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Cell Biology

Postdoc Position in Metabolomics and Proteomics Biomarkers Discovery job with MASARYK UNIVERSITY | 303929 – Times Higher Education

Department:Biomarkers of Disease and HealthFaculty of ScienceDeadline:31 Aug 2022Start date:upon agreementJob type:full-timeJob field:Science and research

Bursar of the Faculty of Science, Masaryk Universityannounces an open competition for the positionPostdoc Position in Metabolomics and Proteomics BiomarkersDiscovery

Workplace:RECETOX, Faculty of Science, Masaryk University in Brno, Czech RepublicType of Contract:temporary position with 1-year contract (with possible extension), non-academicWorking Hours: 1,0 FTE(full-time employment of40 hours per week)Expected Start Date: as soon as possible, or negotiable concerning immigration timelines for non-EU candidatesNumber of Open Positions:1Pay:negotiable Application Deadline:31.8.2022 EU Researcher Profile:R2

About the Workplace

Masaryk Universityis modern, dynamic and the most attractive university in the Czech Republic with ten faculties, more than 6000 staff and 30000 students, awide range of research areas and astrong international position. We are the largest academic employer in the South Moravian Region.

Faculty of ScienceMU,holder of theHR Excellence in Research Awardby the European Commission, is aresearch-oriented faculty, offering university education (Bachelors, Masters, and Doctoral degree programs) closely linked to both primary and applied research and high school teaching of the following sciences: Mathematics, Physics, Chemistry, Biology, and Earth sciences. We are the most productive scientific unit of the Masaryk University generating around 40 % of MU research results.

RECETOXfocuses on interdisciplinary research and education in the area of Environment & Health, studying toxic compounds and their behavior, transport & bioaccumulation to evaluate environmental effects, assess the exposure and health risks to humans, and develop technologies and biotechnologies to break them down.http://www.recetox.muni.cz/en/career/career-at-recetox

Job description

Clinically relevant biochemical, immunological and cellular biomarkers of Alzheimer'sdisease and aging

Dr. Zdenek Spacilis searching for atalented and highly motivated scientistexperienced in mass spectrometry and cell culture. The primary responsibilities will include cerebral organoids' cell culture as amodel system for Alzheimer'sdisease and the application of mass spectrometry-based metabolomics and proteomics to study the underlying mechanisms and early disease biomarkers. The candidate will be involved in amultidisciplinary project combining advanced analytical technology with state-of-the-art cell biology to advance life sciences and medicine.

Biomarkers of health and diseaseresearch group led by Zdenek Spilzdenek.spacil@recetox.muni.czis engaged in metabolomics and targeted proteomics, pioneering non-genetic factors affecting human health.https://www.recetox.muni.cz/en/research/principal-investigators/dr-zdenek-spacil

Skills and Qualifications

The applicant must have:

The applicant should have:

Informalinquiries about the positioncan be sent to Ji Dobe,jiri.dobes@recetox.muni.cz,+420549493268.

We Offer

Application Process

The application shall besubmitted online by 31.8.2022 via an e-application,please find the reference to the e-application in the beginning and end of the advertisement.

The candidate shall provide following:

After submitting your application successfully, you will receive an automatic confirmation email from jobs.muni.cz. In case of problems with filling in the e-application form, please contact us by e-mail:rcx-hr@recetox.muni.cz.

Selection Process

Received applications will be considered carefully in line withprinciples of the EU Charter and Code for Researchers. Selection criteria: (i) meeting qualification requirements described above, (ii) all required documents provided.

If we do not contact you within 10 working days after the application deadline at the latest, it means that we have shortlisted other candidates meeting the position requirements.

Shortlisted candidates will be invited for apersonal or online interview.The Faculty Recruitment Policy (OTM-R) can be seenhere.

Faculty of Science, Masaryk University is an equal opportunity employer. We support diversity and are committed to creating an inclusive environment for all employees.

Visit ourCareer pageand alsoCareer page of Faculty of science.

We are looking forward to hearing from you!

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Postdoc Position in Metabolomics and Proteomics Biomarkers Discovery job with MASARYK UNIVERSITY | 303929 - Times Higher Education

Cell Biology

Mitochondrial DNA mutations are associated with an increased risk of atherosclerosis – News-Medical.Net

Mitochondria are organelles found within most cells, best known for generating the chemical energy required to power cellular functions. Increasingly, however, researchers are discovering how mitochondrial function -; and dysfunction -; play critical roles in numerous diseases, and even aging.

