Targeting specific protein in smooth muscle cells may cut atherosclerotic plaque formation

 A new study shows targeting a protein in smooth muscle cells can block and decrease buildup of atherosclerotic plaque in mouse models, according to researchers with UTHealth Houston.

The study was published today in Arteriosclerosis, Thrombosis, and Vascular Biology.

Atherosclerosis is a common condition that develops when plaque builds up inside the arteries. Diseases linked to atherosclerosis, such as coronary artery disease, are the leading cause of death in the United States, and nearly half of Americans with the condition don't know they have it. Atherosclerosis can affect most of the arteries in the body, including arteries in the heart, brain, arms, legs, pelvis, and kidneys.

"We are trying to identify new pathways that cause atherosclerotic plaque buildup, in particular pathways that involve a certain cell type, called smooth muscle cells," said Dianna Milewicz, MD, PhD, lead author of the study and professor and President George Bush Chair in Cardiovascular Medicine at McGovern Medical School at UTHealth Houston. "For many years, researchers have been focused on other cell types, like endothelial cells and macrophages, but more recent studies have highlighted a role of smooth muscle cells in plaque formation. We found that if we block a specific protein in smooth muscle cells, we can effectively block the majority of plaque formation from occurring in an animal model."

Using a knockout method, researchers fed genetically modified mice a high fat diet and caused the mice to have high cholesterol levels in their blood to drive atherosclerotic plaque formation. Blocking a specific protein called PERK in these mice resulted in an 80% decrease of atherosclerotic plaque buildup in male mice.

"Males tend to have more of this buildup than females. This tells us that blocking PERK in smooth muscle cells is important in plaque formation. Interestingly, this protein is activated in smooth muscle cells by too much cholesterol in the cells," Milewicz said.

Current treatments to help patients who suffer from atherosclerosis-related conditions include lifestyle and diet changes, medications such as statins and PCSK9 inhibitors, and in more severe cases, procedures to open blocked arteries. However, Milewicz says lifestyle changes may not always help, and current medications have side effects or can be prohibitively expensive.

Researchers are hopeful these findings can translate to clinical care.

"There are a lot of drugs on the market that block the smooth muscle cell pathway," said Abhijnan Chattopadhyay, PhD, first author on the study and a research fellow in the Division of Medical Genetics at McGovern Medical School. "Now that we know this buildup can be blocked by targeting smooth muscle cells, we can use medication that is already available and target this pathway to help patients with atherosclerotic plaque buildup. This is just another way we can block or lower the plaque buildup, especially for those who are unable to prevent atherosclerosis with lifestyle modifications or statins."

Additional McGovern Medical School authors include Suravi Majumder, PhD; Kaveeta Kaw, BS; Zhen Zhou, MD; Siddharth K. Prakash, MD, PhD; Anita Kaw, BA; Maximillian Buja, MD; Callie S. Kwartler, PhD, and Pujun Guan, MM, with McGovern Medical School and The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences. Chen Zhang, MD, with Baylor College of Medicine and Texas Heart Institute, also contributed to the study.

---

Story Source:

Materials provided by University of Texas Health Science Center at Houston. Original written by Jeannette Sanchez. Note: Content may be edited for style and length.

---

Journal Reference:

1. Abhijnan Chattopadhyay, Pujun Guan, Suravi Majumder, Kaveeta Kaw, Zhen Zhou, Chen Zhang, Siddharth K. Prakash, Anita Kaw, L. Maximillian Buja, Callie S. Kwartler, Dianna M. Milewicz. Preventing Cholesterol-Induced Perk (Protein Kinase RNA-Like Endoplasmic Reticulum Kinase) Signaling in Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 2022; DOI: 10.1161/ATVBAHA.121.317451

https://www.sciencedaily.com/releases/2022/06/220616101953.htm

How the cerebellum modulates our ability to socialize

 The cerebellum is essential for sensorimotor control but also contributes to higher cognitive functions including social behaviors. In a recent study, an international research consortium including scientists from Inserm -- University of Montpellier (France), the Institut de Neurociències Universitat Autònoma de Barcelona (INc-UAB) (Spain), and the University of Lausanne (Switzerland) uncovered how dopamine in the cerebellum modulates social behaviors via its action on D2 receptors (D2R). By using different mouse models and genetic tools, the researchers' work shows that changes in D2R levels in a specific cerebellar cell type, the Purkinje cells, alter sociability and preference for social novelty without affecting motor functions. These new findings pave the way to determine whether socially related psychiatric disorders, such as autism spectrum disorders (ASD), bipolar mood disorder, or schizophrenia, are also associated with altered dopamine receptors expression in specific cerebellar cell types.

