Publisher Health

Reduced levels of a metabolic hormone known as leptin is linked to poor vaccine antibody responses in the general population, a University of Queensland study has found.
The researchers made the discovery while investigating several cohorts’ responses to the influenza vaccine or hepatitis B vaccine pre-COVID.
UQ’s Professor Di Yu identified a link between the metabolic and immune systems that could be used to develop new strategies for improving vaccine protection in vulnerable populations.
“Using multiple advanced techniques in immunology, genetics and biochemistry, our study found leptin directly promoted the development and function of cells which are vital in triggering an antibody response,” Professor Yu said.
“In collaboration with global teams, we identified the reduction of an essential metabolic hormone called leptin was associated with compromised vaccine responses in both young and older individuals.
“As a result, we can now identify those who are at risk of not generating an antibody response after vaccination.”
Professor Yu said leptin was a metabolic hormone largely produced by fat tissue.

Regular consumption of milk is not associated with increased levels of cholesterol, according to new research.
A study published in the International Journal of Obesity looked at three large population studies and found that people who regularly drank high amounts of milk had lower levels of both good and bad cholesterol, although their BMI levels were higher than non-milk drinkers. Further analysis of other large studies also suggests that those who regularly consumed milk had a 14% lower risk of coronary heart disease.
The team of researchers took a genetic approach to milk consumption by looking at a variation in the lactase gene associated with digestion of milk sugars known as lactose.
The study identified that having the genetic variation where people can digest lactose was a good way for identifying people who consumed higher levels of milk.
Prof Vimal Karani, Professor of Nutrigenetics and Nutrigenomics at the University of Reading said:
“We found that among participants with a genetic variation that we associated with higher milk intake, they had higher BMI, body fat, but importantly had lower levels of good and bad cholesterol. We also found that those with the genetic variation had a significantly lower risk of coronary heart disease. All of this suggests that reducing the intake of milk might not be necessary for preventing cardiovascular diseases.”
The new research was conducted following several contradictory studies that have previously investigated the causal link between higher dairy intake and cardiometabolic diseases such as obesity and diabetes. To account for inconsistencies in sampling size, ethnicity and other factors, the team conducted a meta-analysis of data in up to 1.9 million people and used the genetic approach to avoid confounding.
Even though the UK biobank data showed that those with the lactase genetic variation had 11% lower risk of type 2 diabetes, the study did not suggest that there is any strong evidence for a link between higher milk intake and increased likelihood of diabetes or its related traits such as glucose and inflammatory biomarkers.
Professor Karani said:
“The study certainly shows that milk consumption is not a significant issue for cardiovascular disease risk even though there was a small rise in BMI and body fat among milk drinkers. What we do note in the study is that it remains unclear whether it is the fat content in dairy products that is contributing to the lower cholesterol levels or it is due to an unknown ‘milk factor’.”
The team from the University of Reading, University of South Australia, Southern Australian Health and Medical Research Institute, University College London, and University of Auckland worked together on the study.
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A natural food supplement reduces anxiety in mice, according to a new Weizmann Institute of Science study. The plant-derived substance, beta-sitosterol, was found to produce this effect both on its own and in synergic combination with an antidepressant known under the brand name Prozac. If these findings, published today in Cell Reports Medicine, are confirmed in clinical trials, they could point the way toward the use of beta-sitosterol as a treatment for relieving anxiety in humans.
Anxiety is not always a bad thing. In fact, in evolutionary terms, feeling anxious about potential threats is critical for survival because it helps us mount an appropriate response. That’s precisely why developing antianxiety drugs is so challenging. The circuits for anxiety in the brain are closely related to those responsible for memory, awareness and other functions vital for handling danger, so scientists are on the lookout for compounds that can selectively suppress anxiety without causing unwanted side effects.
The starting point for the present study was research conducted several years ago in the lab of Prof. Mike Fainzilber in Weizmann’s Biomolecular Sciences Department. Dr. Nicolas Panayotis and other lab members studied the roles of proteins that shuttle cargoes into the nuclei of nerve cells, and they discovered that in stressful situations, mice lacking a shuttling protein known as importin alpha-five showed less anxiety than the control mice. The researchers then checked how these “calmer” mice differed from regular ones in terms of gene expression, and they identified a genetic signature of their “calmness”: about 120 genes with a characteristic pattern of expression in the hippocampus, one of the brain regions that regulate anxiety.
