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Researchers move closer to deciphering blood clots from AstraZeneca, J&J’s Covid-19 vaccines

Researchers may be nearing an answer for the mysterious and life-threatening blood clots that appeared on very rare occasions in people who received the J&J or AstraZeneca Covid-19 vaccine.
The new work builds on an early hypothesis researchers in…

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Researchers may be nearing an answer for the mysterious and life-threatening blood clots that appeared on very rare occasions in people who received the J&J or AstraZeneca Covid-19 vaccine.

The new work builds on an early hypothesis researchers in Norway put forward last spring, when the cases first cropped up. They proposed the events were similar to blood clots that can occur in a small subset of patients who receive heparin, one of the most commonly used blood thinners.

In those patients, heparin binds to a protein floating in the blood called platelet factor 4, or PF4, to form a complex. The body recognizes that complex as foreign and begins making antibodies against PF4, triggering a cascade of events. The Norwegian researchers’ smoking gun? People who took the J&J or AstraZeneca vaccine and then suffered life-threatening blood clots also test positive for anti-PF4 antibodies, just as patients with heparin-induced clots do.

But that still left a raft of questions. Most notably: What about these vaccines are causing patients to make antibodies against PF4, a completely unrelated protein?

New work from the Mayo Clinic, Arizona State University and Cardiff University, published this week in Science, points to an answer, as well as potential ways of building new vaccines without the same issue.

Alexander Baker

After reports of the blood clots emerged, Alexander Baker, a researcher at Mayo who focuses on engineering viruses for therapies and vaccines, decided to take a closer look at the AstraZeneca vaccine’s structure. Both J&J and AstraZeneca are viral-vector vaccines. In each case, developers took different versions of a common cold virus called adenovirus, neutered them so they can’t replicate or cause symptoms like a normal virus, and used them as carrier pigeons to deliver the instructions for our cells to produce coronavirus spike protein.

“It seemed reasonable that there was some kind of interaction between the vaccine and [PF4],” Baker told Endpoints News. “But it had not been shown robustly.”

So Baker and his collaborators used a technique called cryo-electron microscopy to look at the AstraZeneca vaccine at an unprecedentedly close scale. They froze the virus to ultra-cool temperatures — less than -180 degrees Celsius — and fired electrons at different angles to get an image of it from different vantage points.

Structure of AstraZeneca vaccine reconstructed from Cryo-Em

Click on the image to see the full-sized version

Abhishek Singharoy

They then stitched those different snapshots to construct a 3D image of the virus’ soccer ball-shaped outer shell. With help from Abhishek Singharoy, a structural biologist at ASU, they determined the atom-by-atom breakdown within the shell.

Using computer simulations, they modeled how that shell would interact in water with a PF4 antibody. Sure enough, it was “regularly forming interactions with the PF4 antibody,” Baker said.

At that point, the groups put the work out as a pre-print, attracting the attention of AstraZeneca executives, who were also trying to decipher the mysterious condition set off by their vaccine. With the company’s help, Baker was able to run a study on a micro-chip to prove out their computer simulation.

Essentially, they strapped the virus to the chip and flowed solution containing a PF4 protein over it. Sure enough, the PF4 latched onto the virus, albeit not too tightly.

“It has moderate binding affinity, which is to say it ain’t that strong, but it ain’t that weak,” Baker said.

That suggests the virus hasn’t evolved to target PF4. Instead, there’s a tragic accidental alignment between the shape of the proteins on the virus and the shape of the human protein.

It also helps reconstruct a plausible story for how the clotting events occur. The AstraZeneca or J&J shot is injected into the muscle in your shoulder. Then, one of two things happens: Either it goes into the bloodstream because it accidentally nicks a vein (as most shots do), or the body drains the virus from your muscle into your lymphatic system, which drains and circulates certain fluid around the body.

In either event, the virus is then exposed to PF4, which is always circulating at low levels but is even more present in inflamed environments, such as directly after a vaccination. The virus binds to PF4 and then drags the human protein on its journey through the body to the lymph nodes, the hub of the immune system.

Researchers have shown that a very small subset of patients has, for whatever reason, pre-existing B cells that can make antibodies against PF4. Once the virus drags it into the lymph nodes, the B cells start churning out those antibodies.