Dopamine (DA) neurons are a major component of the brain reward system. By encoding motivational value and salience, they tighly regulate motivation, emotional states and social interactions. Although the regulation of these processes has been largely ascribed to neural circuits embedded in limbic regions, recent evidence indicate that the cerebellum, a region primarily involved in motor control, may also contribute to higher cognitive functions including social behaviors. However, whether cerebellar dopamine signaling could participate to the modulation of these functions remained unexplored. Researchers from Inserm -- Montpellier University (France), the Institut de Neurociències UAB (Spain), and the University of Lausanne (Switzerland) uncovered a new role for dopamine as modulator of social behaviors in the mouse cerebellum.

By combining cell type-specific transcriptomics, immunofluorescence analyses and 3D imaging, researchers first demonstrated the presence of dopamine D2 receptors (D2R) in Purkinje cells (PCs), the output neurons of the cerebellar cortex. Using patch-clamp recordings, they were able show D2R modulated synaptic excitation onto PCs. "This first set of results was already determinant for us, as they unveiled that D2R were present in the cerebellum and that, despite their low expression level, they were functional," highlights Dr Emmanuel Valjent, research director at Inserm (France), and coordinator of the study.

The researchers then went on to study their functions. By using genetic approaches to invalidate or overexpress D2R selectively in PCs, they analyzed the impact of these alterations on motor and non-motor cerebellar functions. "We have uncovered an unexpected causal link between PCs D2R expression levels right in the center of the cerebellum, the Crus I/II lobules, and the modulation of social behaviors. Reducing the expression of this specific dopamine receptor impaired the sociability of mice as well as their preference for social novelty, while their coordination and motor functions remained unaffected" explains Dr. Laura Cutando, Marie-Curie researcher at the Mitochondrial Neuropathology research group at INc-UAB, and first author of the article.

This study constitutes a first step towards a better understanding of the role of dopamine in the cerebellum and the mechanisms underlying psychiatric disorders such as schizophrenia, ADHD and anxiety disorders, which have all in common aberrant DA signaing and altered social behaviors.

Story Source:

Materials provided by INSERM (Institut national de la santé et de la recherche médicale). Note: Content may be edited for style and length.

---

Journal Reference:

1. Laura Cutando, Emma Puighermanal, Laia Castell, Pauline Tarot, Morgane Belle, Federica Bertaso, Margarita Arango-Lievano, Fabrice Ango, Marcelo Rubinstein, Albert Quintana, Alain Chédotal, Manuel Mameli, Emmanuel Valjent. Cerebellar dopamine D2 receptors regulate social behaviors. Nature Neuroscience, 2022; DOI: 10.1038/s41593-022-01092-8

https://www.sciencedaily.com/releases/2022/06/220616121543.htm

Genes that are key to brain development

 Scientists are starting to understand the precise workings of a type of gene that, unlike other genes, does not code for proteins -- the building blocks of life.

New research led by the University of Bath shows the mechanism by which genes coding for a subset of long non-coding RNA (lncRNA) interact with neighbouring genes to regulate the development and function of essential nerve cells.

Despite their prevalence on genes coding for lncRNA in the genome (estimates range from 18,000-60,000 lncRNA genes in the human genome compared to 20,000 protein-coding genes), these segments of DNA were once written-off as junk precisely because the information contained within them does not result in the production of a protein. However, it is now clear that some lncRNAs are anything but scrap, and these may come to play a key role in restoring physical function in people who have suffered serious nerve damage.

Although the function of most lncRNA genes remains a mystery, a subset are co-expressed in the brain along with neighbouring genes that code for proteins involved in gene expression control. In other words, genes for these lncRNAs and their protein-coding neighbours work as a pair. Together, they regulate the development and function of essential nerve cells, particularly in the brain during embryonic development and in early life.

The new study describes the regulatory pathway involved in controlling the levels of one of these gene pairs. Their location and quantity in the genome need to be carefully coordinated, as does the timing of their activity.

