Category Archives: Human Genetics

01 May 2020

Rare but powerful gene variants help scientists understand how disease develops, but they are hard to find. By pooling data on people with different early onset dementias to get cohorts of a workable size, researchers pulled out an association between mutations in the DNA demethylase ten-eleven translocation 2 (TET2) and elevated risk for Alzheimers disease, frontotemporal dementia, and amyotrophic lateral sclerosis. In the May 7 American Journal of Human Genetics, Jennifer Yokoyama at the University of California, San Francisco, and Richard Myers at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, and colleagues report that both coding and noncoding TET2 variants nearly doubled a persons risk, and also meant faster decline in people who already had mild cognitive impairment.

The findings strengthen the idea that certain epigenetic changes can lead to neurodegeneration. The data also suggest that noncoding variants can have a powerful effect, and may indeed be the source of much of the still-unexplained heritability of these diseases, Yokoyama said.

Julie van der Zee at the VIB-University of Antwerp, Belgium, believes this last point is important. An added value of their study design is that they demonstrate that one can have sufficient power to associate disease risk with noncoding regulatory variants, she wrote to Alzforum (full comment below).

Accelerated Decline. Extrapolations predict that TET2 carriers will worsen faster on the CDR-SB than noncarriers. [Courtesy of Cochran et al., American Journal of Human Genetics.]

Geneticists search for rare disease variants in familial and early onset cohorts, but these are small, making it difficult to know whether a hit is statistically significant (Aug 2017 news). Or they sift through exome sequences, but these leave out noncoding variants.

Instead, Yokoyama and colleagues looked for variants linked to two different forms of early onset dementia. They capitalized on pleiotropy, or the ability of one gene to contribute to multiple diseases. The authors pooled data from clinically diagnosed AD and FTD patients seen at the UCSF Memory and Aging Center and the University of Alabama at Birmingham. The AD patients ranged from 45 to 84 years old, with an average age of 59, hence were enriched for early onset cases. Healthy age-matched controls came from UCSF, UAB, and a National Institute of Mental Health healthy aging cohort. People with known genetic mutations, or those who were related to each other, were excluded. The authors also excluded people with non-European ancestry, hoping to make the sample more homogeneous. They ended up with 671 controls and 435 cases, 227 of whom had EOAD and 208 FTD.

First author Nicholas Cochran at HudsonAlpha analyzed cases versus controls to find rare genetic variants enriched in the former. Cochran weeded out any that were predicted to be harmless. To do that, he used Combined Annotation Dependent Depletion (CADD) scores, a metric for assessing how likely a variant is to be pathogenic. The authors considered only variants with CADD scores above 10.

TET2 was the only gene that came up as significant across the whole cohort. Putative deleterious TET2 variants cropped up in 11 people with EOAD, eight with FTD, and one control. Two of them harbored the same variant, for a total of 19 different variants. Intriguingly, nine were in coding regions, 10 in noncoding regions.

Although the variants were equally enriched among participants with EOAD and FTD, the association with disease did not reach statistical significance in either of these smaller groups alone. This suggests that the strategy of pooling across diseases helped uncover the association.

To see if the finding held up, the authors turned to the much larger, late-onset AD cohorts of the Alzheimers Disease Sequencing Project (ADSP) and the Accelerating Medicines Partnership (AMP-AD), as well as early onset AD participants of non-European ancestry in the UCSF cohort. Together, this dataset comprised 2,849 EOAD, LOAD, and FTD cases, and 2,457 controls. Again, TET2 variants associated with disease in the whole cohort, at p=0.003, but missed statistical significance among AD or FTD patients alone.

The authors also saw an enrichment of TET2 mutations in an ALS cohort, Project MinE, suggesting the gene may contribute to this disease, as well. ALS and FTD form part of a biologically related disease spectrum (Sep 2011 news;Apr 2018 news).

The strength of the disease association varied widely across cohorts, with the greatest effect on early onset disease. In the original UCSF and UAB EOAD cohorts, TET2 mutations gave an odds ratio of 29 for developing early onset AD/FTD, while in the smaller, non-European ancestry UCSF cohort, variants increased the likelihood of early onset AD/FTD by 6.4-fold. In the other replication cohorts, which consisted of mostly late-onset AD cases, the odds ratio was less than two. Across all cohorts, this averaged to an odds ratio of 2.3. Rita Guerreiro at the Van Andel Institute in Grand Rapids, Michigan, noted that because of these group differences, it will be important to replicate the TET2 findings in additional cohorts (see comment below).

Do TET2 variants predict how fast a patient will deteriorate? Among 786 ADNI participants who have LOAD, TET2 mutation carriers worsened faster than noncarriers on the CDR-SB. This was particularly pronounced among people with mild cognitive impairment. In the MCI group, carriers declined by an additional 0.64 points per year on the CDR-SB compared with noncarriers. Extrapolated over 12 years for the whole cohort, this comes out to a 10-point decline for carriers, versus two points for noncarriers (see image above). TET2 mutation carriers with MCI also slid 0.43 points per year faster on the MMSE than did noncarriers. However, this cognition finding did not replicate in the UCSF cohort, which has less longitudinal follow-up.

How might TET2 affect disease risk? Seven of the nine coding variants were predicted to result in a loss of function, suggesting the protein is normally protective. As a group, these coding variants tripled a persons risk of developing AD, FTD, or ALS.

The noncoding variants were even more powerful, with an odds ratio of 3.7. We were quite surprised by that finding, Yokoyama said. It suggests that noncoding variants might nearly abolish expression of the gene, resulting in haploinsufficiency, she noted. The authors are now expressing each variant in cultured cells to determine their effects on gene expression. They will also try to identify which genes TET2 demethylates. Typically, demethylation releases gene repression, allowing more transcription of its targets.

