Immunology

Covid-19 and allergies: Allergy season gets worse every year. Heres why. – Vox.com

The weather is warming. The flowers are blooming. Noses are running. Eyes are watering.

Amid a global pandemic, many miserable Americans are asking themselves: Is it allergies or Covid-19?

The list of coronavirus symptoms continues to get longer fever, coughing, loss of smell, chills and as it does, it overlaps with other health problems even more, making it harder to know whats what. And with a shortage of Covid-19 tests, many people cant be sure whether the pollen or the virus is behind their malaise.

At the same time, its likely to be another brutal year for allergies across the United States. Texas is bracing for its worst allergy season in years. States like Georgia and New York have already seen near-record pollen counts. And in Washington, DC, pollen spiked surprisingly early this year.

If youre concerned about telling allergies apart from Covid-19, the American Academy of Allergy, Asthma, & Immunology (AAAAI) has put together a handy chart comparing their symptoms, as well as signs of the common cold and influenza:

The main symptoms common to Covid-19 but not to allergies are fever, cough, and shortness of breath. However, many people with the coronavirus dont experience any symptoms at all, and there is nothing precluding someone from having both allergies and the virus at the same time. The AAAAI says its important to continue managing allergies during the pandemic, and that its safe to use allergy control medicines like inhaled corticosteroids.

Now that its May, the US is moving away from peak tree pollen season and heading toward grass pollen season. So even more misery is in store. Grass pollen sufferers will face a long and severe season into summer, AccuWeather senior meteorologist Alan Reppert said in a report on the weather forecasters website.

Forecasters expect 2020 to be yet another above-average year for allergies, if not the worst year ever. Just like 2019, the year before that, the year before that, and the year before that.

Allergy season has become so predictably terrible that late-night comedians have taken to venting about warnings of the pollen tsunami or the pollen vortex or the perfect storm for allergies.

But it turns out theres truth behind the bombast: Pollen, an allergy trigger for one in five Americans, is surging year after year. And a major driver behind this increase is climate change.

For instance, rising average temperatures are leading to a longer ragweed pollen season, as you can see here:

A 2019 paper published in The Lancet Planetary Health journal found that airborne pollen counts have increased around the world as average temperatures climbed. The majority of the 17 sites studied showed both an increase in the amount of pollen and longer pollen seasons over 20 years.

And the faster the climate changes, the worse it gets. Thats why residents of Alaska, which is warming twice as fast as the global average, now face especially high allergy risks.

Taken together over the long term, seasonal allergies present one of the most robust examples of how global warming increases health risks. Allergies, which are already a major health burden, will become an even larger drain on the economy.

Its very strong. In fact, I think theres irrefutable data, said Jeffrey Demain, director of the Allergy, Asthma, and Immunology Center of Alaska. Its become the model of health impacts of climate change.

And since so many are afflicted some estimates say up to 50 million Americans have nasal allergies scientists and health officials are now trying to tease out the climate factors driving these risks in hopes of bringing some relief in the wake of growing pollen avalanches.

Heres what scientists have figured out so far about the relationship between climate change and seasonal allergies.

Allergies occur when the bodys internal radar system locks onto the wrong target, causing the immune system to overreact to an otherwise harmless substance.

This can cause mild annoyances like hives or itchy eyes, or life-threatening issues like anaphylaxis, where blood pressure plummets and airways start swelling shut.

About 8 percent of US adults suffer from hay fever, also known as allergic rhinitis, brought on by pollen allergies. Most cases can be treated with antihistamines, but they cost the US between $3.4 billion and $11.2 billion each year just in direct medical expenses, with a substantially higher toll from lost productivity. Complications like pollen-induced asthma attacks have also proven fatal in some instances and lead to more than 20,000 emergency room visits each year in the US.

Pollen is a fine powder produced as part of the sexual reproductive cycle of many varieties of plants, including elm trees, ryegrass, and ragweed.

Its released in response to environmental signals like temperature, precipitation, and sunlight. Grains of pollen range in size from 9 microns to 200 microns, so some types of pollen can travel deep into the lungs and cause irritation, even for people who dont have allergies. High concentrations of pollen in the air trigger allergic reactions and can spread for miles, even indoors if structures are not sealed.

There are three big peaks in pollen production throughout the year. Trees like oak, ash, birch, and maple see pollen surges in the spring. Pollen from timothy grass, bluegrass, and orchard grass peaks over the summer, and ragweed pollen spikes in the fall.

For people who are sensitive to multiple varieties of pollen, it means there will be less relief during warmer weather as these seasons overlap.

In general, pollen is emerging earlier in the year and the season is stretching out longer and longer, especially pollen from ragweed.

Ragweed is handy for studying the impacts of climate on pollen and allergies because its an annual plant, unlike trees or perennials. This allows scientists to separate out how variables like winter temperatures and rainfall in the preceding season influence ragweed pollen.

Lewis Ziska, a plant physiologist who formerly worked at the USDAs Agricultural Research Service, told Vox that the change in carbon dioxide concentrations from a preindustrial level of 280 parts per million to todays concentrations of more than 400 ppm has led to a corresponding doubling in pollen production per plant of ragweed.