In a new study published in the August 4, 2022 online issue of Immunity, scientists at University of California San Diego School of Medicine and Salk Institute for Biological Studies report a surprising link between mitochondria, inflammation and DNMT3A and TET2, a pair of genes that normally help regulate blood cell growth, but when mutated, are associated with an increased risk of atherosclerosis.

We found that the genes DNMT3A and TET2, in addition to their normal job of altering chemical tags to regulate DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints as a new molecular target for atherosclerosis therapeutics. They also interact with mitochondrial inflammatory pathways, which hints at a new molecular target for atherosclerosis therapeutics."

Gerald Shadel, PhD, co-senior study author and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging at Salk Institute

While studying the roles of DNMT3A and TET2 mutations in clonal hematopoiesis, which happens when stem cells begin making new blood cells with the same genetic mutation, co-senior study author Christopher Glass, MD, PhD, professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and colleagues noted that abnormal inflammatory signaling related to DNMT3A and TET2 deficiency in blood cells played a major role in the inflammation response that promotes development of atherosclerosis.

But the question remained how DNMT3A and TET2 genes were involved in inflammation and atherosclerosis -; the buildup of fatty plaques in arteries and the primary underlying cause of cardiovascular disease. It is estimated approximately half of Americans between the ages of 45 and 84 have atherosclerosis, which is the single leading cause of death in the United States and westernized nations.

"The problem was we couldn't work out how DNMT3A and TET2 were involved because the proteins they code seemingly do opposite things regarding DNA regulation," said Glass. "Their antagonistic activity led us to believe there may be other mechanisms at play, which prompted us to take a different approach and contact Shadel, who had uncovered the same inflammatory pathway years earlier while examining responses to mitochondrial DNA stress."

Inside mitochondria resides a unique subset of the cell's DNA that must be organized and condensed correctly to sustain normal function. Shadel's team had previously investigated the effects of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged correctly.

Shadel and colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from mitochondria into the cell's interior, setting off the same molecular alarms that alert cells to a bacterial or viral invader and trigger a defensive molecular pathway that prompts an inflammatory response.

Glass' and Shadel's labs worked together to better understand why DNMT3A and TET2 mutations led to inflammatory responses similar to those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to examine cells from people with normal cells, those with loss of function mutations in DNMT3A or TET2 expression and those with atherosclerosis.

They discovered that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells that had loss of function mutations and to blood cells from atherosclerosis patients. In all three cases, there was an increased inflammatory response.

They also observed that low levels of DNMT3A and TET2 expression in blood cells led to reduced TFAM expression, which in turn led to abnormal mitochondria DNA packaging, instigating inflammation due to released mitochondrial DNA.

"We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene," said first author Isidoro Cobo, PhD, a postdoctoral scholar in Glass' lab. "Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response. We believe this may exacerbate plaque buildup in atherosclerosis."

Shadel said the findings broaden and deepen understanding of mitochondrial function and their role in disease.

"It's very exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now have direct relevance for a disease like atherosclerosis," said Shadel. "Ever since we revealed this pathway, there has been an explosion of interest in mitochondria being involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts."

Therapeutics that target inflammation signaling pathways already exist for many other diseases. Glass and Shadel believe that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations could form the basis for new treatments.

Source:

Journal reference:

Cobo, I.,et al.(2022) DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages.Immunity.doi.org/10.1016/j.immuni.2022.06.022.

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Mitochondrial DNA mutations are associated with an increased risk of atherosclerosis - News-Medical.Net

Cell Biology

Fully reduced form of vitamin K found to efficiently inhibit ferroptotic cell death – News-Medical.Net

A team of researchers at Tohoku University has reported on a novel function of vitamin K, which is generally known for its importance in blood clotting. The researchers discovered that the fully reduced form of vitamin K acts as an antioxidant efficiently inhibiting ferroptotic cell death. Ferroptosis is a natural form of cell death that is characterized by extensive lipid peroxidation in cellular membranes. In addition, the team identified FSP1 as the warfarin-insensitive enzyme reducing vitamin K, the identity of which had been postulated but remained unknown for more than half a century. Recently, ferroptosis has been implicated as a driver of Alzheimer's disease and acute organ injuries among many other diseases. The findings suggest that vitamin K treatment might be a new powerful strategy to ameliorate these ferroptosis-related diseases.