Curiously, global brain methylation drops in aging and AD. This would seem to be at odds with a protective effect for the TET2 demethylase (Jun 2010 conference news). But the effect of a specific demethylase depends on its targets; for example, demethylation boosts expression of reelin, which aids memory formation (Mar 2007 news).TET2 mutations have been found to pop up with high frequency in somatic cells in AD and PD blood and brain (Oct 2018 news). In a mouse model of amyloidosis, loss of TET2 accelerated plaque formation and memory problems (Li et al., 2020).

Recently, TET2 was reported to promote a proinflammatory response in microglia, and to be elevated in microglia surrounding amyloid plaques in mouse models and AD brain (Carrillo-Jimenez et al., 2019). The question remains if TET2 in plaque-associated microglia plays a deleterious or beneficial role in AD, noted Miguel Burguillos, University of Seville, Spain, the senior author of that study, in an email to Alzforum (see comment below). Further studies using conditional TET2 knockout mice crossed with an AD model may answer this. Burguillos believes the varying levels of TET2 in neurons and microglia in mouse models hint that the gene could have multiple effects in AD brain.Madolyn Bowman Rogers

See the original post:
Mutations in Epigenetic Gene Linked to Neurodegeneration - Alzforum

Neurodegenerative diseases such as Alzheimers disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia can be devastating for patients and families, particularly in cases when symptoms show up in people younger than 65.

More than 5 million Americans are currently living with Alzheimers disease. Another 20,000-30,000 people have frontotemporal dementia and at least 16,000 have ALS. While scientists have some ideas about what causes these conditions, theres a lot of information they dont have, particularly about how a persons genome the suite of genetic material or DNA that theyre born with might affect disease onset.

Now, scientists at the HudsonAlpha Institute for Biotechnology, the University of California, San Francisco (UCSF) and the University of Alabama at Birmingham (UAB) have uncovered a gene that doubles the risk of becoming ill with one of these diseases.

This work would have been impossible without the grassroots support of local Huntsville donors, said Richard M. Myers, PhD, HudsonAlpha president and science director. Being able to do projects like this that address the underlying causes of multiple different neurodegenerative diseases could make a real difference in finding earlier diagnostics and new treatments.

The researchers gathered DNA samples from more than 1,100 people in an effort led by Jennifer Yokoyama, PhD, an assistant professor of neurology at the University of California, San Francisco. About half of these people were healthy, while the other half had Alzheimers disease, ALS or frontotemporal dementia. Then the scientists used a technique called whole-genome sequencing to learn what each individuals genetic code looks like.

With more than one thousand genetic codes in hand, the researchers used computer programs to comb through the sequences and find genetic variants, or things that were different. They determined that people with neurodegenerative diseases were more likely to have variants in a gene named TET2. They discovered this gene after analyzing both the parts of the genome that serve as a blueprint for making proteins, the molecules that do things in the bodys cells, and the parts of the genome that control when and where those proteins get made.

Then, the research team looked at DNA sequences from more than 32,000 healthy people and people with neurodegenerative diseases. They confirmed that the variants they saw in the first 1,100 genomes they looked at were also present in other people with Alzheimers disease, ALS and frontotemporal dementia more often than in healthy people.

Were excited that we did find a new genetic association here, said Nicholas Cochran, PhD, a senior scientist in the Myers Lab at HudsonAlpha.

You never know what genes might show up in a research project like this, but TET2 is exciting. This gene is the DNA blueprint for a protein called TET2, which has already been shown to have a role in maintaining the brains DNA. The researchers think the variants that they found that lead to a non-functional version of the protein might disrupt how the brain ages and contribute to the development of Alzheimers disease, ALS and frontotemporal dementia.

In addition to the generous support of local Huntsville donors to the HudsonAlpha Foundation Memory and Mobility Program, the work, which was recently published in The American Journal of Human Genetics, was funded by the Rainwater Charitable Foundation, the Daniel Foundation of Alabama, the Larry L. Hillblom Foundation, and the National Institutes of Health National Institute on Aging.

About HudsonAlpha: HudsonAlpha Institute for Biotechnology is a nonprofit institute dedicated to developing and applying scientific advances to health, agriculture, learning, and commercialization. Opened in 2008, HudsonAlphas vision is to leverage the synergy between discovery, education, medicine, and economic development in genomic sciences to improve the human condition around the globe. The HudsonAlpha biotechnology campus consists of 152 acres nestled within Cummings Research Park, the nations second largest research park. The state-of-the-art facilities co-locate nonprofit scientific researchers with entrepreneurs and educators. HudsonAlpha has become a national and international leader in genetics and genomics research and biotech education and includes more than 30 diverse biotech companies on campus. To learn more about HudsonAlpha, visit hudsonalpha.org.

See the original post:
DNA gives clues into risk of developing Alzheimer's disease and other dementias - Alabama NewsCenter

A multi-institutional team of researchers from the HudsonAlpha Institute for Biotechnology, the University of California, San Francisco (UCSF), and the University of Alabama at Birmingham (UAB), have identified a rare genetic variant that sigifnicantly incresases the risk of developing diseases like Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).

Finding evidence for a risk factor that contributes to multiple neurodegenerative diseases is exciting, said Richard M. Myers, Ph.D., president and science director of HudsonAlpha, in a press release. We already know that these diseases share some pathologies. This work shows that the underlying causes of those pathologies may also be shared.

The teams research, Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases was published April 23 in The American Journal of Human Genetics. For their study, the investigators sequenced and analyzed whole genomes of more than 1,100 people of European descent 435 cases of early-onset Alzheimers disease (EOAD) and frontotemporal dementia (FTD) and 671 controls. They found that rare variation in the gene TET2 nearly doubled the risk of developing diseases like Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).

The project wouldnt have been possible without extensive collaboration between institutions, said first author Nicholas Cochran, Ph.D., a senior scientist in the Myers Lab. You end up being able to find things that you cant find working alone.