How does this happen? If youve looked at a bag or bottle of plant fertilizer, you may have noticed three numbers that represent the ratio of phosphorus, nitrogen, and potassium inside. Different ratios encourage different aspects of a plants growth, like flowering or making seeds. Carbon dioxide is also an important nutrient for plants, though its not included in fertilizer (because its a gas). It turns out that higher carbon dioxide concentrations encourage plants to produce more pollen.

For ragweed, you can see a direct pollen response to increases in carbon dioxide concentrations in the atmosphere:

More pollen usually means more seeds, which means more ragweed in the next season. And warmer average temperatures mean that spring starts earlier and winter arrives later, giving pollen producers more time to spew their sneeze-inducing particles.

We can see the effects of CO2 on smaller scales as well. Researchers have found that grasses and ragweed plants increase their pollen production in response to localized surges in carbon dioxide, like from the exhaust of cars along a highway.

However, for other allergen sources like trees, the groundwork for a severe pollen season can be laid more than a year before the current season.

What happens is if the tree during the previous year has had a good season, it tends to load up on carbs so that in the spring, it has a lot of carbs to put out for flower production, Ziska said. When that happens, you can get a large bloom, and the consequences of that are inherent in the amount of pollen thats being produced.

Alaska is warming so fast that computer models have had a hard time believing the results. Thats having huge consequences for allergy sufferers in the state, and not just from pollen.

Demain from the Allergy, Asthma, and Immunology Center of Alaska explained that rising temperatures are melting permafrost beneath Alaskan towns, causing moisture to seep into homes. This dampness then allows mold to grow, causing more people to seek treatment for mold allergies.

Stinging insects are also a mounting concern. Warmer winters mean that more yellow jackets and wasps are surviving the cold months, increasing the likelihood of Alaskans getting stung. In 2006, Anchorage saw a spike in the numbers of these insects and suffered its first two deaths ever due to insect sting allergies.

It was so bad, they were canceling community outdoor events, Demain said.

Looking at patterns of people seeking medical treatment from insect stings, Demain found that the increases grew starker going northward in Alaska, with the northernmost part of the state experiencing a 626 percent increase in insect bites and stings between 2004 and 2006 compared with the period between 1999 and 2001.

Nonetheless, pollen remains a huge concern in Alaska as well, though the main source is birch trees, not ragweed. Birch pollen around Anchorage can get so bad that even people without allergies get bogged down.

For a high pollen count, you need greater than 175 grains per cubic meter, Demain said. In Alaska, we get highs between 2,000 and 4,000 grains per cubic meter.

In addition to the quantity of pollen, Demain noted that rising carbon dioxide concentrations increase the allergenic peptides on pollen. The peptides are the molecular signal that triggers the bodys immune system, so more peptides on a given pollen grain increase the severity of the allergy.

So its not just more pollen; the pollen itself is becoming more potent in causing an immune response.

For city dwellers, a big issue is that urban planners prefer to plant male trees, because they dont produce seeds, pods, or fruit that can become litter. The downside is that male trees produce pollen that can trigger allergies.

Researchers estimate that pollen counts of all varieties will double by 2040 in some parts of the country, depending on what pathway the world takes on greenhouse gas emissions. Heres how scientists project allergy risks from tree pollen will change in the eastern United States under a high greenhouse gas emissions scenario:

Heres the trajectory for ragweed:

And heres what to expect for grass pollen:

This means that regardless of your pollen of choice, the future holds more misery for allergy sufferers. And as the Covid-19 pandemic rages, it may be a long time before millions of Americans can breathe easy.

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Immunology

Fighting autoimmunity and cancer: The nutritional key – Science Codex

Scientists at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH) revealed a novel mechanism through which the immune system can control autoimmunity and cancer. In the special focus of the researchers were regulatory T cells - a specific type of white blood cells that in general act as a brake on the immune system. The LIH research team led by Prof Dirk Brenner, FNR ATTRACT fellow and Head of Experimental & Molecular Immunology, revealed a mechanism that controls the function of regulatory T cells and determines the balance between autoimmunity and anti-cancer activity. In a preclinical model, the scientists further showed that the elucidation of the metabolic mechanism of a disease can lead to disease reduction by a rationally-designed diet that specifically addresses these metabolic alterations. This sets a new direction for future treatment of metabolic diseases. These findings, which were published today in the leading international journal Cell Metabolism, hold important implications for the development of personalised treatment options for autoimmune disorders and cancer.

"Our immune system is needed for a healthy body function and protects us from all kinds of infections. Particularly important in this respect are T cells, and specifically regulatory T cells. Although these represent only a small fraction of all T cells, they are crucial to keep our immune system in check" explains Prof Brenner. "If regulatory T cells are not functional, the immune system gets out of control and turns against its own body. This can lead to detrimental autoimmune diseases like multiple sclerosis, type I diabetes or arthritis. However, a highly reactive immune system can kill cancer cells very efficiently. This has led to the development of 'checkpoint inhibitors', specific drugs that unleash an immune system attack on cancer cells and which won the Nobel Prize in Medicine in 2018". The Luxembourgish scientists took this angle and revealed a novel mechanism by which this balance between an extreme or subdued immune reaction can be controlled by modifying regulatory T cell metabolism.