Because antibodies have two arms that can each bind to different PF4 proteins, you end up “grouping together clusters of PF4,” Baker said. “And when this happens, it can overactivate platelets. And from that point, platelets become activated and do what they’re supposed to do — you start forming clots.”

The problem is that the clots are forming in the absence of a wound or the “proper environment,” he said.

Fortunately, their work points to a possible solution. The virus’ soccer ball shell is studded with little protein loops that interact with other proteins. If researchers can pin down exactly how they bind to PF4, they might be able to swap out amino acids to produce a virus that’s still functional for vaccines but can’t bind to PF4 or cause blood clots.

In the meantime, though, these vaccines are still safe and effective, Baker noted. And the risk of blood clots from Covid-19 — along with all the other risks the disease brings — far outstrips the risk from the shot.

“So you’re much better off getting your vaccine,” he said.

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Emergent Health (OTCMKTS: EMGE) Up Big and Getting Noticed by Investors After Biotech Signs LOI to Acquire Fusion Specialty Pharmacy

Emergent Health (OTCMKTS: EMGE) is making an explosive move up the charts after the Company reported it has executed a Binding Letter of Intent to acquire…

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Emergent Health (OTCMKTS: EMGE) is making an explosive move up the charts after the Company reported it has executed a Binding Letter of Intent to acquire Fusion Specialty Pharmacy subject to financing and execution of certain definitive agreements. Fusion generated $3,801,497 in 2021 Revenues, an approximate 100% increase from 2020 Revenues of $1,971,599. The acquisition is projected to close during the 3rd quarter of this year. 

Fusion Specialty Pharmacy is a nationally accredited compounding pharmacy licensed in 27 states and located in St. George, Utah dedicated to formulating creative, individualized, and compounded medications that can improve compliance, maximize the potential for therapeutic success, and reduce the overall cost of healthcare. One of Fusions goals is to offer a personalized service to their patients and help them understand their core ailment. This allows Fusion to work closely with their physicians and create a customized formulation. Fusion offers the personalized attention that other pharmacies are unable to offer due to their business environment. 

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Emergent Health (OTCMKTS: EMGE) Curates Companies and Products, Develops and Sells in the Regenerative Health Space … Its products comprise ingestibles as well as topicals for the whole family. The company distributes its products online and through Content Based Shopping using Influencers to position products in their produced content throughout the United States and Internationally. PharmaZu Corp., its newly acquired subsidiary, is a pure play, e-commerce products and service provider focused on The Pet Community, Pet Pharmacy and Wellness using Influencers and their content, including the pet pharmacy, vet telehealth and pet wellness businesses. Emergent does not claim any of its products are approved by the FDA to diagnose, treat, cure or prevent any disease. 

Earlier this year EMGE executed an agreement with DynaCord, LLC. of Baton Rouge, LA for the co-development and exclusive marketing and distribution of a line of various injectable and topical biologic Exosomes for treatment of arthritis, joint care, wound care, and inflammation for Pets. 

The Human Exosomes market recorded revenue of approximately USD 174.04 million in 2020 and is projected to register a CAGR of 27.89% during the forecast period of 2018 – 2026. During the current period of the COVID-19 pandemic, there is a rising demand for Exosomes, which is driving the market growth. In 2020, Dog ownership increased 54%, Pet Industry sales topped $100 billion dollars and Industry forecasts say pet spending will exceed $275 billion by 2030.

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According to the Agreement, DynaCord shall be the exclusive manufacturer and PharmaZu the exclusive marketer and distributor to retail, veterinarians direct-to-consumer of a line of Pet related Exosome products. Exosomes are small vesicles that are secreted by stem cells. Exosomes have been shown to be key mediators of cell-to-cell communication, delivering a distinct cargo of lipids, proteins and nucleic acids that reflects their cell of origin. The Exosomes released by regenerative cells such as stem cells, for example, are indicated as potent drivers of healing and repair. Whereas Exosomes secreted from diseased cells could be used to detect and diagnose conditions such as cancers at their earliest and most readily treatable phase. Exosomes offer a potential new paradigm in the diagnosis and treatment of disease. A broad range of Exosome-based biomedical applications are now beginning to be assessed in clinical trials. 