"We previously defined one of the most profound functions for lncRNA in the brain and our new study identifies an important signalling pathway that acts to coordinate the expression of this lncRNA and the key protein coding gene that it is paired with," explains Dr Keith Vance, lead author of the study from the Department of Biology & Biochemistry at Bath.

"This new research takes us closer to understanding the basic biology of nerve cells and how they are produced. Regenerative medicine is the end-game and with further research we hope to develop a deeper understanding of how lncRNA genes operate in the brain."

He adds: "This knowledge could be important for scientists looking for ways to replace defective neurons and restore nerve function -- for instance in people who have had strokes."

The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and is published today in PLOS Genetics.

---

Story Source:

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

---

Journal Reference:

1. Ioanna Pavlaki, Michael Shapiro, Giuseppina Pisignano, Stephanie M. E. Jones, Jelena Telenius, Silvia Muñoz-Descalzo, Robert J. Williams, Jim R. Hughes, Keith W. Vance. Chromatin interaction maps identify Wnt responsive cis-regulatory elements coordinating Paupar-Pax6 expression in neuronal cells. PLOS Genetics, 2022; 18 (6): e1010230 DOI: 10.1371/journal.pgen.1010230

https://www.sciencedaily.com/releases/2022/06/220616142713.htm

'Early Omicron infection unlikely to protect against current variants': Chinese in Nature

 People infected with the earliest version of the Omicron variant of the coronavirus, first identified in South Africa in November, may be vulnerable to reinfection with later versions of Omicron even if they have been vaccinated and boosted, new findings suggest.

Vaccinated patients with Omicron BA.1 breakthrough infections developed antibodies that could neutralize that virus plus the original SARS-CoV-2 virus, but the Omicron sublineages circulating now have mutations that allow them to evade those antibodies, researchers from China reported on Friday in Nature.

Omicron BA.2.12.1, which is presently causing most infections in the United States, and Omicron BA.5 and BA.4, which now account for more than 21 per cent of new U.S. cases, contain mutations not present in the BA.1 and BA.2 versions of Omicron.

Those newer sublineages "notably evade the neutralizing antibodies elicited by SARS-CoV-2 infection and vaccination," the researchers found in test-tube experiments.

The monoclonal antibody drugs bebtelovimab from Eli Lilly and cilgavimab, a component of AstraZeneca's Evusheld, can still effectively neutralize BA.2.12.1 and BA.4/BA.5, the experiments also showed.

But vaccine boosters based on the BA.1 virus, such as those in development by Pfizer/BioNTech and Moderna, "may not achieve broad-spectrum protection against new Omicron variants," the researchers warned.

Previous research that has not yet undergone peer review has suggested that unvaccinated people infected with Omicron are unlikely to develop immune responses that will protect them against other variants of the coronavirus.

"My personal bias is that while there may be some advantage to having an Omicron-specific vaccine, I think it will be of marginal benefit over staying current with the existing vaccines and boosters," said Dr. Onyema Ogbuagu, and infectious diseases researcher at Yale School of Medicine in New Haven, Connecticut who was not involved in the new study.

"Despite immune evasion, the expectation can be that vaccines will still protect against serious disease," Ogbuagu said. "If you're due for a booster, get a booster. What we've learned clinically is that it's most important to stay up-to-date with vaccines" to maintain high levels of COVID-19 antibodies circulating in the blood.

Adolfo Garcia-Sastre, a microbiology and infectious diseases researcher at the Icahn School of Medicine at Mount Sinai in New York City, suggested that better protection might be seen with vaccines that target multiple strains of the virus or with intranasal vaccines that would increase protection from infection and transmission by generating immunity in the lining of the nose, where the virus first enters.

Garcia-Sastre, who was not involved in the research, said by the time one variant-specific vaccine becomes available, a new variant may well have taken over.

https://www.ctvnews.ca/health/coronavirus/early-omicron-infection-unlikely-to-protect-against-current-variants-1.5953717

North Korea deploys national medical teams to battle intestinal epidemic

 North Korea has dispatched medical crews and epidemiological investigators to a province battling the outbreak of an intestinal disease, state media reported on Sunday.

At least 800 families suffering from what North Korea has only called an "acute enteric epidemic" have received aid in South Hwanghae Province so far.

Enteric refers to the gastrointestinal tract and South Korean officials say it may be cholera or typhoid.

The new outbreak, first reported on Thursday, puts further strain on the isolated country as it battles chronic food shortages and a wave of COVID-19 infections.