Initially, the researchers focused on how regulatory T cells cope with stress. Cellular stress can originate from the cells themselves, for example when they get activated and divide, but also from their environment, especially from nearby tumour cells. Free radicals called reactive oxygen species (ROS) are the molecular mediators of cellular stress. These are harmful for the cells and therefore need to be inactivated. "Free oxygen radicals are 'neutralised' by antioxidants and the major antioxidant in T cells is a molecule known as glutathione. We were surprised when we realised that regulatory T cells had about three times as much glutathione as other T cells. This pointed to an important function", says Henry Kurniawan, first author of the study and PhD student in Prof Brenner's group. Through a sophisticated genetic approach, the scientists removed a gene named 'glutamate cysteine ligase' (Gclc) only in a small population of regulatory T cells in mice. The Gclc gene is instrumental for glutathione production. Prof Brenner's team discovered that free radicals accumulated in these genetically altered regulatory T cells and that these cells lost their ability to act as a brake on the immune system. Strikingly, this led to a massive immune activation and a fatal autoimmune disease.

The team also found that the absence of glutathione in regulatory T cells increased serine metabolism massively. Serine is one of the 22 different amino acids that constitute the building blocks of proteins, which are in turn important for the structure and function of cells. No previous research group had studied the connection between glutathione, free radicals, serine and regulatory T cell function before. Prof Brenner's team characterised the metabolic alteration that led to the observed autoimmune disease in their mutant mice. Based on their findings, they designed a specific nutritional plan with the aim of correcting these disease-causing metabolic shifts. This dietary plan lacked both the amino acids serine and the closely related glycine. Interestingly, this engineered precision diet suppressed the severe autoimmunity and no disease developed. "Importantly, our study shows that the absence of only 2 out of 22 amino acids can cure a complex autoimmune disease. Therefore, elucidating the exact metabolic and molecular basis of a disease offers the possibility to correct these metabolic abnormalities through a special diet that is precisely adapted to the delineated disease mechanism. Our study might be a first step in the direction of the personalised treatment of metabolic diseases and autoimmunity", explains Prof Brenner.

"The relationship between glutathione, free radicals and serine can be used as a 'switch' to modulate immune cell activation. A higher immune cell activity is beneficial for cancer patients. We were intrigued by the idea of using our findings also to boost anti-tumor responses" he adds. Indeed, the team further showed that lower glutathione levels in regulatory T cells and the resulting rise in immune cell activation led to a significant tumour rejection, which might open up new therapeutic avenues for cancer treatment. "These astonishing results show the enormous potential of tweaking metabolism to prevent autoimmunity and target cancer. This could pave the way for the development of a new generation of immunotherapies," explains Prof Markus Ollert, Director of LIH's Department of Infection and Immunity. "The publication of these results in such a competitive and prestigious international journal is a momentous accomplishment not just for our department and institute, but for the entire Luxembourgish biomedical research community", he concludes.

In future projects, the researchers will use their findings to elaborate new approaches for therapeutic intervention. In that respect, the scientists have already proven that their delineated disease-controlling mechanism is also relevant in human regulatory T cells.

Due to its significance, the publication was selected by Cell Metabolism to be featured as the cover story of the May issue of the journal.

Involved research teams

Prof Dirk Brenner is the Deputy Head of Research & Strategy at LIH's Department of Infection and Immunity. He is Professor for Immunology & Genetics at the Luxembourg Center for Systems Biomedicine (LCSB) of the University of Luxembourg and Professor of Allergology at the University of Southern Denmark. He received a prestigious ATTRACT Consolidator grant from the Luxembourg National Research Fund (FNR), in 2015 to set up the Experimental & Molecular Immunology research group at LIH. The FNR-ATTRACT programme supports the national research institutions by expanding their competences in strategic research areas by attracting outstanding young researchers with high potential to Luxembourg.

The present study was performed in close collaboration with a national and international team and involved partners from LIH's Department of Infection and Immunity, LIH's Department of Oncology, the Braunschweig Integrated Center of Systems Biology (BRICS) of the Technische Universitt Braunschweig (Germany), the Helmholtz Centre for Infection Research (Germany), the Campbell Family Institute for Breast Cancer Research at the University of Toronto (Canada), the Institute for Medical Microbiology and Hospital Hygiene at the University of Marburg (Germany), the Department of Environmental Health Sciences at the Yale School of Public Health (USA), the Odense Research Center for Anaphylaxis (ORCA) of the Odense University Hospital (Denmark), the Department of Biomedical Genetics and Wilmot Cancer Institute of the University of Rochester Medical Center (USA), the Departments of Medical Biophysics and Immunology at the University of Toronto (Canada) and the University of Hong Kong (China).

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Fighting autoimmunity and cancer: The nutritional key - Science Codex

Immunology

FTC Clears AbbVie and Allergan’s $63 Billion Merger – PharmaLive

The U.S. Federal Trade Commission gave the green light to the $63 billion mergerof AbbVie and Allergan. That leaves one last hurdle for the two companies, approval from the Irish High Court. A hearing is set for today.