Jennifer Yokoyama, Ph.D., an assistant professor of neurology at UCSF, collaborated with Cochran on technical details and also managed the projects sample collection, the majority of which were collected over decades at the UCSF Memory and Aging Centerand then sequenced and analyzed at HudsonAlpha.

Once they had the sequencing results, the researchers noticed that many of the patients had early-onset versions of neurodegenerative disease, suggesting there would be a genetic component of their illness. During genome analysis, the researchers looked at both coding and non-coding regions of the genome for DNA sequence variants, a strategy that allowed them to be more confident that any possible genes they discovered would be implicated in these diseases

Upon identifying TET2, the investigators then compared their findings with existing genetic data from more than 32,000 healthy people and people with neurodegenerative diseases. This data confirmed that variants in TET2, in both protein-coding and non-coding regions, were more likely to be present in the genomes of people with AD, ALS, or FTD than in people without these diseases.

Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes, the researchers wrote. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

Next steps for this continued research will focus on how changes in TET2 levels or function could contribute to aging and neurodegenerative disease.

View original post here:
Rare Gene Discovered That Nearly Doubles Risk of Developing a Neurodegenerative Disease - Clinical OMICs News

WASHINGTON: In a breakthrough study, a global collaboration of scientists have discovered more than double human genome regions that influence the risk of developing melanoma.

Joint study leader and QIMR Berghofer statistical geneticist Associate Professor Matthew Law said the researchers identified 33 new regions of the genome and confirmed another 21 previously reported regions that are linked to a person's risk of developing melanoma of the skin.

The research, co-led by QIMR Berghofer, the University of Leeds in the UK, and the National Cancer Institute in the US, has been published today in the prestigious journal of Nature Genetics.

"We also found an association between melanoma and common genetic variants in the gene TP53, which is a gene critical in controlling DNA repair when cells divide, and in suppressing cancer," added Prof Law.

The UK based co-lead author, Dr Mark Iles from the University of Leeds' Institute for Data Analytics, said the researchers examined DNA from 37,000 people who had been diagnosed with melanoma and compared their genetic information to that of nearly 400,000 people with no history of the disease.

"The large population sample made it possible to recognise which regions of the genome were active in people with melanoma," said Dr Iles.

Dr Iles also said: "The population sample we used is three times larger than any previous genetic study on melanoma risk and gives us strong confidence that the new regions we've discovered all play a role in the disease."

"It's a product of power in numbers. The only way to discover these things is by having such a large study population that spans across the globe, and we'd urge more people to sign up for these large melanoma research projects," said Dr Iles.

Melanoma begins in melanocytes, cells in the skin responsible for making the pigment melanin that gives colour to the skin.

Melanin can block some of the harmful effects of UV radiation, which is why people with pale skin are at a higher risk of skin cancer, but the protection is not complete.

Moles also develop from melanocytes and having a high number of moles is a risk factor for melanoma.

Dr Maria Teresa Landi, the co-lead author on the study and senior investigator at the US National Cancer Institute, part of the National Institutes of Health, said the research also uncovered other important clues to the genetic causes of melanoma.

Original post:
Scientists discover human genome regions that influence risk of developing melanoma - Times of India

GE

Global Human Genetics Market: Competitive Landscape

This section of the report lists various major manufacturers in the market. The competitive analysis helps the reader understand the strategies and collaborations that players focus on in order to survive in the market. The reader can identify the players fingerprints by knowing the companys total sales, the companys total price, and its production by company over the 2020-2026 forecast period.

Global Human Genetics Market: Regional Analysis

The report provides a thorough assessment of the growth and other aspects of the Human Genetics market in key regions, including the United States, Canada, Italy, Russia, China, Japan, Germany, and the United Kingdom United Kingdom, South Korea, France, Taiwan, Southeast Asia, Mexico, India and Brazil, etc. The main regions covered by the report are North America, Europe, the Asia-Pacific region and Latin America.

The Human Genetics market report was prepared after various factors determining regional growth, such as the economic, environmental, technological, social and political status of the region concerned, were observed and examined. The analysts examined sales, production, and manufacturer data for each region. This section analyzes sales and volume by region for the forecast period from 2020 to 2026. These analyzes help the reader understand the potential value of investments in a particular country / region.

We Offer up to 30% Discount @ https://www.marketresearchintellect.com/ask-for-discount/?rid=177432&utm_source=LHN&utm_medium=888

Key Benefits for Stakeholders:

The report provides an in-depth analysis of the size of the Human Genetics world market, as well as recent trends and future estimates, in order to clarify the upcoming investment pockets.

The report provides data on key growth drivers, constraints and opportunities, as well as their impact assessment on the size of the Human Genetics market.

Porters 5 Strength Rating shows how effective buyers and suppliers are in the industry.

The quantitative analysis of the Human Genetics world industry from 2020 to 2026 is provided to determine the potential of the Human Genetics market.

This Human Genetics Market Report Answers To Your Following Questions:

Who are the main global players in this Human Genetics market? What is the profile of your company, its product information, its contact details?

What was the status of the global market? What was the capacity, the production value, the cost and the profit of the market?

What are the forecasts of the global industry taking into account the capacity, the production and the value of production? How high is the cost and profit estimate? What will be the market share, supply, and consumption? What about imports and export?

What is market chain analysis by upstream raw materials and downstream industry?

Get Complete Report @ https://www.marketresearchintellect.com/need-customization/?rid=177432&utm_source=LHN&utm_medium=888

About Us:

Market Research Intellect provides syndicated and customized research reports to clients from various industries and organizations with the aim of delivering functional expertise. We provide reports for all industries including Energy, Technology, Manufacturing and Construction, Chemicals and Materials, Food and Beverage and more. These reports deliver an in-depth study of the market with industry analysis, market value for regions and countries and trends that are pertinent to the industry.