On Sunday state news agency KCNA detailed prevention efforts, including quarantines, "intensive screening for all residents," and special treatment and monitoring of vulnerable people such as children and the elderly.

A national "Rapid Diagnosis and Treatment Team" is working with local health officials, and measures are being taken to ensure that farming is not disrupted in the key agricultural area, KCNA said.

Disinfection work is being carried out, including of sewage and other waste, to ensure the safety of drinking and household water, the report said.

https://www.zawya.com/en/life/health/north-korea-deploys-national-medical-teams-to-battle-intestinal-epidemic-rqz6dyba

Fauci Refuses To 'Stop Funding Chinese' Research With US Tax Dollars

 by Eva Fu via The Epoch Times (emphasis ours),

Dr. Anthony Fauci said he was unable to commit to stop federal funding from going to Chinese scientific research, despite the U.S. intelligence community assessing the regime as America’s top adversary.

Fauci, the head of the National Institute of Allergy and Infectious Diseases (NIAID), made the remarks while appearing virtually at the Health, Education, Labor & Pensions Committee hearing on June 16, during an exchange with Sen. Roger Marshall (R-Kansas).

“The NIH is still funding research in China, at least $8 million since 2020. In the Intelligence Community’s 2022 Annual Threat Assessment, the Chinese Communist Party is presented as one of the top threats to the United States, along with Russia, Iran, Syria, and North Korea. To my knowledge, only China is receiving U.S. research dollars,” said the senator during the hearing. “When will you as director of NIAID stop funding research in China?”

Since 2020, the National Institutes of Health (NIH) has awarded a total of $8.3 million in grants to the Chinese Center for Disease Control and Prevention and its division National Center for AIDS/STD Control and Prevention, along with five top public universities in mainland China and Hong Kong, according to the NIH website.

Although this amount doesn’t capture dollars later funneled to a Chinese institution through a U.S.-based organization, such as New York-based EcoHealth Alliance, which had partnered with the Wuhan Institute of Virology to perform coronavirus-related experiments that some experts said fit the definition of gain-of-function research, that is, experiments that increase the pathogenicity or transmissibility of a virus.

Fauci, in response to Marshall’s question, said that the U.S. federal agencies “had very productive peer-reviewed highly regarded research projects with our Chinese colleagues that have led to some major advances in biomedical research.”

“So I don’t think I’d be able to tell you that we are going to stop funding Chinese,” Fauci said.

“We obviously need to be careful and make sure that when we do fund them we have the proper peer review and we go through all the established guidelines,” he continued, adding that “grants that go to foreign countries, including China, have State Department clearance.”

“Dr. Fauci’s remarks prove that China is the drug he just can’t quit,” Marshall later told The Epoch Times about the NIAID head’s response.

Sen. Roger Marshall (R-Kansas) questions Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, at a Senate panel on June 16, 2022. (The Epoch Times via the Senate Health, Education, Labor, and Pensions Committee)

Read more here...

https://www.zerohedge.com/covid-19/fauci-refuses-stop-funding-chinese-research-us-tax-dollars

Questions about the first brain reference charts

 Scientists have created the first reference charts for the human brain, mapping its growth from infancy to 100 years old. Now, they have to grapple with difficult ethical questions about how they should — and perhaps shouldn’t — be used.

The reference charts are visualizations created from aggregating analyses of over 120,000 brain scans to show ranges in brain size, or gray matter volume, for each age. They also track the human brain’s rapid expansion early in life and its gradual shrinking over time. The researchers primarily developed the charts to provide a standardized measurement that other neuroscientists could use for brain imaging research, with the hope that maybe one day it could lead to a tool used in clinics.

“It’s an absolutely spectacular advancement in neuroscience and neuroimaging,” said Judy Illes, professor of neurology and neuroethics at the University of British Columbia.

Right now, the tool is designed purely for research and comes with caveats, including that it’s limited by a lack of age and geographic diversity in the datasets used to build it.

As the researchers build on the charts and as they’re rolled out for use in scientific studies, there are three important questions experts say will have to be answered about how the charts can be used.

What do scientists mean by a benchmark?