On Tuesday, the FTC consented to the merger agreement that was initially proposed in June 2019. The FTCs consent followed approval from the European Commission, which gave a nod to the deal in March of this year. Like the previous approval from the European Commission, the FTCs consent was contingent on the divestiture of brazikumab, an investigational IL-23 inhibitor in development for autoimmune diseases, to AstraZeneca. Brazikumab is currently in Phase IIb/II development for Crohns Disease and in Phase II development for ulcerative colitis. A deal for brazikumab was struck in January, along with the divestiture of two other assets, Zenpep (pancrelipase), a treatment for exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, and Viokace, a pancreatic enzyme preparation, to Nestle.

In its announcement Tuesday, the FTC said it conducted a 10-month investigation into the merger and concluded that the divestitures were required in order to prevent the combined companies from having a monopoly on the treatment of various conditions.

Over the course of their 10-month investigation, commission staff explored a wide range of theories of competitive harm, including harm to innovation. They uncovered no evidence of such harm beyond those remedied by the proposed consent, the FTC said in its announcement.

Some consumer groups have raised their collective voices in opposition of the merger, claiming that the combination of AbbVie and Allergan would create a monopoly in the immunology market. Even with the divestiture of brazikumab, those in opposition, which includes unions and consumer groups, point out that the drug is still under investigation and should it fail, the divestiture will be meaningless. They also argue that AbbVie dominates the immunology market through a variety of exclusionary tactics to hamper rivals.

In addition to the divestiture of the assets, AbbVie and Allergan said that the companies amended their Transaction Agreement to allow for only one member of the Allergan Board of Directors to join AbbVies board upon closing. Allergans current chairman and chief executive officerBrent Saundershas elected not to join the AbbVie Board to provide more flexibility to pursue other opportunities in the sector.

In January, AbbVie and Allergan announced plans for a new, stand-alone company calledAllergan Aestheticsthat will include Allergans blockbuster aesthetics treatment Botox as a tent pole.

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Immunology

Demand for Immunology Drug Skyrockets with the Surge in Covid-19 Cases, Supporting Global Revenue 3w Market News Reports – 3rd Watch News

Given the debilitating impact of COVID-19 (Coronavirus) on the Immunology Drug market, companies are vying opportunities to stay afloat in the market landscape. Gain access to our latest research analysis on COVID-19 associated with the Immunology Drug market and understand how market players are adopting new strategies to mitigate the impact of the pandemic.

Analysis of the Global Immunology Drug Market

Persistence Market Research (PMR) recently published a market study which provides a detailed understanding of the various factors that are likely to influence the Immunology Drug market in the forecast period (20XX-20XX). The study demonstrates the historical and current market trends to predict the roadmap of the Immunology Drug market in the coming years. Further, the growth opportunities, capacity additions, and major limitations faced by market players in the Immunology Drug market are discussed.

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Regional Overview

Our team of analysts at PMR, trace the major developments within the Immunology Drug landscape in various geographies. The market share and value of each region are discussed in the report along with graphs, tables, and figures.

Competitive Outlook

This chapter of the report discusses the ongoing developments, mergers and acquisitions of leading companies operating in the Immunology Drug market. The product portfolio, pricing strategy, the regional and global presence of each company is thoroughly discussed in the report.

Product Adoption Analysis

The report offers crucial insights related to the adoption pattern, supply-demand ratio, and pricing structure of each product.

key players and products offered

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Cell Biology

MSU’s Gregg Howe elected to the National Academy of Sciences – MSUToday

Michigan State University plant scientist Gregg Howe has been elected to the National Academy of Sciences, or NAS. Founded in 1863, the NAS is one of the oldest and most prestigious scientific membership organizations in the United States.

Howe is among 120 new members and 26 international members elected to the NAS in 2020 in recognition of their distinguished and continuing achievements in original research.

He joins 10 current and emeritus MSU faculty as members of NAS.

Professor Howe has made important contributions to our understanding of the complex biochemical mechanisms through which plants respond to challenges such as insect attack, said Stephen Hsu, senior vice president for research and innovation at MSU. His work informs fundamental questions in biology such as the evolutionary trade-off between defense and growth that are relevant to all organisms and also has applications to practical problems such as sustainable agriculture. Michigan State University is very proud of his accomplishments.

Howe, a University Distinguished Professor, MSU Foundation Professor and a member of both the MSU-DOE Plant Research Laboratory, or PRL, and the Plant Resilience Institute, is an internationally recognized leader in research on plant hormone biology and plant-insect interactions. Howe uses a combination of genetic, cell biological, molecular and biochemical analyses to study how plants use defensive compounds to protect themselves against herbivorous insects. His many honors and awards include selection as a fellow of American Association for the Advancement of Science and the American Society of Plant Biologists and being named a Clarivate Analytics Highly Cited Researcher for the past six years.

I am greatly honored to be elected into the National Academy of Sciences, said Howe, who also a professor in the Department of Biochemistry and Molecular Biology in the MSU College of Natural Science and an MSU AgBioResearch scientist. This recognition reflects the combined efforts of many talented students and collaborators over the years. I am also grateful for the very supportive research environment and terrific colleagues at MSU.