Since ferroptosis prevention is considered a highly promising approach for the therapy of many degenerative diseases, new mechanisms and compounds regulating ferroptosis are extensively being explored. To identify these new molecules, a team of researchers led by Dr Eikan Mishima (Tohoku University) and Dr Marcus Conrad (Helmholtz Munich), systematically studied several naturally occurring vitamins, as well as their derivatives. "Surprisingly, we identified that vitamin K, including phylloquinone (vitamin K1) and menaquinone-4 (vitamin K2), are able to efficiently rescue cells and tissues from undergoing ferroptosis" Dr Mishima explained.

In 2019 a team of researchers, led by Dr Conrad, identified an enzyme as a novel and strong inhibitor of ferroptosis: ferroptosis suppressor protein-1, short FSP1. The current research team has now found that the fully reduced form of vitamin K (i.e., vitamin K hydroquinone) acts as a strong lipophilic antioxidant and prevents ferroptosis by trapping oxygen radicals in lipid bilayers. In addition, they identified that FSP1 is the enzyme that efficiently reduces vitamin K to vitamin K hydroquinone, thereby driving a novel non-canonical vitamin K cycle. Since vitamin K is critically involved in blood clotting processes, the team additionally showed that FSP1 is responsible for the vitamin K-reduction pathway insensitive against warfarin, which is one of the most prescribed anticoagulants.

Unraveling the identity of this enzyme solved the last riddle of vitamin K metabolism in blood clotting and elucidated the molecular mechanism of why vitamin K constitutes the antidote for warfarin overdosing. Dr Mishima and Dr Conrad have indicated that "our results have the potential to connect the two worlds of ferroptosis research and vitamin K biology. They will serve as a stepping stone for the development of novel therapeutic strategies for diseases where ferroptosis has been implicated." In addition, since ferroptosis most likely constitutes one of the oldest types of cell death, the researchers hypothesize that vitamin K might be one of the most primitive types of naturally occurring antioxidants. "Thus, new aspects of the role of vitamin K throughout the evolution of life are expected to be unveiled."

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Fully reduced form of vitamin K found to efficiently inhibit ferroptotic cell death - News-Medical.Net

Cell Biology

RoslinCT and Lykan Bioscience Combine to Create Leading Advanced Cell Therapy CDMO – GlobeNewswire

RoslinCT and Lykan Bioscience Combine to Create Leading Advanced Cell Therapy CDMO

EDINBURGH, UK AND HOPKINTON, MA, 4 August 2022 RoslinCT, a cell and gene therapy Contract Development and Manufacturing Organisation (CDMO) developing life-changing therapies in Edinburghs BioQuarter, and Lykan Bioscience (Lykan), an innovative CDMO focused on cell-based therapies, today announce that they have entered into a business combination agreement to form a global leading innovative advanced therapies CDMO.

The combined group will offer process development expertise and cGMP manufacturing for a broad range of autologous and allogeneic cell therapies, with unparalleled expertise in gene editing and industry-leading induced Pluripotent Stem Cell (iPSC) capabilities.

The group will benefit from significantly expanded capacity, with process and analytical development laboratories and cGMP manufacturing facilities in Edinburgh, Scotland, and in Hopkinton, Massachusetts. Lykan has a 64,000 sq. ft. state-of-the-art cell therapy manufacturing facility and innovation/development laboratories with 16 cGMP processing suites running by the end of 2022. Further laboratory and cGMP capacity expansion in Scotland is planned to build on RoslinCTs existing 40,000 sq. ft facilities, including 8 cGMP suites.

With demand for high-quality development and manufacturing capacity increasing across the world, this complementary pairing of RoslinCT and Lykan will shorten development and manufacturing timelines for advanced therapy sponsors, facilitating clinical and commercial GMP product release on both sides of the Atlantic.

Earlier in 2022, Global Healthcare Opportunities, or GHO Capital Partners LLP (GHO), the European specialist investor in global healthcare, announced its investment in RoslinCT. As part of the new agreement, GHO is making a majority investment in Lykan and is backing the funding of the combined entity. WindRose Health Investors, previously the majority owner of Lykan Bioscience, have reinvested in the new combined group along with Lykan Management.