In the new study, Panayotis, now a senior intern in Fainzilber’s lab, together with colleagues, searched an international genomic database for existing drugs or other compounds that might mimic the same gene expression signature. He identified five candidates and tested their effects on behavior in mice. That was how the researchers zeroed in on beta-sitosterol, a plant substance sold as a dietary supplement intended mainly to reduce cholesterol levels.
In a series of behavioral experiments, mice given beta-sitosterol showed much less anxiety than the controls. They were, for example, less fearful than the controls when placed in an illuminated enclosure, daring to walk into its brightly lit center, whereas regular mice were careful to stay on the darker periphery, avoiding the stress of the bright light. Moreover, the mice receiving beta-sitosterol did not exhibit any of the side effects that might be expected from antianxiety medications — their locomotion was not impaired, and they did not refrain from exploring novel stimuli.
Next, the researchers tested the effects of beta-sitosterol on mice when given in combination with fluoxetine, a drug belonging to the class of selective serotonin reuptake inhibitors, or SSRIs, and sold under the brand name Prozac, among others. The combination had a synergistic effect: Both beta-sitosterol and fluoxetine reduced the anxiety of mice at lower doses when given together, compared with the doses needed to produce the same effect when they were administered separately.

Scientists are investigating whether rising global temperatures may lead to more stillbirths, saying further study is needed on the subject as climates change.
Researchers from The University of Queensland’s School of Earth and Environmental Science and the Mater Research Institute reviewed 12 studies, finding extreme ambient temperature exposures throughout pregnancy appeared to increase risk of stillbirth, particularly late in pregnancy.
UQ PhD candidate Jessica Sexton said while this was very early research, it did show a possible link between stillbirth and high and low ambient temperature exposures during pregnancy.
“Overall, risk of stillbirth appears to increase when the ambient temperature is below 15 degrees Celcius and above 23.4 degrees Celsius, with the highest risk being above 29.4 degrees Celsius,” Ms Sexton said.
“An estimated 17 to 19 per cent of stillbirths are potentially attributable to chronic exposure to extreme hot and cold temperatures during pregnancy.
“And, as the world’s temperatures rise due to climate change, this link will potentially increase stillbirth likelihood globally.

CRISPR technology allows researchers to edit genomes by altering DNA sequences and by thus modifying gene function. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases and improving crops.
Genome editing tools, such as the CRISPR-Cas9 technology, can be engineered to make extremely well-defined alterations to the intended target on a chromosome where a particular gene or functional element is located. However, one potential complication is that CRISPR editing may lead to other, unintended, genomic changes. These are known as off-target activity. When targeting several different sites in the genome off target activity can lead to translocations, unusual rearrangement of chromosomes, as well as to other unintended genomic modifications.
Controlling off-target editing activity is one of the central challenges in making CRISPR-Cas9 technology accurate and applicable in medical practice. Current measurement assays and data analysis methods for quantifying off-target activity do not provide statistical evaluation, are not sufficiently sensitive in separating signal from noise in experiments with low editing rates, and require cumbersome efforts to address the detection of translocations.
A multidisciplinary team of researchers from the Interdisciplinary Center Herzliya and Bar-Ilan University report in the May 24th issue of the journal Nature Communications the development of a new software tool to detect, evaluate and quantify off-target editing activity, including adverse translocation events that can cause cancer. The software is based on input taken from a standard measurement assay, involving multiplexed PCR amplification and Next-Generation Sequencing (NGS).
Known as CRISPECTOR, the tool analyzes next generation sequencing data obtained from CRISPR-Cas9 experiments, and applies statistical modeling to determine and quantify editing activity. CRISPECTOR accurately measures off-target activity at every interrogated locus. It further enables better false-negative rates in sites with weak, yet significant, off-target activity. Importantly, one of the novel features of CRISPECTOR is its ability to detect adverse translocation events occurring in an editing experiment.
“In genome editing, especially for clinical applications, it is critical to identify low level off-target activity and adverse translocation events. Even a small number of cells with carcinogenic potential, when transplanted into a patient in the context of gene therapy, can have detrimental consequences in terms of cancer pathogenesis. As part of treatment protocols, it is therefore important to detect these potential events in advance,” says Dr. Ayal Hendel, of Bar-Ilan University’s Mina and Everard Goodman Faculty of Life Sciences. Dr. Hendel led the study together with Prof. Zohar Yakhini, of the Arazi School of Computer Science at Interdisciplinary Center (IDC) Herzliya. “CRISPECTOR provides an effective method to characterize and quantify potential CRISPR-induced errors, thereby significantly improving the safety of future clinical use of genome editing.” Hendel’s team utilized CRISPR-Cas9 technology to edit genes in stem cells relevant to disorders of the blood and the immune system. In the process of analyzing the data they became aware of the shortcomings of the existing tools for quantifying off-target activity and of gaps that should be bridged to improve applicability. This experience led to the collaboration with Prof Yakhini’s leading computational biology and bioinformatics group.