Contact Us:

Mr. Steven Fernandes

Market Research Intellect

New Jersey ( USA )

Tel: +1-650-781-4080

Tags: Human Genetics Market Size, Human Genetics Market Trends, Human Genetics Market Growth, Human Genetics Market Forecast, Human Genetics Market Analysis

Original post:
Human Genetics Market Size by Top Key Players, Growth Opportunities, Incremental Revenue , Outlook and Forecasts to 2026 - Latest Herald

"Vaccines take time to develop years, if not decades. But, due to the urgency of the pandemic, the timetable is being shortened."Getty

A COVID-19 vaccine may not be available in Ireland for another year and a half, experts have warned.

The Irish Pharmaceutical Healthcare Association (IPHA) noted that while progress is being made, it could be as late as October 2021 before a vaccine is developed, tested, approved, and manufactured.

The IPHA said, Vaccines take time to develop years, if not decades. But, due to the urgency of the pandemic, the timetable is being shortened.

But scientists know that there can be no short-cuts on the testing needed to ensure a vaccine, or a treatment, is safe and effective.

Read more:Irish scientist leads Oxford COVID-19 vaccine drive considered most promising

Several medicines to treat the virus are already in various stages of development while some are even in the late phase of clinical trials.

Ultimately the IPHA said a vaccine is the only way to effectively protect the worlds population against any further waves of the deadly coronavirus.

Ireland, like many nations around the world, is contributing to the development of a vaccine or treatment, with figures in the pharmaceutical industry working in partnership with government officials, academics, health authorities, patient advocacy groups, and charities in a coordinated response.

Jon Barbour, director of Medical Affairs with pharmaceutical giant GSK Ireland, said, The great challenge in the Covid-19 pandemic is to develop an effective vaccine quickly.

The good news is that this is the first time in history that there has been such a concerted global effort and collaboration between pharmaceutical companies and research organizations to find a specific vaccine.

According to the latest data from the World Health Organization, there are three vaccine candidates in clinical evaluation and at least 67 vaccine candidates in preclinical evaluation globally.

GSK is currently collaborating with fellow pharmaceutical firm Sanofi on an adjuvanted Covid-19 vaccine designed to promote a better immune response to the virus.

Read more:New drug effective against COVID-19 clinical trial shows

Adjuvants can also reduce the amount of a virus required to produce a vaccine.

However, Barbour warned that vaccine development is a lengthy, complex process and there are no shortcuts.

Once a vaccine has come through the clinical trial process, the next challenge will be scaling up manufacturing to produce millions of doses which will require a partnership approach between pharmaceutical manufacturers that have the expertise and resources to produce vaccines to meet global need, he said.

Despite his calls for patience, several other potential vaccines are already heading towards clinical trials.

Johnson & Johnson is to begin human clinical trials on a vaccine this September, with a view to have a several batches available for emergency uses as early as next year.

Pfizer is also Germanys BioNTech to co-develop a potential vaccine while the British American Tobacco Company is also working on a possible solution.

The most advanced effort is taking place at the University of Oxford, where the first human trials for a Covid-19 vaccine began last week.

Professor Adrian Hill, an Irish scientist who has worked on Ebola and malaria vaccines, is heading up the Oxford University Covid-19 vaccine effort which The New York Times says is currently the leader in the search for a workable vaccine.

In the worldwide race for a vaccine to stop the coronavirus, the laboratory sprinting fastest is at Oxford University, the Times reports.

Hill and Oxford researchers had already been working on coronavirus type vaccines and just very recently monkey trials showed the Oxford vaccine protected the animals from Covid-19.

Dublin-born Hill 61, head of the Jenner Institute in Oxford and Professor of Human Genetics developed a fascination with malaria and other tropical diseases as a medical student in Dublin in the early 1980s when he visited an uncle who was a priest working in a hospital during the civil war in what is now Zimbabwe.

Read more:Irish create 3D printed ventilators to fight COVID-19 pandemic

"Vaccines take time to develop years, if not decades. But, due to the urgency of the pandemic, the timetable is being shortened."Getty

Read the original post:
COVID-19 vaccine in Ireland could take a year and a half - IrishCentral

Aspergillus fumigatus colony growth perturbed upon drug exposure. Are lncRNAs involved in antifungal drug response? (photo credit: Darren Thomson)

One of the greatest threats facing global wheat production is the disease, Septoria tritici Blotch, which is caused by the fungus Zymoseptoria tritici. In Europe alone, Z. tritici is responsible for up to 700 million worth of wheat yield loss annually, and an estimated 70% of the total annual fungicide usage is targeted against it. Z. tritici can rapidly evolve resistance in the field and so novel management strategies are urgently required.

Circadian clocks are molecular machineries which are entrained by environmental signals, such as light and temperature, and which regulate key life processes. The aim of this project is to understand whether the circadian clock regulates pathogenicity and development in Z. tritici.

Z. tritici is responsible for up to 700 million worth of wheat yield loss annually, and an estimated 70% of the total annual fungicide usage is against it, with consequent risk of resistance.

Our initial results demonstrated that Z. tritici can detect light, and that this signal influences vegetative growth. We therefore hypothesised that light could be a primary input which regulates the circadian clock of the pathogen.

In the model fungus Neurosopora crassa, the circadian clock is encoded by the three genes white collar-1 (wc-1), white collar-2 (wc-2) and frequency (frq). Our bioinformatic analyses identified homologs in Z. tritici to all three of the N. crassa genes, and these were designated ztwco-1, ztwco-2 and ztfrq. Yeast-two hybrid assays demonstrated that the ZTWCO-2 and ZTWCO-2 proteins interact; a result which is also similar to observations from N. crassa.