RoslinCT CEO Peter Coleman and Lykan President & CEO Patrick Lucy will remain in their current roles. Together, the new entity will have a global headcount of ~300 employees.

Peter Coleman, Chief Executive Officer of RoslinCT said: This combination puts us in a strong position as a leading global CDMO in the process development and manufacturing of advanced cell therapies, and we look forward to working with our new colleagues at Lykan to fuel future growth and meet the increasing demand for innovative therapies.

Patrick Lucy, President & Chief Executive Officer of Lykan Bioscience, commented: We are delighted to combine with RoslinCT to better serve the growing demand for manufacturing capacity and expand the range of innovative services we can provide our partners to support the development of advanced cell and gene therapies.

The Partners at GHO Capital, said, This is a significant step towards the realisation of our shared ambition for RoslinCT and Lykan to build a leading global CDMO in the development and manufacture of advanced cell therapies. The collaboration represents an important step in the continued growth and internationalisation of the two businesses and we look forward to partnering with the combined Management teams and WindRose Health Investors to realise this vision.

CJ Burnes, Partner at WindRose Health Investors, said, Lykan has grown tremendously during our ownership, including completion of their state-of-the art facility and the subsequent doubling of cGMP manufacturing capacity. The combination of RoslinCT and Lykan will further accelerate this growth as it creates a unique platform providing key value-added services to the highly complex segment of advanced cell therapies and we look forward to partnering with GHO, RoslinCT and Lykan Management through this next phase.

Advisors

Ropes & Gray and Slaughter & May acted as legal advisors to GHO, Alvarez & Marsal as financial and tax advisor, Dark Horse Consulting Group as technical advisor and ERM as ESG advisor. McDermott Will & Emery LLP acted as legal advisor to Lykan, and William Blair & Company served as financial advisor.

ENDS

About RoslinCT

RoslinCT is a leading UK Cell Therapy Contract Development and Manufacturing Organisation (CDMO) focused on providing services for companies developing cell-based therapeutic products. Originally founded in 2006 as a spin-out from the Roslin Institute, we built on the broad range of scientific expertise available in the field of cell biology. Based at the Edinburgh BioQuarter, we operate fully licensed GMP manufacturing facilities and have a proven track record in the delivery of cell-based products. For further information, please visit http://www.roslinct.com.

About Lykan Bioscience

Lykan Bioscience is an innovative contract development and manufacturing services organization (CDMO) focused on cell-based therapies. With decades of biopharmaceutical industry experience, Lykan offers a full range of development and manufacturing services. The state-of-the-art, purpose-built facility offering eight independent manufacturing suites is uniquely designed to fully integrate cGMP principles and advanced software solutions to enable real-time testing and release of product. Located in Hopkinton, Massachusetts, 25 miles southwest of downtown Boston and in the proximity of four international airports, Lykan Bioscience is ideally situated to deliver life-saving cell therapy treatments to patients on behalf of their partners. Visit http://www.lykanbio.com

About GHO Capital

Global Healthcare Opportunities, or GHO Capital Partners LLP, is a leading specialist healthcare investment advisor based in London. We apply global capabilities and perspectives to unlock high growth healthcare opportunities, targeting Pan-European and transatlantic internationalisation to build market leading businesses of strategic global value. Our proven investment track record reflects the unrivalled depth of our industry expertise and network. We partner with strong management teams to generate long-term sustainable value, improving the efficiency of healthcare delivery to enable better, faster, more accessible healthcare. For further information, please visit http://www.ghocapital.com

About WindRose Health Investors

WindRose makes equity investments in companies that operate within the services sectors of the healthcare industry. The firm focuses on companies with profitable business models and a demonstrated ability to deliver cost-effective solutions. WindRose manages over $2.6 billion in investments. WindRose is based in New York City. For more information, please email us at info@windrose.com.

Tel: +44 (0) 20 3709 5700ghocapital@consilium-comms.com

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RoslinCT and Lykan Bioscience Combine to Create Leading Advanced Cell Therapy CDMO - GlobeNewswire

Physiology

What is Physiology | American Physiological Society

Physiology is the study of how the human body works under normal conditions. You use physiology when you exercise, read, breathe, eat, sleep, move or do just about anything. Physiology is generally divided into ten physiological organ systems: the cardiovascular system, the digestive system, the endocrine system, the immune system, the muscular ...