Prof. Zohar Yakhini, of IDC Herzliya and the Technion, adds that “in experiments utilizing deep sequencing techniques that have significant levels of background noise, low levels of true off-target activity can get lost under the noise. The need for a measurement approach and related data analysis that are capable of seeing beyond the noise, as well as of detecting adverse translocation events occurring in an editing experiment, is evident to genome editing scientists and practitioners. CRISPECTOR is a tool that can sift through the background noise to identify and quantify true off-target signal. Moreover, using statistical modelling and careful analysis of the data CRISPECTOR can also identify a wider spectrum of genomic aberrations. By characterizing and quantifying potential CRISPR-induced errors our methods will support the safer clinical use of genome editing therapeutic approaches.”
The Hendel Lab and the Yakhini Research Group plan to apply the tool towards the study of potential therapies for genetic disorders of the immune system and of immunotherapy approaches in cancer.
The study is a collaboration between the Hendel Lab at Bar-Ilan University (BIU) and the Yakhini Research Group (IDC Herzliya and the Technion). The project was led by Ido Amit (IDC) and Ortal Iancu (BIU). Also participating in this research were Daniel Allen, Dor Breier and Nimrod Ben Haim (BIU); Alona Levy-Jurgenson (Technion); Leon Anavy (Technion and IDC); Gavin Kurgan, Matthew S. McNeil, Garrett R. Rettig and Yu Wang (Integrated DNA Technologies, Inc. (IDT, US)). Additional contributors included Chihong Choi (IDC) and Mark Behlke (IDT, US).
This study was supported by a grant from the European Research Council (ERC) under the Horizon 2020 research and innovation program, and the Adams Fellowships Program of the Israel Academy of Sciences and Humanities.
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New research indicates that certain anti-cancer therapies may hasten cellular aging, where changes in the DNA of patients may contribute to greater inflammation and fatigue. The findings are published by Wiley early online in CANCER, a peer-reviewed journal of the American Cancer Society.
Gene activity is often adjusted during life through epigenetic changes, or physical modifications to DNA that do not involve altering the underlying DNA sequence. Some individuals may experience epigenetic age acceleration (EAA) that puts them at a higher risk of age-related conditions than other individuals of the same chronological age. Investigators recently examined EAA changes during and following cancer treatment, and they looked for a potential link between these changes and fatigue in patients with head and neck cancer (HNC).
In the study of 133 patients with HNC, half of the patients experienced severe fatigue at some point. EAA was most prominent immediately after radiation therapy, when the average epigenetic age was accelerated by 4.9 years. Increased EAA was associated with elevated fatigue, and patients with severe fatigue experienced 3.1 years higher EAA than those with low fatigue. Also, patients with high levels of markers of inflammation exhibited approximately 5 years higher EAA, and inflammation appeared to account for most of the effects of EAA on fatigue.
“Our findings add to the body of evidence suggesting that long-term toxicity and possibly increased mortality incurred from anti-cancer treatments for patients with HNC may be related to increased EAA and its association with inflammation,” said lead author Canhua Xiao, PhD, RN, FAAN, of the Emory University School of Nursing, in Atlanta. “Future studies could examine the vulnerabilities that may account for sustained high EAA, fatigue, and inflammation among patients.”
The authors noted that interventions to reduce inflammation, including prior to cancer treatment, might benefit patients by decelerating the aging process and subsequently reducing age-related chronic health problems such as fatigue.
An accompanying editorial stresses that chronic fatigue in patients receiving treatment for cancer is not just a symptom; it may also play an important role in influencing patients’ health.
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Having a stroke or a transient ischemic attack (TIA), sometimes called a “mini-stroke,” increases the risk for a stroke in the future. Identifying the cause of the stroke or TIA can lead to specific prevention strategies to reduce the risk of additional strokes, according to an updated guideline from the American Heart Association/American Stroke Association. The guideline is published today in Stroke, a journal of the American Stroke Association, a division of the American Heart Association.