The reference charts are designed to be used as benchmarks — or a population average of sorts — that are standardized and can be used across studies. With so many different neuroimaging studies, datasets, and imaging approaches, it’s a technical challenge to understand how the brain evolves across the lifespan, particularly when researchers aren’t able to easily image someone’s brain over time. By having a benchmark built on data from different studies, scientists running other research studies can all use a consistent measure for any time point in the lifespan, and compare it to population averages at the same time.

That kind of reference can help researchers study the structure of the human brain, traits that are specific to age, how the brain develops over time, and how different diseases can affect it. Unlike other benchmarks — like the height and weight percentiles used to measure a baby’s growth — the brain reference charts aren’t ready to be used in clinical care. But even in research, benchmarking can still suggest something universal, and plays into a complex conversation about the role of any sort of “average” in neuroscience research.

“There are always challenges when you aggregate or consolidate data. Invariably people who represent the tails become underrepresented,” said Illes.

Marcello Ienca, a research fellow at the department of health sciences and technology at the Swiss Federal Institute of Technology Zurich, said that an implicit concern is that developing any new benchmark of the human brain could risk medicalization of — and discrimination against — neurodiversity. Ienca said the charts should be used to advance science, but also open the door for a public discussion about the importance of neurodiversity within neuroscience research.

And when the charts are being used as a benchmark, experts said, they need to be carefully accompanied by context whenever they’re used. The study authors said that positions within it don’t confer any value judgment nor any specific clinical disposition. Each brain is unique, resilient, and compensates in different ways in response to damage or dysfunction — a phenomenon known as plasticity, and the reference charts are based on measures of brain structure, not function.

“Just because an individual falls somewhere on a trajectory that isn’t favorable compared to their peers, doesn’t mean it will be a bad outcome. There’s a lot of individual variability in growth trajectories — both for the brain and human development,” said Lucina Uddin, professor in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles.

How do you avoid creating or exacerbating stereotypes?

One critical question is whether people could make associations between brain charts and other features, including education, race and ethnicity, employment status, and criminality, particularly if brain charts are combined with other datasets. There’s a risk that such a use could perpetuate or create inaccurate racist or gender-based stereotypes or fuel discrimination against individuals.

It’s an issue that has also been raised with regard to genetics research. In genetics, such instances of discrimination have already been documented, including cases in which insurance companies and employers have used genetic data to deny hundreds of people employment or insurance based on genetic predisposition to illness.

“We shouldn’t look at this [tool] as the holy grail. We don’t want to get to a point where we say based on your brain chart, you’re not qualified for a job,” said Laura Cabrera, an associate professor of engineering science and mechanics and chair in neuroethics at Penn State University.

For now, experts say that’s not an imminent concern, because of how the researchers designed the scientific framework for the study. If the charts become used more widely, the tool needs to be used in a focused manner with consideration of the negative impacts on self-image that could happen to people who fall outside of normal ranges.

What risks could research carry?

Experts say that for all the research benefits the reference charts could bring, they also come with clear risks if they’re used in the wrong way. Right now, the charts are nowhere close to being used clinically — so many of the most troubling scenarios around clinical use aren’t a reality at this point. And in modern medicine and science, people can’t get their brain scanned for no clinical purpose or anything other than possible disease. But that could change in the long run, particularly given the growth of direct-to-consumer neurotechnologies.

And even the use of reference charts in research carries ethical concerns. Nita Farahany, professor of law and philosophy at Duke Law School, said the charts “holds the potential for important advancements in understanding changes in neurodevelopment over time” — but noted that it also raises the question of what happens if researchers compare brain features between different populations, continents, and cultures. The same questions could be raised by studies that examine associations between the charts and non-clinical outcomes.

Ultimately, “the use of the models — ethically, scientifically, or clinically — comes down to the people who use them. People with expertise also share a responsibility to flag unethical use if it occurs,” said Aaron Alexander-Bloch, director of the Brain-Gene-Development Laboratory at the Children’s Hospital of Philadelphia and senior author of the study.

Illes said it’s critical for neuroethicists to be actively working with neuroscientists to help them ask the right research questions and avoid inappropriate applications of technology. This could include developing an ethics guide that specifies how the tool could be applied in research, and specifying what are the risks of other sensitive research topics including longer-term associations with demographics not related to health and changes in people who don’t need brain scans.

“The goal is never to impede progress or fear-monger, but to very positively anticipate problems that may come down the pipe and provide frameworks and solutions that are responsive to them,” Illes said.

https://www.statnews.com/2022/06/17/brain-reference-charts-questions/