In order to understand the role of the putative circadian clock genes in Z. tritici, we generated deletion mutants. Our results to date show that deletion of some of these candidate genes causes defects in vegetative growth, but that the mutants are still able to infect the wheat host.

This is the first in-depth study of the circadian clock in Z. tritici, and our findings open up multiple avenues for future investigation. The long-term aim of this research is to inform future control strategies against Z. tritici, such as timing of fungicide application and identification of novel targets for future fungicide screens.

Anna Tiley is a Government of Ireland Postdoctoral Fellow based in the School of Agriculture and Food Science at University College Dublin, Ireland. She holds a degree in Biological Science from the University of Oxford, and a PhD in Molecular Plant Pathology from the University of Bristol. Anna has over seven years experience working with the wheat pathogen Zymoseptoria tritici, and her research focuses on the genetic basis of development and pathogenicity in this species. Follow on Twitter @tileyanna

I am fascinated by the way how diverse microbial species in the environment establish various modes of molecular interplay. That leads to the formation of complex microbial communities which make remarkable contributions to biogeochemical cycles, biotechnology and maintaining ecosystems.

Our group at the University of Tsukuba, steered under the guidance of Professor Norio Takeshita, contemplates the aspects of reciprocity in environmental microbial communities.

Bacterial-fungal interactions are crucial for understanding the microbial ecosystems that are closely related to agriculture, medicine and the environment.

Currently, our focus falls on fungi and bacteria which comprise a large fraction of the overall soil biomass. Bacterial-fungal interactions are crucial for the understanding of microbial ecosystems that is closely related to agriculture, medicine and the environment.

It is well known that microbial interactions are promoting the activation of cryptic biosynthetic pathways, thereby leading to the production of secondary metabolites. Those metabolites possess not only defense functions but also steer cell to cell communication and other interactive dynamics. However, the majority of studies based on the dynamics of microbiota have used monocultures.

Co-culturing has been proven to be an effective method to mimic conditions existing among microbial interactions within nature. Hence this approach may potentially facilitate the production of novel antimicrobials as well as facilitator molecules.

Together with Momoka Kuchira we were able to characterize the mutualistic relationship between the filamentous fungus Aspergillus nidulans and the gram-positive bacterium Bacillus subtilis (currently under review). Our studies provide evidence of their spatial and metabolic interaction that facilitate inter-species communication thereby exploring untraveled environmental niches and obtaining nutrients. It is understandable that there are extensive untraveled territories of microbial communities. Hence, our next milestone was to further exploit this prospect.

We conducted growth experiments of different combinations of fungal and bacterial species in coculture in selected nutrient rich and minimal conditions to observe the interactive dynamics of bacteria and fungi.

(I) Co-culture of Fungi and Bacteria on solid media. (II & III) Dispersal of bacterial cells (fluorescence) on fungal hyphae. (IV) SEM image denoting fungal-bacterial interaction.

Cocultures were incubated for 1 day up to 4 days prior to microscope imaging. An array of parameters such as velocity of the movement of bacterial cells, travel distance, colonization degree and growth rate were considered to define the specificity of interaction. According to the degree of these interactions and dynamics the combinations were classified into positive, negative and neutral genres.

A selected array of combinations was subjected to LC-MS and tandem spectroscopic analysis and the differences of chemical profiles of pure and co cultures have been analyzed to determine and contrast the production levels of bioactive compounds. By chemically defining the bioactive compounds we subsequently observed the transcriptomic and genomic expression to establish an inference of their genomic potential in the state of co-existence.

We are certain that this approach would gain a more reliable perspective on the ecological context of environmental microbiota in their natural setting. Moreover, it would aid in economical and societal aspects such as bio control and therapeutic value as well as in new possible avenues for yielding antimicrobial compounds.

Gayan Abeysinghe is a graduate student in Microbiology Research Center for Sustainability, Graduate School of Life and Environmental Sciences at the University of Tsukuba, Japan. Gayans research focus directs to impart insights on the microbial communication in the community setting and aims to the discovery and development of novel antimicrobials with better efficiency.

lncRNA remained relatively elusive until sequencing exploded, with the discovery of genomes with small numbers of genes and surprising amounts of junk being transcribed.

In the 1960s, DNA not coding for protein was termed junk DNA. It took another three decades before we begun to understand the gene regulatory potential of this so-called rubbish. In the 1990s, studies discovered small noncoding RNA able to silence gene translation via RNA interference. At this time, a group termed long noncoding RNA (lncRNA) were also uncovered.

Human lncRNAs such as the X chromosome-silencer, Xist, emerged first. Mechanisms included regulating gene expression by altering local epigenetics or by guiding proteins to distant genes. However, lncRNA remained relatively elusive until sequencing exploded, and we were suddenly faced with genomes with unexpectedly small numbers of genes and surprising amounts of junk being transcribed.

Aspergillus fumigatus colony growth perturbed upon drug exposure (photo credit: Darren Thomson).

We now know of numerous regulatory lncRNA which deploy a variety of mechanisms in animals, plants and fungi. For example, Neurospora crassa produces over 2500 lncRNA. However, in the human pathogen, Aspergillus fumigatus, only a handful are known. I sought to uncover A. fumigatus lncRNA and hypothesised that they could influence its response to antifungal drugs.

Using drug exposure RNAseq experiments and a bioinformatics pipeline, we identified over 3000 lncRNA candidates. I was surprised to find over 500 lncRNA were significantly expressed upon exposure to a frontline antifungal, itraconazole. Clustering analysis showed that the lncRNA display similar dose-responsive expression patterns to genes, suggesting these lncRNA are not transcriptional noise. Instead, they are co-ordinately regulated features which may play a role in the A. fumigatus drug response.

Further investigation into these novel lncRNA may inform our understanding of antifungal drug resistance mechanisms.