Ischemic strokes account for 87% of strokes in the United States. An ischemic stroke occurs when blood flow in a vessel leading to the brain is blocked, by either clots or plaques. Strokes can lead to serious disability and/or death. A transient ischemic attack, commonly referred to as a TIA, occurs when an artery is blocked for a short amount of time; thus, the blockage is transient (temporary) and does not cause permanent brain injury.
As prevention strategies have improved, studies have noted a reduction in recurrent stroke rates from 8.7% in the 1960s to 5.0% in the 2000s. Yet many risk factors for a second stroke remain poorly managed among stroke survivors.
A new recommendation of the “2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack” is for health care professionals to perform diagnostic evaluations to determine the cause of the first stroke or TIA within 48 hours of symptom onset. The guideline includes a section outlining treatment recommendations based on the cause of the initial stroke/TIA. Underlying causes could be related to blockages in large arteries in the neck or brain, small arteries in the brain damaged from high blood pressure or diabetes, irregular heart rhythms and many other potential causes.
“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” said Dawn O. Kleindorfer, M.D., FAHA, chair of the guideline writing group, and professor and chair of the department of neurology at the University of Michigan School of Medicine in Ann Arbor, Michigan. “If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke.”
For patients who have survived a stroke or TIA, the secondary prevention guidelines recommend:
Managing their vascular risk factors, especially high blood pressure, as well as Type 2 diabetes, cholesterol, triglyceride levels and not smoking.

A study of 1,095 patients hospitalized with COVID-19 discovered that two easily measurable signs of health — respiration rate and blood-oxygen saturation — are distinctly predictive of higher mortality. Notably, the authors said, anyone who receives a positive COVID-19 screening test can easily monitor for these two signs at home.
This context is lacking in current guidance from the Centers for Disease Control and Prevention, which tells people with COVID-19 to seek medical attention when they experience overt symptoms such as “trouble breathing” and “persistent pain or pressure in the chest” — indications that may be absent even when respiration and blood oxygen have reached dangerous levels, the authors say.
“These findings apply to the lived experience of the majority of patients with COVID-19: being at home, feeling anxious, wondering how to know whether their illness will progress and wondering when it makes sense to go to the hospital,” said Dr. Neal Chatterjee of the University of Washington School of Medicine.
Chatterjee and fellow cardiologist Dr. Nona Sotoodehnia were co-lead authors of the paper, which was to be published May 24 in the journal Influenza and Other Respiratory Viruses.
They said the findings suggest that, for some people with COVID-19, by the time they feel bad enough to come to the hospital, a window for early medical intervention might have passed.
“Initially, most patients with COVID don’t have difficulty breathing. They can have quite low oxygen saturation and still be asymptomatic,” said Sotoodehnia. “If patients follow the current guidance, because they may not get short of breath until their blood oxygen is quite low, then we are missing a chance to intervene early with life-saving treatment.”
The researchers examined the cases of 1,095 patients age 18 and older who were admitted with COVID-19 to UW Medicine hospitals in Seattle or to Rush University Medical Center in Chicago. The study span was March 1 to June 8, 2020. The lone exclusions were people who chose “comfort measures only” at time of their admission.

Although many forms of autism spectrum disorder (ASD) are thought to have genetic causes, the cellular and molecular functions of the identified genes remain unclear. Scientists at the Institute of Science and Technology (IST) Austria studied a high-risk gene and discovered its important role during a critical phase of brain development.
Within the European Union alone, about three million people are affected by an autism spectrum disorder (ASD). Some are only mildly affected and can live independent lives. Others have severe disabilities. What the different forms have in common is difficulty with social interaction and communication, as well as repetitive-stereotypic behaviors. Mutations in a few hundred genes are associated with ASD. One of them is called Cullin 3, and it is a high-risk gene: A mutation of this gene almost certainly leads to a disorder. But how exactly does this gene affect the brain? To learn more about it, Jasmin Morandell and Lena Schwarz, PhD students at Professor Gaia Novarino’s research group, turned to mice whose Cullin 3 gene has been partially deactivated and compared them to their healthy siblings. Their results have just been published in the journal Nature Communications.