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What is Physiology | American Physiological Society

Physiology

Lecturer in Physiology, Teaching and Leadership job with MACQUARIE UNIVERSITY – SYDNEY AUSTRALIA | 303859 – Times Higher Education

The Role

We seek a dynamic and exciting lecturer in physiology to join Macquarie Medical School in the Teaching & Leadership academic job family. You will have experience in teaching in the physiological sciences, ideally with broad expertise in reproductive, musculoskeletal or gastrointestinal physiology, immunology, pharmacology, endocrinology or anatomy.

Teaching & Leadership Academics are specialist academics who dedicate their workload contribution to Teaching, Teaching Leadership, and Service. You will contribute to units within the Bachelor of Clinical Science, Bachelor of Medical Science, and Doctor of Medicine programs through the design & delivery of tutorials, lectures and practical classes, both in person and using innovative asynchronous technologies; convening, review and development of units; designing, administering and marking assessments; participating in peer review of teaching and further educational skill development. Higher degree research supervision may also form a part of teaching-related activities in this job family. The Macquarie University Academic Job Family Framework recognises and rewards the breadth of academic work.

About Us

Macquarie is a university engaged with the real and often complex problems and opportunities that define our lives. Since our foundation 54 years ago, we have aspired to be a different type of university. Over the years, we've grown to become the centre of a vibrant local and global community. Connect with us today.

Macquarie University's Faculty of Medicine, Health, and Human Sciences builds on our aspiration to have the nation's first fully integrated Academic Health Sciences Centre under a university's leadership. It brings together the excellent work of medical and allied-health clinicians and researchers across the University and around the country, with unparalleled access to world-leading clinical resources and research facilities found only on our campus.

The Faculty offers a distinctive suite of capability-based educational programs. Macquarie Medical School is a newly formed unit that combines research excellence in the biomedical and clinical sciences and passion and innovation in our educational missions. In research, the School consists of multidisciplinary teams that span cellular and systems neuroscience, cancer, ophthalmology, cardiovascular and respiratory diseases. In education we train the next generation of successful scientists and doctors to be impactful, insightful and collaborative members of society through out innovative Bachelor of Clinical Science, Bachelor of Medical Science, and MD programs.

To Apply

To be considered for this position please apply online by submitting your CV and a separate (2-3 page) document that describes how you meet each of the itemised selection criteria below.

Essential

Desirable

Appointment level will be in accordance with demonstrated qualifications, skills, and experience. Please note: Applications for this position are only being accepted from Australian citizens or permanent residents or people currently residing in Australia with full working rights.

Specific Role enquiries: Associate Professor Simon McMullan at simon.mcmullan@mq.edu.au

Recruitment Enquiries: Jasmine Xia, HR Assistant at jasmine.xia@mq.edu.au

Applications Close: Sunday 28 August 2022 AEDT 11:55 pm

If you're already part of the Macquarie Group (MQ University, U@MQ, MQ Health, MGSM), you'll need to apply through your employee Workday account. To apply for this job: Login to Workday and go to the Careers App > Find Jobs.

At Macquarie University, we are committed to providing a working environment where each individual is valued, respected and supported to progress. Our priority is to ensure culture, policies and processes are truly inclusive and that no-one is disadvantaged on the basis of their Aboriginal and Torres Strait Islander identity, gender, culture, disability, LGBTIQA+ identities, family and caring responsibilities, age, or religion. We encourage everyone who meets the selection criteria and shares Macquarie University's values of scholarship, empowerment and integrity to apply.

Learn more about our progress towards Equity, Diversity and Inclusion.

https://staff.mq.edu.au/work/diversity-inclusion

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Lecturer in Physiology, Teaching and Leadership job with MACQUARIE UNIVERSITY - SYDNEY AUSTRALIA | 303859 - Times Higher Education

Physiology

Meet a Loper Graduate: Madi Stearnes reminds Lopers to work hard, but also have fun – University of Nebraska at Kearney

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Madi Stearnes of Omaha graduates Friday with a bachelors degree in biology with a health science emphasis. She plans to pursue a nursing degree through the accelerated UNMC program in Kearney.

What does this moment mean to you?This moment is a symbol of all the hard work and amazing times Ive had in the last five years.

How did UNK help prepare you for your future career?UNK helped me prepare by giving me resources that I learned to use during my time here and will continue to use along my path in life.

