Publisher Health

It’s not clear whether three doses of the Pfizer-BioNTech vaccine will adequately protect young children. But the F.D.A. may authorize the first two doses anyway.The Food and Drug Administration’s upcoming review of the Pfizer-BioNTech coronavirus vaccine for young children is without precedent in recent history.Next week, scientific advisers to the agency will decide whether to endorse two doses of the vaccine for children 6 months through 4 years of age, before clinical trials have shown the full course — three doses — to be effective. Such an authorization would be a first for the agency, many experts say.In fact, interim results from the trial suggested that two doses of the vaccine did not produce a strong immune response in children aged 2 through 4. Results from trials of the third dose are expected in a few weeks.The companies applied for authorization at the urging of the F.D.A., also highly unusual. The fast-moving pandemic has forced federal health officials to make important decisions with limited data before, and they argue that it’s important to begin vaccinating young children now, before a new, potentially more dangerous variant arrives.But the agency’s review of incomplete data as a basis for authorization has alarmed some experts.“We’ve never done that before, that’s what gives me some pause,” said Dr. Gregory Poland, founder and director of the Mayo Vaccine Research Group in Minnesota, and editor in chief of the journal Vaccine. “I don’t like that there isn’t more data.”The third dose is likely to build up immunity in young children, Dr. Poland and several other experts said, but it is not guaranteed to do so. With the ebbing of the Omicron surge, many scientists feel the agency could afford to wait for results on the third shots, which are expected in just a few weeks.Authorizing a vaccine before that may undermine the public’s trust in the regulatory process, and deter parents who are already anxious about immunizing their children, they warn. What if the third dose simply doesn’t work, and millions of parents have already given their children the first two doses?Although children generally do not become seriously ill when infected with the coronavirus, more of them have been hospitalized during the Omicron surge than at any other point in the pandemic. But multiple studies have shown that children who are hospitalized with Covid tend to have conditions that predispose them to severe illness, including diabetes, chronic lung disease or heart problems.Instead of authorizing the vaccine for all 18 million children aged 6 months to 4, the agency might consider recommending it only for children at high risk until more evidence becomes available, some experts said.Still, the spate of infections during the Omicron surge has left some parents eager for a vaccine.“On one side, parents are desperate to get their kids protected. On another side, there is extreme distrust,” said Natalie Dean, a biostatistician at Emory University in Atlanta. “The whole process will need to be approached with care and a lot of transparency.”Today’s 3 Key Reads About Covid1. Mask Debate: Health experts agree masks should come off in schools. But they differ on when.2. How Americans Feel: The U.S. public is frustrated with the pandemic. A wave of new polls shows how much.3. Canada’s Trucker Protests: With no end in sight, the demonstrations in Ottawa are reverberating beyond Canada’s borders.Scientific advisers to the F.D.A. will meet on Feb. 15 to weigh the current data, which will be released on Friday. The Centers for Disease Control and Prevention could recommend the two-dose regimen for the youngest children shortly after that.The Biden administration has promised to respect the recommendations of the advisers. “Please know that the F.D.A. will not cut any corners in their review process,” Dr. Vivek Murthy, the surgeon general, told reporters last week. “They know that they are the gold standard that all of us rely on.”As with the booster recommendations for all adults, the push to immunize children is part of the administration’s plan for the future, according to two federal officials familiar with the discussions: Omicron may be on its way out, but children should be protected before the next variant arrives.“We are also concerned by the notable increase in reports of children experiencing Covid-19 long haul symptoms, including in some cases children developing autoimmune diseases and Type 1 diabetes after having had Covid-19,” Stephanie Caccomo, a spokeswoman for the F.D.A., said.Pediatric doses of the Pfizer-BioNTech vaccine approved for 5- to 11-year-olds.Taylor Glascock for The New York TimesEven if vaccination of young children begins in April, it will be summer before they have had three doses, noted Dr. Diego Hijano, a pediatric infectious disease specialist at St. Jude Children’s Research Hospital, and an investigator for the Pfizer-BioNTech trial. “For sure, by summer we may have a variant of concern that’s spreading around.”But other researchers said preparing for the future was not a compelling enough reason to get ahead of the third-dose clinical trial. The risk-benefit calculus for young children now is very different from that of adults at the start of the pandemic, Dr. Poland said.“When we’re making these considerations for kids, we’re not making it in the smoke and fog and chaos of war,” he said.“I would, as a vaccinologist, just have to sit and think about it a little bit,” Dr. Poland added of the F.D.A.’s decision. “I can just guess that that puzzling is going to take a lot longer for the majority of America’s parents.”Authorization of a two-dose regimen before it is certain the third dose will cinch immunity is likely to encourage some parents to get their children the first two doses in hopes it will put them on the road to protection against the virus; others will want to wait until all the data are available.Evaluation of the Pfizer-BioNTech vaccine has proceeded in stages. First came the large trials of adults that delivered an efficacy of 95 percent, laying the groundwork for the vaccine’s swift authorization for Americans aged 16 and older.The companies then tested the vaccine in adolescents aged 12 to 15, but opted for a 10-microgram dose, a third of the dose for adults. In the youngest children, the companies tested three doses — 3, 10 and 30 micrograms — and chose the lowest dose because it seemed to be safe and yet strong enough to fend off the virus.Unlike the adult trials, the pediatric groups were too small to gauge efficacy by comparing the rate of infections in those who got the vaccine versus just saline water. The F.D.A. instead set antibody levels in people aged 16 to 25 as the benchmark the vaccine must meet in these children.This method, called immunobridging, is commonly used; it was the basis for the vaccine’s authorization in adolescents.As of Jan. 20, the trial had enrolled 1,570 children aged 6 months to 2 years, and 2,328 children aged 2 to 4, according to Pfizer. Roughly twice as many children in each group got the vaccine as received the placebo.In results Pfizer-BioNTech announced in December, children aged 2 to 4 did not produce as many antibodies as adolescents and young adults — meaning that the trial did not meet the bar the F.D.A. had set. The investigators decided to test a third dose in all the children.The Coronavirus Pandemic: Key Things to KnowCard 1 of 3Some mask mandates ending.