In a series of behavioral and motoric tests, the team wanted to see if the modified mice mimicked some of the characteristics of patients with this form of autism and could therefore be used as model organisms. In one of these tests, the so-called three-chamber sociability test, a mouse could freely explore three adjacent chambers of a box connected by little doors. Now, the scientists put two other mice in the outer boxes: One was already familiar to the studied mouse, the other mouse it had never met. “Healthy mice usually prefer the new over the already familiar mouse,” Jasmin Morandell, co-first author of the study, explains. The mouse with the altered Cullin 3 gene, however, showed no sign of recognition. Furthermore, the mice had motor coordination deficits as well as other ASD-relevant cognitive impairments. With the help of this mouse model, the team was then able to get to the bottom of the mechanisms that bring about these changes.
A Dangerous Accumulation of Proteins
While studying the mouse brain, the researchers noticed a very subtle but consistent change in the position of some brain cells. These so-called neurons or nerve cells originate from a special region in the brain. From there, they migrate toward the uppermost layers until they find their designated place in the cortex. It is a very sensitive process, where even small changes in the speed at which they travel can change the structure of the cortex. By marking the migrating neurons, the scientists could trace their movements. “We could observe migration deficits — the neurons are stranded in the lower cortex layers,” Lena Schwarz, the other co-first author of the study, describes. But why are the cells not moving as they should?
The answer lies in the important role Cullin 3 plays at the end of life of proteins. When their time has come, the gene Cullin 3 tags them for degradation — a process that has to be tightly regulated to prevent proteins from accumulating. To find out, which proteins are misregulated when Cullin 3 is defective, Morandell and Schwarz systematically analyzed the protein composition of the mouse brain. “We were looking at proteins that accumulate in the mutant brain and found a protein called Plastin 3. Then Gaia came across a poster describing the work of IST Austria’s Schur group in the hallway, and we got very excited,” says Jasmin Morandell. “They independently had been working on Plastin 3 as a regulator of cell motility and had complementary results to ours. That’s when we started working together,” Professor Gaia Novarino remembers.
It turned out that the protein Plastin 3, which was previously unknown in the context of neuronal cell migration, actually plays an important role in this process. “If the Cullin 3 gene is deactivated, the Plastin 3 protein accumulates, causing cells to migrate slower and over shorter distances. This is exactly what we saw happening in the cortex of the Cullin 3 mutant mice,” says PhD student Lena Schwarz.
A Risky Pathway?
All this is taking place during a very early stage of brain development around halfway through pregnancy — long before anyone would notice any difference in the fetus. “Determining these critical windows during brain development could be extremely important to fine-tune the treatment of patients with specific forms of ASD,” explains Novarino, who is committed to improving diagnosis and treatment options for people with ASD. “Following up with the research on Plastin 3 could pave the way for some therapeutics. Inhibiting the accumulation of this protein could eventually alleviate some of the symptoms patients have,” Schwarz says.
“We now know that defective Cullin 3 leads to increased levels of Plastin 3. This tight correlation shows that Plastin 3 protein levels may be an important factor for the control of cell-intrinsic movements,” says Jasmin Morandell. She recently graduated and may use her expertise in brain development to study Huntington’s disease. Lena Schwarz will next turn to additional high-risk ASD genes to see how other proteins in the degradation pathway may be linked to ASD. For the present study, the Novarino group joined forces with the Danzl and Schur groups and a colleague from the University of Rome. “Finishing this extensive study in around two and a half years despite the pandemic was only possible with the support from our neighbors at IST Austria,” Novarino praises the multidisciplinarity at the Institute.

The swift development of vaccines has provided a vital tool to combat the spread of the deadly SARS-CoV-2 virus, but challenges to reaching herd immunity posed by the rise of new mutations and the inability of immunosuppressed people to develop an effective immune response following vaccination point to a need for additional solutions to maximize protection.
A new USC study published in the Journal of Biological Chemistry reveals how therapies targeting a molecular chaperone called GRP78 might offer additional protection against COVID-19 and other coronaviruses that emerge in the future.
Chaperones like GRP78 are molecules that help regulate the correct folding of proteins, especially when a cell is under stress. But in some cases, viruses can hijack these chaperones to infect target cells, where they reproduce and spread. GRP78 has been implicated in the spread of other serious viruses, such as Ebola and Zika.
GRP78 plays more than one role in COVID-19
While studies have shown that SARS-CoV-2, the virus that causes COVID-19, infects cells by binding with ACE2 receptors on their surface, researchers from the Keck School of Medicine of USC examined whether GRP78 has a role as well.
They found that GRP78 serves as a co-receptor and stabilizing agent between ACE2 and SARS-CoV-2, enhancing recognition of the virus’ spike protein and allowing more efficient viral entry into host cells.