What activities/organizations were you involved in at UNK? How did that enhance your education?I played volleyball at UNK during my freshman through junior years. This helped a lot with time management and teamwork.

What was your most memorable experience at UNK?I would have to say my most memorable experience was probably when they have the booths out on campus at the beginning of the year (Blue and Gold Welcome Week) and you get to see people you havent seen all summer. It really got me excited for the upcoming school year!

Whos someone from UNK youll never forget?Paul Twigg. He was my Biology 106 professor freshman year and also my research mentor. Not only was he my research mentor, but he offered a lot of good life advice and help in many more ways than just research. For that I have to thank him.

Whats your favorite place on campus?Its got to be Bruner Hall of Science. I spent the majority of my days in that building for classes. Its also where I made a lot of friends.

Tell me about the time when you worked the hardest during your undergraduate career:Probably during my sophomore year when I was in organic chemistry and anatomy and physiology while playing volleyball. That was the year I got little sleep.

What was your favorite class?I would have to say anatomy and physiology was probably my favorite, because it doesnt just have to do with the bones, muscles, organs, etc. Its the what is it and what all can it do that I loved the most.

Who was the most influential person during your undergrad career?My best friend Lexie Trimble. We struggled, laughed, cried and had so much fun together, and today we are still the best of friends. I dont think I would have made it through without her.

What advice do you have for current and future Lopers?Study hard, but dont forget to have fun. And most importantly, if you feel like someones holding you back, let them go. There will be someone a million times better on the other side!

If you could go back in time and do something differently, what would it be?I wish I wouldnt have been so hard on myself. People make mistakes and college is hard. I wish I would have been able to tell myself that.

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Meet a Loper Graduate: Madi Stearnes reminds Lopers to work hard, but also have fun - University of Nebraska at Kearney

Physiology

Engineering the Microbiome to Potentially Cure Disease – UC San Diego Health

Residing within the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human ailments, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease.

Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that dont involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems.

An artists rendering of the concept of re-engineered native bacteria that serve as chassis to introduce therapeutics into the gut microbiome to treat or cure disease. Photo credit: Thom Leach, Amoeba Studios

Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment.

The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individuals native microorganisms and largely disappear quickly.

The lack of engraftment severely limits the use of LBTs for chronic conditions for curative effect or to study specific functions in the gut microbiome, said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health. Published human trials using engineered LBTs have demonstrated safety, but still need to demonstrate reversal of disease. We believe this may be due to problems with colonization.

In a proof-of-concept study, published in the August 4, 2022, online issue of Cell, Zarrinpar and colleagues at University of California San Diego School of Medicine report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies.

Using this method, the group found they can provide long-term therapy in a mouse model of type 2 diabetes.

In theory, native bacteria are already maximally adapted to the luminal environment, Zarrinpar said. Thereby bypassing nearly all the barriers to engraftment and making them an ideal chassis for therapeutic delivery.

In the study, the research team showed that they can take a strain of E. coli native to the host and engineer it to express transgenes that affect its physiology, such as blood glucose levels. The modified native bacteria were then reintroduced into the mouses gut.

After a single treatment, Zarrinpar said the engineered native bacteria engrafted throughout the gut for the lifetime of the treated mice, retained functionality and induced improved blood glucose response for months. The researchers also demonstrated that similar bacterial engineering can be done in human native E. coli.

This work is an exciting step in demonstrating that live bacterial therapeutics can be used for treating or possibly even curing chronic conditions, said the studys first author Baylee Russell, now a graduate student at Harvard University.

In principle, live bacterial therapeutics may be a relatively non-invasive, low risk and cost-effective option for treating a number of diseases. It is worthy of additional exploration. There's still a lot of work that needs to be done, but it will be exciting to see this technology expand in the years ahead.

Zarrinpar said the reluctance by some groups to use undomesticated native bacteria rather than well-known laboratory strains is driven by the assumption that they are difficult to culture and modify, although the study authors note recent studies have demonstrated they can be modified more consistently using newer methods.

None of the individual steps we used or described are particularly difficult, but in combination, they are novel. Together, they clearly demonstrate that we can accomplish what has yet to be achieved with other synthetic biology approaches, said Zarrinpar. That is, functional manipulation of the luminal gut environment to create persistent physiological effects.