Dynacord is led by Keyon Janini. Janini has spent the majority of his life in the medical industry. He co-founded and helped develop DMS, a telemedicine platform. He then went on the become the president of Neuro Technology Institute, an intraoperative monitoring company. Most recently, he founded and grew 5 Leaf Laboratories, a hemp product manufacturer and distributor. He has spent the last 5 years actively navigating the regulatory body surrounding the stem cell industry. 

DynaCord is a leading Exosome biotechnology research and manufacturer, specializing in the development and production of Umbilical Cord Derived Mesenchymal Stem Cell (MSC) Exosome products. 

On the Fusions LOI Koby Taylor CEO of Fusion stated, “I’m looking forward to joining the Emergent Health team and anxious to add my skills and experience to enhancing the overall Emergent Health family of products.” 

James Zimbler, CEO of Emergent added, “We’re very excited about the upcoming acquisition of Fusion Specialty Pharmacy. Fusion will allow us to greatly expand our on-line pet-med offerings through our subsidiary, PharmaZu, Inc. Fusion will also allow Emergent to fulfill orders in all states.” 

Adam Brooks, President of PharmaZu, Inc., stated, “With the addition of Fusion, we will obtain licensure in all 50 States which will allow PharmaZu the ability to fill prescriptions nationwide, greatly expanding the reach of PharmaZu’s pet medicine business.” 

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Currently trading at a $600,000 market valuation EMGE has 75,851,111 shares outstanding out of 200 million authorized, 50,327,516 of which are restricted leaving just 25,523,595 free trading shares and float of 4,083,089 shares. EMGE is an exciting story developing in small caps; while the Company has little assets, they do have some revenues and have just $283,000 in total liabilities. The stock is up big after the Company reported it has executed a binding LOI to acquire Fusion Specialty Pharmacy subject to financing and execution of certain definitive agreements. Fusion generated $3,801,497 in 2021 Revenues, an approximate 100% increase from 2020 Revenues of $1,971,599. The acquisition is projected to close during the 3rd quarter of this year. Biotech’s are particularly explosive and with EMGE shares structure and pending acquisition big things could be in the works here. Microcapdaily will be covering EMGE so make sure you subscribe to Microcapdaily right now so you don’t miss it. 

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Disclosure: we hold no position in EMGE either long or short and we have not been compensated for this article.

The post Emergent Health (OTCMKTS: EMGE) Up Big and Getting Noticed by Investors After Biotech Signs LOI to Acquire Fusion Specialty Pharmacy first appeared on Micro Cap Daily.

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University of Kentucky researchers develop online portal to show how biases in RNA sequences affect gene expression

LEXINGTON, Ky. (June 29, 2022) — A recent publication from researchers at the University of Kentucky explains the importance of identifying and understanding…

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LEXINGTON, Ky. (June 29, 2022) — A recent publication from researchers at the University of Kentucky explains the importance of identifying and understanding how differences between tissues and cells alter gene expression without changing the underlying genetic code.

Credit: Pete Comparoni | University of Kentucky Photo

LEXINGTON, Ky. (June 29, 2022) — A recent publication from researchers at the University of Kentucky explains the importance of identifying and understanding how differences between tissues and cells alter gene expression without changing the underlying genetic code.

Introductory biology classes teach that DNA is transcribed into RNA, which is then translated into proteins. However, many cellular processes affect how quickly transcription and translation occur. Gene expression looks at the differences in RNA concentrations within a cell, and it can help scientists know which genes are active within that tissue or cell.

“Changes in gene expression can significantly affect various diseases and disease trajectories,” said Justin Miller, Ph.D., assistant professor in the UK College of Medicine’s Department of Pathology and Laboratory Medicine.

Miller, who is also affiliated with the Sanders-Brown Center on Aging and Biomedical Informatics, says he and his colleagues previously developed the first algorithm to identify ramp sequences from a single gene sequence. Through their recent work, Miller and fellow UK co-authors Mark Ebbert, Ph.D., and Matthew Hodgman created an online version of that algorithm and showed that ramp sequences change between tissues and cells without changing the RNA sequence.

A ramp sequence is part of the RNA sequence that slows translation at the beginning of the gene by using codons (sequences of three DNA or RNA nucleotides) that are not easily translated. Ramp sequences counterintuitively increase overall gene expression by evenly spacing the translational machinery and preventing collisions later in translation.