We are delighted about Gregg Howes election to the National Academy of Sciences, said Christoph Benning, PRL director. He has made outstanding contributions to science and the MSU community since his arrival here in 1997, and I congratulate him on behalf of the entire PRL community.

This years election brings the total number of active NAS members to 2,403 and the total number of international members to 501. International members are nonvoting members of the academy, with citizenship outside the United States.

For a complete list of the 2020 NAS cohort, available in July, visit the NAS website.

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Cell Biology

Advances in Research and Disease Modeling Expanding the Horizon of 3D Cell Culture Market – TMR BLOG

A paradigm shift from the conventional cell culture techniques to 3D cell culture is predicted to bring humongous growth for the 3D cell culture market across the forecast period of 2017-2025. From the validation of new targets and disease modeling to screening for safety and efficacy, 3D cell cultures bring the tremendous potential for the development of new drugs. They offer cutting-edge tools that assist in exploring the major factors of a particular disease.

In addition, 3D cell culture market gains mainly from the cancer segment as 3D models can mimic the interplay between the host environment and tumor for analyzing the efficacy of drug candidates in cancer patients. Greater biological relevance as compared to 2D monolayers is a prime advantage for an increase in the growth rate of the 3D cell culture market. In addition, 3D cell culture systems allow better cell interactions than done in 2D cell culture systems. Advances in microfabrication techniques, tissue engineering, and cell biology are supporting the development of varied 3D cell culture technologies.

The stem cell segment is anticipated to observe prominent growth during the forecast period of 2017-2025. Increased differentiation potential of stem cells under 3D cell culture may benefit the 3D cell culture market to a great extent. Pharmaceuticals and biotechnology sector expects to bring a larger revenue share throughout the forecast period owing to increasing demand for 3D cell culture systems for toxicity screening, drug discovery, and regenerative medicine.

Mergers, Acquisitions, and Partnerships Fuelling Market Growth

The advantages associated with the 3D cell culture system are resulting in frequent partnerships and acquisitions. Key players are involved in such activities to increase their footprint in the 3D cell culture market as well as speed up the process of new developments. zPREDICTA, a San Jose-based company, recently partnered with Labcorp for extending its customer base. zPREDICTAis a specialist in the development of tumor-specific 3D cell culture models and Labcorp is involved in operating a nationwide network of clinical laboratories. In another development, Nichirei Biosciences Inc. partnered with UPM Biomedicals to offer hydrogels that mimic the extracellular matrix (ECM) to encourage cell growth and differentiation. This development will help in bridging the gap between in vitro and in vivo studies by enabling 3D cell organoids for use in regenerative and personalized medicine. Similarly, Greiner Bio-One acquired Nano 3D Biosciences 3D cell culture technology.

New Insights and Developments Accelerating the Growth Rate

Disease modeling is an essential component for the discovery of a drug-related to a specific disease or disorder. With the help of 3D bioprinting and tissue engineering techniques, it is possible to unravel drug discovery. Therefore, this aspect can propel the growth rate of the 3D cell culture market.

For instance, the COVID-19 outbreak is motivating key players in the 3D cell culture market to come up with new developments and technologies for novel treatments that can tackle the deadly disease. For instance, the SARS-CoV-2 pandemic prompted Inventialifescience, an Australia based startup, to create 3D lung microtissues for drug testing. This is being developed through the companys bioprinting platform, Rastrum, which is being used to print human cells with cancer drug testing at a rapid rate.

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From the regional perspective, developed regions like North America and Europe are predicted to show an increasing growth curve across the forecast period, with increasing cancer cases and rising investment in research and development activities being the prime factors for growth. Asia Pacific also expects steady growth due to considerable demand for 3D cell culture systems in the developing regions.

Key players involved in the 3D cell culture market are ReproCELl, Thermo Fisher Scientific Inc., Global Cell Solutions, Hamilton Company, Kuraray Co. Ltd., and Merck.

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Cell Biology

What is the Secretome? – News-Medical.net

Biological organisms are incredibly complex machines made up of innumerable parts working in complementary ways. Understanding the complex, intricate interactions between tissues and cells is, therefore, key to a holistic understanding of the organism as a whole, and over the centuries that have encompassed the science of biology many advances in scientific knowledge have been made.

Image Credit: Kateryna Kon/Shutterstock.com

One recent area of research that has been gaining prominence in the understanding of the complex inter-and-intracellular dynamics of biological organisms is the science of secretomics, a type of proteomics concerned with the study of the secretome.

The secretome as a term was coined in 2004 by Tjalsma et al. It denotes all the factors secreted by the cell, along with the constituents of the secretory pathway. The term was revised in 2010 to include specifically the proteins which are secreted into the extracellular space.

Related terms include the matrisome (the subset which includes extracellular matrix proteins and associated proteins) receptome (membrane receptors) and the adhesome (proteins involved in cell adhesion.)

Cells such as endocrines and B-lymphocytes are two classes of cells that are specifically involved in the secretion of proteins. The liver and bone marrow are major secretory organs in the human body.

In humans, secreted proteins account for between 13 and 20% of the entire proteome (the entire set of proteins expressed in an organism, cell, tissue, or genome at any given time.) Included in the secretome are such things as growth factors, coagulation factors, adhesion molecules, cytokines, proteases, and chemokines.