Co-authors include: Steven D. Brown, Nicole Siguenza, Irene Mai, Anand R. Saran, Amulya Lingaraju, Erica Maissy, Ana C. Dantas Machado, Antonio F. M. Pinto, Concepcion Sanchez, Leigh-Ana Rossitto, Yukiko Miyamoto, R. Alexander Richter, Lars Eckmann, Jeff Hasty, David J. Gonzalez and Rob Knight, all at UC San Diego; Samuel B. Ho, UC San Diego and VA Health Sciences; and Alan Saghatelian, Salk Institute for Biological Studies.

Funding and support for this research came, in part, from the National Institutes of Health (grants F32 DK113721, F31 HD106762, R01 HL148801-02S1, T32 AR064194, T32 GM007752, K08 DK102902, R03 DK114536, R21 609 MH117780, R01 HL148801, R01 EB030134, R01HL157445, U01 CA265719, P30 DK120515, P30 DK063491, P30 CA014195, P50 AA011999, and UL1 TR001442), the Glenn Foundation for Medical Research Postdoctoral Fellowships in Aging Research, UC San Diego Eureka Foundation, UC San Diego Collaborative Center of Multiplexed Proteomics, AFAR Research Grant for Junior Faculty, National Phenylketonuria Alliance, American Heart Association Beginning Grant-in-Aid (16BGIA27760160), Kavli Institute for Brain and Mind at UC San Diego, Jon I. Isenberg Endowed Fellowship, AASLD Liver Scholar Award and AGA Microbiome Junior Investigator Award.

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Engineering the Microbiome to Potentially Cure Disease - UC San Diego Health

Physiology

WVU Today | EXPERT PITCH: WVU toxicologist calls passage of burn pit bill ‘critical step in improving veteran health’ – WVU Today

Timothy Nurkiewicz, chair of the WVU Department of Physiology and Pharmacology, conducts research in WVUs Inhalation Facility. Nurkiewicz can discuss burn pits, why they pose serious health risks and how theyve made veterans ill. (WVU Photo)

A West Virginia University researcher with expertise in air pollution and inhalation exposures is available to discuss burn pits following this weeks U.S. Senate passage of a bill expanding health care benefits for veterans who developed illnesses after being exposed to such pits.

At WVUs Inhalation Facility, Timothy Nurkiewicz, chair of the School of Medicines Department of Physiology and Pharmacology, and his research team are safely recreating burn pit conditions to examine why they pose such health risks and how theyve made veterans sick.

Quotes:

On the contents of burn pits

A military base isnt like a campsite. In camping, what you pack in, you pack out, right? Well, the military has to prevent the enemy from benefiting from their presence. So, they destroy everything they have. In concept, that makes perfect sense, but in practice, its a horrible thing because youre throwing in everything from standard garbage paper, plastic, fabric, food to paint, oil, batteries, computers and unspent ordnance. And I havent even mentioned the medical waste as well as standard human waste. All of that goes into burn pits, too. Jet fuel was widely used as the main accelerant and the collective process burns at a lower temperature than incinerators. The result is incomplete combustion and tremendous emission production.

On the prevalence of burn pit exposure

If you were deployed in the Middle East, you were probably exposed to the emissions from a burn pit. Every base was a different size, had different operations and burned different things, so everybody was exposed to different toxicants in different combinations. If you jump forward, now you have veterans who are ending their deployments and theyre coming back in large numbers and presenting with some very serious health issues.

On the passage of this bill

The passage of this bill is a critical step in improving veteran health. It comes at a time when a significant number of veterans are ending their deployments and returning home. We have a large population of exposed veterans who can be identified and proactively treated. The challenges in diagnosing CMI (chronic multisymptom illness) associated with burn pit exposures have made it difficult to allocate resources for the illness. This, in turn, leads to the symptoms being treated,but not the root cause. Identifying the mechanisms of toxicity that result from burn pit exposures will lead to more effective treatment, so, thats the greater goal of our research, to provide a more exact diagnosis that is irrefutable from a clinical perspective.

West Virginia University experts can provide commentary, insights and opinions on various news topics. Search for an expert by name, title, areas of expertise or college/school/department in the Experts Databaseat WVU Today.

-WVU-

se/08/04/22

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WVU Today | EXPERT PITCH: WVU toxicologist calls passage of burn pit bill 'critical step in improving veteran health' - WVU Today