Danielle Weaver is a postdoctoral researcher at the Manchester Fungal Infection Group at the University of Manchester, UK. She completed her PhD on glycosylation in the foodborne bacterial pathogen, Campylobacter jejuni, but has since shifted focus to work on fungal pathogens. Her current research aims to harness next generation sequencing technologies to develop pathogen and drug resistance diagnostics and investigate RNA biology in Aspergillus fumigatus. Follow on Twitter@dan_weaver1@UofMMFIG

I have developed synthetic biology based-tools for scalable regulation or activation of transcriptionally silent secondary metabolite (SM) gene clusters in filamentous fungi.

Filamentous fungi produce a large variety of interesting SMs, molecules that are not essential for growth, but typically possess bioactivities that are of great value to medicine, agriculture and manufacturing. Many of these SM gene clusters are not expressed under laboratory conditions and may need to be activated or heterologously expressed before the desired products can be obtained.

Synthetic biology has revolutionized metabolic engineering and brings the exploitation of industrial microorganisms to a new level by enabling fine-tuning of gene expression allows the control of entire pathways.

Although filamentous fungi are attracting increasing interest as biotechnological production hosts, efficient genetic tools for their exploitation are limited.

Our work represents the development of synthetic gene regulatory devices, that enables scalable expression of a target gene, ranging from hardly detectable to a level similar to that of highest expressed native genes. Synthetic promoters, which were transcriptionally silent on their own, could be activated at desired level by the introduction of binding sites for the synthetic transcription factor (STF). A gene cluster may require expression levels tuned individually for each gene which is a great advantage provided by this system.

Fluorescence microscopy image of hyphae of a fungal strain expressing fluorescent reporters (STF-GFP-NLS, RFP-SKL).

In the STF, the DNA-binding domain of the qa-1F transcription factor from Neurospora crassa is fused to the VP16 activation domain. This STF controls the expression of genes under control of a synthetic promoter containing quinic acid upstream activating sequence (QUAS) binding elements. Control devices were characterized with respect to three main features: expression of the STF, number of QUAS elements, and the type of core promoter used downstream of the QUAS element.

The versatility of the control device was demonstrated by fluorescent reporters and its application was confirmed by synthetically controlling the penicillin gene cluster in Penicillium chrysogenum for antibiotic production. We anticipate that these well-characterized and robustly performing control devices will be useful tools for silent SM gene cluster activation and for development of filamentous fungi as production hosts.

Lszl Mzsik is a fourth-year PhD student in the laboratory of Arnold Driessen at the University of Groningen, the Netherlands. Within the Horizon 2020 Marie Skodowska-Curie COFUND ALERT program, his project aims at developing new genetic tools for the discovery of novel antibacterial compounds in fungi to tackle the increasing problem of multi-drug resistant bacteria.

View original post here:
Scientists of the future at the 15th European Conference on Fungal Genetics - On Biology - BMC Blogs Network

In December, we reported on an intervention study in Canada by Bosman et al. which investigated whether repeated exposure of the skin to UVB light would alter the gut microbiota composition of healthy female volunteers.

Bosman et al. presented evidence that skin exposure to narrowband UVB light modulated the gut microbiome of a specific human cohort. This study presented an increase of biodiversity, Firmicutes and Proteobacteria, and a decrease of Bacteroidetes.

In the present study, scientists at the Laboratory of Molecular Genetics of Microorganisms, Oswaldo Cruz Institute, Rio de Janeiro, Brazil, used that research to compare it to their own data on Yanomami, an indigenous population in the Amazon. The researchers identified similarities in the gut microbiome of the two studies. Both presented a high abundance of Proteobacteria, which had been observed as a unique feature in the Yanomami gut microbiome, and based on Bosman et al. study, could be associated with their natural sunlight exposure.

The Canadian study reported that human exposure to UVB light could impact the human gut microbiome modulating diverse bacterial taxa. This conclusion was reached after they analyzed a controlled cohort composed of healthy Caucasian females from Vancouver, Canada. The gut microbiome of this cohort was analyzed before and after repeated skin exposure to a Narrow Band UVB light using a phototherapy device.

The scientists in Brazil note that,People living in this city located at 49N latitude are often unexposed to natural UVB light for up to 6 months of the year. Under these circumstances, individuals are unable to produce significant vitamin D3 in their skin, resulting in its reduction in the serum level, with impact to their health...Human exposition to UVB light is a direct consequence of the latitude, altitude, weather, time of day and season of the year and, indirectly, of human behavior and lifestyles.

The Yanomami inhabit a vast area in the Amazon Region, located around the equator in distinct altitudes. This population is naturally exposed to a high incidence of sunlight and ultraviolet radiation. Additionally, this region also lacks air pollution, a factor that blocks the UVB light from sunlight. The authors also note that for the most part, the group does not wear clothing, sunscreen or any type of protection from sun exposure.

The scientists found similarities in the gut microbiome makeup in the Bosman et al.s group artificially exposed to UVB light and the Amazonian hunter-gatherer Yanomami. Moreover, the UVB light exposure seems to modulate and explain some Yanomami gut microbiome features.

In the Canadian study, the gut microbiome of the cohort presented a higher alpha diversity after the exposition to UVB light, as well as an increase in the relative abundance of Firmicutes and Proteobacteria and a decrease in the relative abundance of Bacteroidetes. When looking at Firmicutes phylum, it was noted that the abundance of Lachnospiraceae, Ruminococcus and Clostridiaeae families was significantly enriched. Additionally, some individuals experienced a Verrucomicrobia increase.