A significant number (36%) of the 19670-human protein-coding genes transcribe secretory proteins. Other proteins coded for by these genes are membrane-spanning, intracellular (the main type 12631 genes encode for these) and 9% have at least one secreted protein product as well as membrane-spanning products. The secretome plays a major role in cell migration, signaling, and communication.

Several methods are used by researchers to study the secretome. These include:

Image Credit: science photo/Shutterstock.com

Each method has its distinct advantages and disadvantages for studying and identifying secretory proteins. A knowledge of them is advantageous for any study using secretomics.

The growing body of research on the secretome is proving more and more important to the field of modern medical research. Many medically important secreted proteins include coagulation factors, cytokines, and growth factors and they play a myriad of physiological and pathological roles within the body.

An understanding of the secretory pathways confers knowledge of how these secretory proteins play a role in the healthy biological processes of an individual.

All cells secrete proteins to varying degrees. The study and analysis of these proteins are providing valuable sources for new drugs and therapeutics. Not only this, but a large percentage of clinical blood diagnostic tests are directed at secretory proteins.

Medically important secretory proteins include:

The secretome is still poorly understood and represents a very recent area of research in the study of intercellular pathways in the body. Secretory proteins play a role which is becoming more apparent to medical scientists as the field of secretomics evolves.

Knowledge of how the secretome functions and which pathways are specifically involved is therefore of paramount importance and will no doubt contribute to the ongoing development of novel drugs and therapeutics.

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What is the Secretome? - News-Medical.net

Cell Biology

Researchers identify transcription factor that preserves the genomic integrity of germline – News-Medical.net

Reviewed by Emily Henderson, B.Sc.May 7 2020

The germline is the cell lineage of an organism that passes on its genetic material to its progeny. Genetic damage to the germline can cause developmental defects and even death of that same progeny. It is thought that biological mechanisms exist that ensure that aberrant germline cells are eliminated to maintain germline integrity, although the specific molecular basis for this is unknown.

In a new study published in Communications Biology, researchers from the University of Tsukuba identified the transcription factor Myc as a central molecular actor within the process of preserving the genomic integrity of the germline after DNA damage.

To achieve their goal, the researchers studied the fruit fly Drosophila to understand how germline integrity is maintained. This fly model presents a sterility syndrome called P-M (paternal-maternal) hybrid dysgenesis (HD), which results from a high rate of mutations and rearrangements in the DNA, leading to germline-loss and sterility.

At the molecular level, so-called P-elements are responsible for HD. P-elements are DNA segments of which the protein transposase. Transposases have an ability known as P-element mobilization wherein they move segments of DNA, which leads to mutations and DNA instability.

When male fruit flies carrying P-elements are crossed with females lacking P-elements, P-element mobilization and thus DNA damage occurs in their progeny, resulting in sterility.

The Drosophila P-M hybrid dysgenesis model has been known for decades, but the molecular basis of the resulting sterility is still not fully understood. The goal of our study was to further our understanding of the molecular mechanisms governing the elimination of damaged germline cells during reproduction.

Interestingly, in a separate set of experiments, we found that knockdown of the transcription factor Myc resulted in a similar germline-loss phenotype that we observe in hybrid dysgenesis. We wanted to know how Myc and hybrid dysgenesis were interconnected in the process of maintaining germline integrity."

Satoru Kobayashi, Study Corresponding Author and Professor

The researchers first investigated the number of germline cells at different embryonic stages in HD progeny and in normal flies that did not produce Myc.

They found that in both models the number of germline cells decreased at a similar stage of embryonic development, suggesting that both processes are connected. The researchers then followed the expression of Myc in HD progeny and found that it was reduced in germline cells before the number of germline cells decreased, suggesting that HD causes Myc downregulation to result in a germline-loss phenotype.

They then examined what happens if Myc continued to be expressed in HD progeny by overexpressing the transcription factor. While Myc overexpression in the HD germline led to increased germline cell numbers, the resulting germline exhibited a higher DNA mutation frequency and a lower capacity to develop into adulthood.

"These are striking results that show that Myc-dependent germline cell reduction serves to eliminate aberrant germline cells in which the genetic material has been damaged," says Professor Kobayashi. "We think that Myc is a central molecular actor in this process, serving as a quality-control during embryonic development."

Source:

Journal reference:

Ota, R & Kobayashi, S. (2020) Myc plays an important role in Drosophila P-M hybrid dysgenesis to eliminate germline cells with genetic damage. Communications Biology. doi.org/10.1038/s42003-020-0923-3.

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Researchers identify transcription factor that preserves the genomic integrity of germline - News-Medical.net

Cell Biology

UB investigators uncover cellular mechanism involved in Krabbe disease – UB Now: News and views for UB faculty and staff – University at Buffalo…

A group of UB researchers have published a paper that clarifies certain cellular mechanisms that could lead to improved outcomes in patients with globoid cell leukodystrophy, commonly known as Krabbe disease.

The paper, titled Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction, was published May 5 in the journal Neuron.

The research was led by Lawrence Wrabetz and M. Laura Feltri. Wrabetz and Feltri head the Hunter James Kelly Research Institute and both are professors in the departments of Biochemistry and Neurology in the Jacobs School of Medicine and Biomedical Sciences at UB.