On Valentine’s Day, couples all over the world will enjoy romantic dinners to celebrate love and relationships. The association between nutrition and mating is not unique to humans but is reflected across species throughout the animal kingdom. However, direct physiological links connecting food consumption and reproductive behaviors were not suspected until recently.
Scientists from the University of California San Diego studying fruit flies report that a molecule released from the gut after a meal switches their focus from eating to mating. Publishing in the journal Nature, the researchers found that protein-rich food triggers the release of diuretic hormone 31, or “Dh31,” a signaling molecule discovered to be released from the fly’s gastrointestinal tract. Their identification of Dh31, a neuropeptide considered to be a type of chemical messenger, opens the door to the largely unexplored area of gut-to-brain communication beyond feeding behavior.
“We found the transition from feeding to mating and were very surprised that a single molecule would have such a profound influence on behavior decisions,” said Jing Wang, a professor of Neurobiology in the UC San Diego Division of Biological Sciences and the study’s senior author. “Our study provides a mechanistic explanation of how the Dh31 neuropeptide acts on the brain to change the motivational drive of two evolutionarily critical behaviors.”
In investigating the question of how animals change from a feeding-focused behavior to a mating mindset, UC San Diego researchers and their colleagues at UC Santa Cruz used several methods to arrive at their Dh31 molecule discovery, including genetics, three-photon microscopy and fluorescence imaging.
To confirm their finding, the researchers performed genetics experiments in which Dh31 was knocked out of fruit flies. In these cases, the flies kept feeding and held off mating behavior. In other experiments they activated Dh31 and found the flies rapidly flipped to courtship. Instead of the brain, an expected area for the molecule’s release, they found Dh31 originated in the fly’s gut.
“These results indicate that Dh31 is a signaling molecule that reorders the priority of these two contending behaviors: feeding over courtship in the absence of Dh31 and courtship over feeding when Dh31 is released from the gut,” said Wang.
The researchers further described parallels to Dh31’s function as a signaling molecule. Orexin, a neuropeptide molecule, has proven to play a similar role in mammals in the transition from wakefulness to sleep patterns, including rapid eye movement (REM) sleep and non-REM sleep.
These explorations provide insight into decision-making processes when animals switch from one behavior that promotes survival — such as nourishment intake — to a different fundamental behavior such as courtship. Wang said their findings only scratch the surface of understanding how gut hormones function beyond feeding. Future work will investigate how microbiomes factor into gut-to-brain communication.
“This work embodies a multidisciplinary approach to understand behavioral prioritization at multiple levels, from molecules to neurons and circuit function,” said Wang. “This line of work provides us with an empirical paradigm to study the hierarchical organization of different need-based behaviors, a framework established by Abraham Maslow 80 years ago to explain the orderly transition of human behaviors.”
The scientists who contributed to the study include: Hui-Hao Lin, Meihua Christina Kuang, Imran Hossain, Yinan Xuan, Laura Beebe (graduate student), Andrew Shepherd, Marco Rolandi and Jing Wang.
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Materials provided by University of California – San Diego. Original written by Mario Aguilera with contributions from Susy Kim. Note: Content may be edited for style and length.