Several of these taxonomic features were also observed in the Yanomami and other hunter-gatherers. The microbiome of these traditional groups has been characterized by higher biodiversity and higher Firmicutes to Bacteroidetes ratio contrasting with urban groups. In Bosman et al.s study, Firmicutes increased after UVB exposure with the enrichment of Lachnospiraceae, Ruminococcus and Clostridiaeae families. These Firmicutes families were also abundant in the traditional groups, and abundance of other Firmicutes families/genera was also observed. In fact, genera from Firmicutes phylum are biomarkers of Amazonian traditional groups: Roseburia and Enterococcus (Yanomami/Brazil), Streptococcus and Anaerostipes (Yanomami/Venezuela), Eubacterium and Lachnoclostridium (Matses), Intestinomonas, Flavonicater and Magasphaera (Tunapuco). Therefore, we concluded that Firmicutes taxa could be related to the lifestyle, diet, and environment among human groups.

Another observation in the Canadian study is the fact that Proteobacteria was enriched after UVB light exposure. A high abundance of Proteobacteria was a unique feature within the Yanomami gut microbiome when compared to other traditional groups and urban groups. The authors say this aspect is unexplainable, noting that it seems that the high exposure to UVB light by the Yanomami due to the environment and their particular lifestyle may be related to the enrichment of Proteobacteria. The Brazilian researchers add that the genus Akkermansia from Verrucomicrobia phylum is a Yanomami biomarker and this phylum also presented an increase in few individuals from Bosman et al. after artificial UVB exposure.

Altogether, the association of UVB light with specific microbiome taxonomic profiles observed in distinct populations leads us to consider that UVB light/sunlight is a tangible factor that should be considered as a modulator of the gut microbiome.

The authors conclude that the environment represents one of the main forces associated with the inter-person microbiome variability over the host genetics and other factors, further studies on gut microbiome should take into consideration sunlight exposure as well as latitude in-depth.

Therefore, a broad exploration of the relationship between human beings, the microbiome and the environment fills gaps in knowledge that can lead us to understand the relationship between the preservation of health and the development of diseases.

Sources:Gut Microbes

2020; DOI: 10.1080/19490976.2020.1745044

Skin exposure to sunlight: a factor modulating the human gut microbiome composition

Authors: L. Conteville et al.

Frontiers in Microbiology

2019; 10:2410. DOI:10.3389/fmicb.2019.02410

Skin exposure to narrow band ultraviolet (UVB) light modulates the human intestinal microbiome

Authors: E. Bosman et al.

The rest is here:
Sunlight exposure and its role in skin-gut axis - NutraIngredients-usa.com

The immune responses of a female mouse before pregnancy can predict how likely her offspring are to have behavioral deficits if the immune system is activated during pregnancy, according to researchers from the Center for Neuroscience at the University of California, Davis. The findings, published April 23 in the journal Brain, Behavior, and Immunity, could help resolve what role serious infections during pregnancy play in the later development of conditions such as autism and schizophrenia in offspring.

Both genetics and a variety of environmental risk factors are thought to play a role in mental illness, said Professor Kim McAllister, director of the Center for Neuroscience and senior author on the paper. Most pregnancies are resilient, she said. Although the risk from maternal immune activation is low, it could provide a way in to the underlying problems that lead to schizophrenia or autism.

We dont have a good handle on what causes these diseases, she said. But, maternal infection is a risk factor that we know contributes. So, our research focuses on how to predict which pregnancies are at risk and discover new ways to intervene and prevent disease in offspring.

The first evidence for a role for maternal infection in mental and developmental disorders came from the influenza epidemic of 1918, McAllister said. Epidemiological studies 15 to 20 years later of children who were in gestation at the time showed an increase in these disorders. Other evidence comes from animal studies.

Apart from influenza, a wide variety of viruses and bacteria have been implicated in maternal immune activation. So the effect is more likely due to the mothers reaction to infections than with the infectious organism itself.

To reproduce this in mice, McAllisters team doses pregnant mice with a molecule called polyinosinic:polycytidylicacid, or poly (I:C), which is double-stranded RNA, the genetic material for many viruses including influenza and coronaviruses. The immune system recognizes poly (I:C) as if it were a virus and triggers an immediate inflammatory response, especially releasing a molecule called interleukin-6, or IL-6.

The mice continue with pregnancy and when the offspring are about 2 months old, the researchers test them for behavioral abnormalities, such as repetitive behaviors or freezing in place.

One of the advantages of working with laboratory mice is that they are bred so that they are genetically very similar. That makes it easier to see the effect of particular genes or environmental risk factors.

But when graduate student Myka Estes tried to treat laboratory mice with poly (I:C), she found to her surprise that their responses varied widely, even though the mice were all of the same age and genetic background, housed in the same cages in the same conditions.

Professor Judy Van de Water, an immunologist at the UC Davis School of Medicine and part of Estes thesis committee, suggested looking at baseline immune reactivity in the mice before they became pregnant.

When they did that, the team found that the IL-6 response of a particular mouse to poly (I:C) before it became pregnant could predict the likelihood of behavioral problems in offspring if the mouse were treated with poly (I:C) later during pregnancy.

People assume that their mice are all the same, but there is clearly a wide range of baseline immunoreactivity, McAllister said. That baseline immunoreactivity turns out to predict resilience or susceptibility to immune activation during pregnancy.

We can dose them with poly (I:C) and look at the IL-6 response and predict which ones will have affected offspring if we treat them during pregnancy, she said.

That has a couple of important implications. Firstly, with a reliable model for resilience and susceptibility, researchers can start to work out what genes and proteins involved in brain development are affected by immune activation and how this could lead to neurodevelopmental disorders.

The next steps are to figure out what it is that is different about those mice, McAllister said. Now that we can predict which mice are at risk, we want to determine how specific patterns of immune signaling in the mom cause distinct outcomes in offspring.We are hoping to figure out how maternal infection can lead to no problem in many pregnancies and to a range of distinct diseases in offspring from other pregnancies.

Secondly, it could lead to biomarkers for identifying pregnancies at higher risk from infections and taking steps to protect mothers by vaccination or treatment. That will likely involve further work in mice followed up with experiments in nonhuman primates before moving into human studies.