The institute is named for the son of former Buffalo Bills quarterback Jim Kelly. Hunter Kelly died at age 8 in 2005 from complications of Krabbe disease.

Krabbe disease is a progressive and fatal neurologic disorder that usually affects newborns and causes death before a child reaches the age of 2 or 3.

Traditionally, hematopoietic stem cell transplantation, also known as a bone marrow transplant, has improved the long-term survival and quality of life of patients with Krabbe disease, but it is not a cure.

It has long been assumed that the bone marrow transplant works by a process calledcross-correction, in which an enzyme called GALC is transferred from healthy cells to sick cells.

Using a new Krabbe disease animal model and patient samples, the UB researchers determinedthatin reality cross-correctiondoes not occur. Rather, the bone marrow transplant helps patients through a different mechanism.

The researchers first determined which cells are involved in Krabbe disease and by which mechanism. They discovered that both myelin-forming cells, or Schwann cells, and macrophages require the GALC enzyme, which is missing in Krabbe patients due to genetic mutation.

Schwann cells require GALC to prevent the formation of a toxic lipid called psychosine, which causes myelin destruction and damage to neurons. Macrophages require GALC to aid with the degradation of myelin debris produced by the disease.

The research showed that hematopoietic stem cell transplantation does not work bycross-correction, but by providing healthy macrophages with GALC.

According to Feltri, the data reveal that improvingcross-correctionwould be a way to makebone marrow transplants and other experimental therapies such as gene therapy more effective.

Bone marrow transplantation and other treatments for lysosomal storage disorders, such as enzyme replacement therapy, have historically had encouraging but limited therapeutic benefit, says study first author Nadav I. Weinstock, an MD-PhD student in the Jacobs School. Our work defined the precise cellular and mechanistic benefit of bone marrow transplantation in Krabbe disease, while also shedding light on previously unrecognized limitations of this approach.

Future studies, using genetically engineered bone marrow transplantation or other novelapproaches,may one day build on our findings and eventually bridge the gap for effectively treating patients with lysosomal disease, he continues.

UB investigators included Daesung Shin, research assistant professor at the Hunter James Kelly Research Institute; Nicholas Silvestri, clinical associate professor of neurology, Jacobs School; Narayan Dhimal, PhD student; Chelsey B. Reed, MD-PhD student; and undergraduate student Oliver Sampson.

Also participating in the research were Eric E. Irons, MD-PhD student, and Joseph T.Y. Lau, a distinguished faculty member from the Department of Molecular and Cellular Biology at Roswell Park Comprehensive Cancer Center.

The research was funded by multiple grants from the National Institutes of Health awarded to Weinstock, Shin, Wrabetz and Feltri, and also supported by Hunters Hope.

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Cell Biology

AVROBIO and Magenta Therapeutics Announce Collaboration to Evaluate Targeted Antibody-Drug Conjugate as a Potential Conditioning Regimen for…

CAMBRIDGE, Mass.--(BUSINESS WIRE)--AVROBIO, Inc. (Nasdaq: AVRO) and Magenta Therapeutics (Nasdaq: MGTA) today announced a research and clinical collaboration agreement to evaluate the potential utility of MGTA-117, Magentas novel targeted antibody-drug conjugate (ADC) for conditioning patients before they receive one of AVROBIOs investigational lentiviral gene therapies.

The collaboration will combine AVROBIOs leadership in lentiviral gene therapies with Magentas expertise in ADC-based conditioning and is expected to further the two companies shared mission to enable patients to live free from disease. Under the collaboration, AVROBIO and Magenta will jointly evaluate MGTA-117 in conjunction with one or more of AVROBIOs investigational gene therapies. Magenta will retain all commercial rights to MGTA-117. AVROBIO will retain all commercial rights to its gene therapies and will be responsible for the clinical trial costs related to the evaluation of MGTA-117 with AVROBIOs gene therapies.

This agreement with Magenta springs from our strategic focus on maintaining technology leadership in gene therapy, said Geoff MacKay, AVROBIOs president and CEO. AVROBIO has always led by investing early in technological innovations that further the field of lentiviral gene therapy, such as plato, our proprietary platform designed to optimize the safety, potency and durability of our investigational lentiviral gene therapies. Were continually assessing new technologies that could be complementary to our plato platform to sustain our cutting-edge advantage and continue to evolve platos capabilities.

We believe targeted ADCs represent the next generation of medicines to prepare patients for gene therapy or transplant in a targeted, precise way. AVROBIOs investigational gene therapies complement our platform as well as our focus and commitment to patients. This partnership will allow Magenta to validate our conditioning platform in lentiviral gene therapy applications, said Jason Gardner, D.Phil., president and chief executive officer, Magenta Therapeutics. Weve selected ADCs as the preferred modality for our conditioning programs, as we believe they offer the most promising option for more patients. We have optimized our ADCs for gene therapy and transplant settings and look forward to collaborating with AVROBIO to evaluate MGTA-117 in specific gene therapy settings. Magenta will continue to develop MGTA-117 in other diseases, including blood cancers and genetic diseases.

