska-Curie Actions, Teagasc — the Agriculture and Food Development Authority.


Story Source:

Materials provided by University of Queen Mary London. Note: Content may be edited for style and length.


Journal Reference:

  1. Elizabeth S. A. Sollars, Andrea L. Harper, Laura J. Kelly, Christine M. Sambles, Ricardo H. Ramirez-Gonzalez, David Swarbreck, Gemy Kaithakottil, Endymion D. Cooper, Cristobal Uauy, Lenka Havlickova, Gemma Worswick, David J. Studholme, Jasmin Zohren, Deborah L. Salmon, Bernardo J. Clavijo, Yi Li, Zhesi He, Alison Fellgett, Lea Vig McKinney, Lene Rostgaard Nielsen, Gerry C. Douglas, Erik Dahl Kjær, J. Allan Downie, David Boshier, Steve Lee, Jo Clark, Murray Grant, Ian Bancroft, Mario Caccamo, Richard J. A. Buggs. Genome sequence and genetic diversity of European ash trees. Nature, 2016; DOI: 10.1038/nature20786

 

Source: University of Queen Mary London. “Ash tree genome aids fight against disease.” ScienceDaily. ScienceDaily, 26 December 2016. <www.sciencedaily.com/releases/2016/12/161226175339.htm>.

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