In their recent publication in NAR Genomics and Bioinformatics, the researchers present the first comprehensive analysis of tissue- and cell type-specific ramp sequences and report more than 3,000 genes with ramp sequences that change between tissues and cell types, which correspond with increased gene expression within those tissues and cells.

“This research is the first time that variable ramp sequences have been described. Our comprehensive web interface allows other researchers to creatively explore ramp sequences and gene expression,” said Miller.

The research team says this work is important because while there are multiple ways for our RNA to encode the same proteins, the specific RNA sequence is important to regulate protein and RNA levels.

“Essentially, a ramp sequence works like an on-ramp to a freeway so that ribosomes do not crash into each other, but the length and speed limit of that onramp can change depending on the cell and the available resources within that cell,” Miller explained.

He says he enjoyed working on this project not only with his colleagues at UK but as well as his former colleagues at Brigham Young University and his brother, Kyle Miller, at Utah Valley University. Together, the group created a web interface for people to see how ramp sequences correspond with human and COVID-19 gene expression in different tissues and cells.

Miller says he believes this work will eventually impact patient care. “We created an online interface for researchers to query all human genes and see if a specific gene has a ramp sequence in a given tissue and how that gene is expressed within that tissue,” said Miller. “We also show that various COVID-19 genes and human entry factors for COVID-19 have ramp sequences that change between different tissues. Ramp sequences are much more likely to occur in tissues where the virus is known to proliferate.”

So, the researchers believe that COVID-19 genes have genetic biases (ramp sequences) that allow them to use the available cellular machinery to increase their expression. “Our research may help us better predict which tissues and cells new viruses will infect and also provides a potential therapeutic target to regulate tissue-specific gene expression without changing the translated protein,” said Miller.

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers P30AG072946 and R01AG068331, and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM138636. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This work was also funded by the BrightFocus Foundation, under awards A2020118F and A2020161S, and the Alzheimer’s Association, under award 2019-AARG-644082.

The University of Kentucky is increasingly the first choice for students, faculty and staff to pursue their passions and their professional goals. In the last two years, Forbes has named UK among the best employers for diversity, and INSIGHT into Diversity recognized us as a Diversity Champion four years running. UK is ranked among the top 30 campuses in the nation for LGBTQ* inclusion and safety. UK has been judged a “Great College to Work for” three years in a row, and UK is among only 22 universities in the country on Forbes’ list of “America’s Best Employers.”  We are ranked among the top 10 percent of public institutions for research expenditures — a tangible symbol of our breadth and depth as a university focused on discovery that changes lives and communities. And our patients know and appreciate the fact that UK HealthCare has been named the state’s top hospital for five straight years. Accolades and honors are great. But they are more important for what they represent: the idea that creating a community of belonging and commitment to excellence is how we honor our mission to be not simply the University of Kentucky, but the University for Kentucky.


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Advancing Diagnostics for Infectious Diseases

With an ever-expanding menu of assays and products that are germane to the precision medicine landscape we are delighted to be producing this informative…

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Prior to the pandemic, most folks outside of the industry wouldn’t have been familiar with the term reagent. The word, much like PCR, has now become part of common parlance. For those of us immersed in the world of diagnostic assays we know only too well how important reagents are in the process of identifying disease. They are truly an indispensable cog in the life science wheel of productivity. These may take different forms and guises depending on the task at hand but at their heart they serve to do one thing—to provide critical scientific answers in the pursuit of propelling research forward. Yet, in order to do that they need to be produced to the highest quality and reproducibility. Producing highly specified antibodies, for example, is no trivial task and takes careful planning and execution. Custom manufacturer Fortis Life Sciences, powered by a family of leading life science brands, has been at the forefront of producing premium, custom configured products and services to clients across a spectrum of disciplines for a number of years, spanning a broad portfolio of research and commercial applications. Their unrivalled expertise in the design, development and manufacturing of high-quality custom enzymes combined with a tailored, collaborative approach ensures your infectious disease molecular diagnostic assay will be primed for configuration to the exact specifications you need.

With an ever-expanding menu of assays and products that are germane to the precision medicine landscape we are delighted to be producing this informative eBook in partnership with Fortis. We hope it will give you a snapshot into the world of custom reagent manufacturing with a particular focus on infectious disease applications.

 

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The post Advancing Diagnostics for Infectious Diseases appeared first on Inside Precision Medicine.

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