Additional authors on the study are: at the UC Davis Center for Neuroscience, Kathryn Prendergast, Jeremy MacMahon, Scott Cameron, John Paul Aboubechara, Kathleen Farrelly, Gabrielle Sell, Aurora Horta, Ida Shaffer, Catherine Le, Greg Kincheloe, Danielle John Tan, Cameron Carter and Deborah van der List; and at the UC Davis School of Medicine, Lori Haapanen, Joseph Schauer and Melissa Bauman.

The work was supported by grants from the Simons Foundation Autism Research Initiative, Autism Speaks, several UC Davis fellowships and awards, the NIH and by the NIH-funded Silvio O. Conte Center at UC Davis.

See the original post here:
New Insight on Maternal Infections and Neurodevelopmental Disorders - UC Davis

When Pitt announced last month that its researchers were working on a COVID-19 vaccine and seeing promising results, we held our collective breath. Some of us did celebratory handstands, others made GIFs or imagined the new, intolerable heights Pittsburgh pride might reach with a eureka moment in Oakland.

But weeks after the announcement, few of us know the names or faces of the people leading the charge. We know Jonas Salk, whose Pitt-made polio vaccine ended one of the deadliest epidemics in American history. And now wed like to introduce some of the people working to end this pandemic, which has claimed more than 245,000 lives worldwide in a matter of months.

At Pitt, work is primarily focused on two projects: A vaccine delivered via a fingertip-sized patch called a microneedle array vaccine and a measles vaccine thats been genetically modified to also target the novel coronavirus. (Thats the virus that causes the COVID-19 disease.)

These projects are two of the more than 175 vaccine candidates in various stages of development or testing around the world. And these are the people working to make another medical miracle possible in Pittsburgh.

Quotes have been provided by Pitt.

Title: Associate professor of surgery, Pitt School of Medicine

Hometown: Bari, Italy

Bio: Attended the Bari University School of Medicine and did a post-doctoral fellowship with the Department of Molecular Genetics and Biochemistry at Pitts School of Medicine. Gambotto has also worked on a Zika vaccine, a MERS vaccine, development of an Ebola vaccine, and more.

COVID-19 project: Microneedle Array Vaccine

How it works: A vaccine is delivered with a fingertip-sized patch containing 400 tiny needles. The patch goes on like a Band-Aid and then the needles which are made entirely of sugar and the protein pieces simply dissolve into the skin.

Why its promising: The vaccine was tested on mice and produced enough coronavirus antibodies to potentially neutralize the virus.

Where it stands: The researchers have applied for FDA approval to begin a human clinical trial in the coming months. UPMC spokesperson Erin Hare says the researchers are still negotiating with the FDA and that its hard to know exactly when that testing might start.

Quote: Thats why its important to fund vaccine research, Gambotto said. You never know where the next pandemic will come from.

Research team members: Eun Kim, Shaohua Huang, and Thomas W. Kenniston

Title: Professor and chair, Department of Dermatology at Pitts School of Medicine

Hometown: Greensburg

Bio: Attended Pitt and Harvard Medical School and did an internship at Massachusetts General Hospital in Boston and a fellowship at the Dana-Farber Cancer Institute, also in Boston. Falos career has focused on developing skin cancer immunotherapies, skin-targeted vaccines, treatments for skin aging, and more.

COVID-19 project: Microneedle Array Vaccine

Quote: Our ability to rapidly develop this vaccine was a result of scientists with expertise in diverse areas of research working together with a common goal.

Do microneedles hurt? We developed this to build on the original scratch method used to deliver the smallpox vaccine to the skin, Falo explained. And its actually pretty painless it feels kind of like Velcro.

Hurdles: The major challenges are how to take the vaccine we developed and improve upon it. Right now we dont know what the response will be in humans but we know there are multiple approaches we can take to make an even better vaccine in animals, and so we see this as an iterative process

Lab members: Geza Erdos, Stephen Balmert, Cara Carey, Emrullah Korkmaz, Nikita Patel, and Jiying Zhang

Titles: Director, Center for Vaccine Research at UPMC; Professor of Microbiology and Molecular Genetics, University of Pittsburgh

Hometown: Lurgan, Northern Ireland

Bio: Attended Queens University in Belfast and Boston University School of Medicine. Duprex said his Center for Vaccine Research at Pitt was quickly awarded funding to join the COVID-19 fight because of Pitts long history of working with viruses.

COVID-19 project: Measles Vector Vaccine

How it works: This method involves genetically modifying a measles vaccine to include coronavirus proteins, essentially piggybacking on a time-tested inoculation. The small amounts of weakened coronavirus do the same thing that small amounts of rubeola virus proteins (the cause of measles) do when injected into the body they jumpstart our immune response without causing a full-blown illness, priming our immune systems to recognize and combat the virus ahead of any future exposures.

Why its promising: The measles vaccine is commonplace and considered safe. Using it in this way speeds up development of a potential COVID-19 vaccine. The same has been done with vaccine attempts for Ebola, HIV-1, MERS, SARS, West Nile, Zika, and more.

X factor: Its unclear if a prior measles vaccination has any impact on the effectiveness of this measles-based COVID-19 vaccine. Hare said while that question will need to be addressed in testing, prior research indicates it wont be an issue.

Where it stands: Duprexs research team and their partners have made a candidate vaccine that theyre preparing for animal testing in Paris and Pittsburgh. But mass doses likely wouldnt be available for a year or more.

Quote: There are virologists all around the world who have been trained for this moment.

Lab members: Linda Murphy, Sham Nambulli, and Natasha Tilston-Lunel

Like stories like this? Support us bybecoming a memberorcontributing to our crowdfunding campaign.

By Colin Deppen

Go here to see the original:
Meet the Pitt researchers working to end the COVID-19 pandemic - The Incline