MGTA-117, Magentas most advanced conditioning program, is a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, a toxin in-licensed from Heidelberg Pharma. It is designed to precisely deplete only hematopoietic stem and progenitor cells and has shown high selectivity, potent efficacy, wide safety margins and broad tolerability in non-human primate models, suggesting that it may be capable of clearing space in bone marrow to support long-term engraftment and rapid recovery in humans. Magenta plans to complete IND-enabling studies this year.

AVROBIO currently uses a personalized conditioning regimen with precision dosing of busulfan, an extensively validated conditioning agent generally considered to be the gold standard for ex vivo lentiviral gene therapy, based on decades of general use and administration to hundreds of patients treated with lentiviral gene therapy candidates. The treating clinician uses therapeutic drug monitoring (TDM) to evaluate how quickly the patient metabolizes busulfan and adjusts the dose regimen accordingly with the goal of achieving the optimum result. AVROBIO has reported early clinical data with this precision conditioning regimen with TDM in its own clinical trials, adding to a body of data that suggest busulfan can effectively clear space in the patients bone marrow, where stem cells engraft, produce generations of daughter cells carrying the therapeutic gene and make the functional protein the patient needs to maintain cellular health.

About AVROBIO

Our mission is to free people from a lifetime of genetic disease with a single dose of gene therapy. We aim to halt or reverse disease throughout the body by driving durable expression of functional protein, even in hard-to-reach tissues and organs including the brain, muscle and bone. Our clinical-stage programs include Fabry disease, Gaucher disease and cystinosis and we also are advancing a program in Pompe disease. AVROBIO is powered by the plato gene therapy platform, our foundation designed to scale gene therapy worldwide. We are headquartered in Cambridge, Mass., with an office in Toronto, Ontario. For additional information, visit avrobio.com, and follow us on Twitter and LinkedIn.

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with autoimmune diseases, genetic diseases and blood cancers. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients. Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com. Follow Magenta on Twitter: @magentatx.

AVROBIO Forward-Looking Statements

This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as aims, anticipates, believes, could, designed to, estimates, expects, forecasts, goal, intends, may, plans, possible, potential, seeks, will, and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our prospective product candidates, the design, commencement, enrollment and timing of ongoing or planned clinical trials, clinical trial results, product approvals and regulatory pathways, anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, timing and likelihood of success, the expected benefits and results of our implementation of the plato platform in our clinical trials and gene therapy programs, the expected safety profile of our investigational gene therapies, and the potential and expected benefits of MGTA-117, Magentas investigational antibody-drug conjugate, including the ability of MGTA-117 to deplete hematopoietic stem and progenitor cells in order to clear space in bone marrow to support long-term engraftment in humans, as well as MGTA-117s potential application to AVROBIOs investigational gene therapies. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Results in preclinical or early-stage clinical trials may not be indicative of results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented.

Any forward-looking statements in this press release are based on AVROBIOs current expectations, estimates and projections about our industry as well as managements current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of AVROBIOs product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials of AVROBIO or our collaborators, the risk that AVROBIO may not successfully recruit or enroll a sufficient number of patients for our clinical trials, the risk that AVROBIO may not realize the intended benefits of our gene therapy platform, including the features of our plato platform, the risk that AVROBIO may not realize the intended benefit of MGTA-117 with respect to AVROBIOs investigational gene therapies, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that we anticipate, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or trials involving AVROBIOs product candidates, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and growth potential of the market for our product candidates will not materialize as expected, risks associated with our dependence on third-party suppliers and manufacturers, risks regarding the accuracy of our estimates of expenses and future revenue, risks relating to our capital requirements and needs for additional financing, risks relating to clinical trial and business interruptions resulting from the COVID-19 outbreak or similar public health crises, including that such interruptions may materially delay our development timeline and/or increase our development costs or that data collection efforts may be impaired or otherwise impacted by such crises, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause AVROBIOs actual results to differ materially and adversely from those contained in the forward-looking statements, see the section entitled Risk Factors in AVROBIOs most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIOs subsequent filings with the Securities and Exchange Commission. AVROBIO explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

Magenta Therapeutics Forward Looking Statements

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including, without limitation, statements regarding the research and clinical collaboration agreement between Magenta and AVROBIO, including the timing, progress and success of the collaboration contemplated under the agreement, the successful evaluation MGTA-117 in conjunction with one or more of AVROBIOs investigational gene therapies under the agreement, the anticipated cost allocation and other commercial terms under the agreement, Magentas strategy and business plan, as well as the future development, manufacture and commercialization between AVROBIO and Magenta. The use of words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation, risks set forth under the caption Risk Factors in Magentas most recent Annual Report on Form 10-K, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission, as well as risks, uncertainties and assumptions regarding the impact of the COVID-19 pandemic to Magentas business, operations, strategy, goals and anticipated timelines, including, without limitation, Magentas ongoing and planned preclinical activities, ability to initiate, enroll, conduct or complete ongoing and planned clinical trials, timelines for regulatory submissions and financial position. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

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AVROBIO and Magenta Therapeutics Announce Collaboration to Evaluate Targeted Antibody-Drug Conjugate as a Potential Conditioning Regimen for...