In a recent study from Lund University in Sweden, researchers discovered that metabolic changes affect how blood cells are formed during embryonic development. They found a previously unknown metabolic switch with a key role in how different types of blood cells develop. This means blood cell formation can be directed towards producing natural killer cells in the laboratory to ultimately be used in a new anti-cancer treatment.
Around two billion natural killer cells circulate in our bodies and play an important role in the body’s defense against cancer and infection. This has led researchers to believe that natural killer cells can be used in immunotherapy treatment for those same illnesses. Therefore, we need to understand how these anti-cancer cells are first produced from blood stem cells originating in the embryo.
“By taking cells from an adult’s tissue — for example a hair follicle or a skin cell — we can reprogram them to an embryonic-like state — so-called iPS cells, induced pluripotent stem cells. Because of the embryonic state, these cells can then develop into different cell types of the body, including blood cells,” says Niels-Bjarne Woods, Associate Professor at Lund University and a corresponding author of the study.
In our system to generate blood cells from iPS cells, the research team found a metabolic switch that can activate the generation of specific blood cell types, and consequently increase the production of natural killer cells.
“In our cells there are mitochondria that function as power plants, where chemical reactions deliver energy for the cells. By feeding the cells differing substances we could impact the energy production and influence which types of blood cells were developed. We performed the studies in the lab first, and then confirmed the result in animals, achieving similar results,” says Niels-Bjarne Woods.
Increased activity in the mitochondria resulted in substantially higher levels of natural killer cells. This shows that metabolism is an important regulator of blood development during the embryonic stage.
“Using metabolic factors, we identified how to control the production of specific blood cells from iPS cells. We plan to modify the natural killer cells to target and destroy specific cancers. Transplanting genetically modified natural killer cells from iPS cells is the next big hope for anti-cancer therapies,” concludes Niels-Bjarne Woods. “We just made producing natural killer cells more on-demand.”
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Transcription factors (TFs) are the most essential protein group for the cellular development, differentiation and maintaining homeostasis. They drive complex patterns of gene expression in cells in all stages of development. Defects in TF signalling often lead to developmental disorders and diseases.
However, while TF DNA binding has been widely studied, we are still lacking a systems-level understanding on how TF activity and signalling is controlled via their interactions with multiple proteins, such as cofactors, dimerization partners, chromatin modulating proteins, enzymes, inhibitory proteins and general transcription factors.
A research team at the University of Helsinki decided to initiate a large study to shed light on TF protein-protein interactions and TF regulation. The new study is published in Nature Communications.
“We introduced a comprehensive interactome analysis of more than 100 TFs, revealing over 7,000 TF protein-protein interactions, most of which are in nuclear and play important roles in transcriptional regulation,” says Research Director Markku Varjosalo from the Institute of Biotechnology, HiLIFE.
Findings pave the way for further studies on the TF regulation
The large number of TF interactions discovered in this study enabled researchers to conduct a systems-level analysis that revealed groups of TFs with specific biological functions, such as chromatin remodelling and RNA splicing.
“Interestingly, almost half of the studied TFs interacted with the nuclear factor family of TFs. Nuclear factors are known to control a plethora of genes and organogenesis during development and their aberrant activity is linked to several human cancer types. Our data suggest that transcription control by NFIs may be regulated by nuclear factor interactions with other TFs,” states Dr. Helka Göös, the lead author of the study.
The study provides the first comprehensive and complementary overview on the physical and functional interactions of the human transcription factors. The new findings pave the way for further studies on the TF regulation.
“Our lab has been for that last 10 years heavily involved in identifying and studying the disease mechanisms of individual transcription factor mutations in cancer and in immunodeficiencies. TFs have proven to be difficult drug targets, however several of their key regulators are much more promising. Our generated large information atlas on the TFs could act as a rich resource for also drug discovery studies to identify pharmaceutical treatment for TF-related diseases,” ends Dr. Varjosalo.
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Materials provided by University of Helsinki. Note: Content may be edited for style and length.

Scientists at McMaster University who have developed an inhaled form of COVID vaccine have confirmed it can provide broad, long-lasting protection against the original strain of SARS-CoV-2 and variants of concern.
The research, recently published in the journal Cell, reveals the immune mechanisms and significant benefits of vaccines being delivered directly into the respiratory tract, rather than by traditional injection.
Because inhaled vaccines target the lungs and upper airways where respiratory viruses first enter the body, they are far more effective at inducing a protective immune response, the researchers report.
The reported preclinical study, which was conducted on animal models, has provided the critical proof of concept to enable a Phase 1 clinical trial that is currently under way to evaluate inhaled aerosol vaccines in healthy adults who had already received two doses of a COVID mRNA vaccine.
The tested COVID vaccine strategy was built upon a robust tuberculosis vaccine research program established by Zhou Xing, a co-lead author of the new study and a professor at the McMaster Immunology Research Centre and Department of Medicine.
“What we’ve discovered from many years’ research is that the vaccine delivered into the lung induces all-around protective respiratory mucosal immunity, a property that the injected vaccine is lacking,” Xing says.

The microbiome is home to an estimated 100 trillion bacteria, existing as a dense colony of many different strains and species. Similar to all organisms, bacteria must also compete with one another for space and resources, engaging in “warfare” by releasing toxins to kill competitors. One of the many weapons bacteria use in this inevitable fight is the type VI secretion system (T6SS), which delivers toxic effectors into their enemies. The groups of Stefan Raunser from the Max Planck Institute of Molecular Physiology in Dortmund and John Whitney from McMaster University in Canada, have now together uncovered the high-resolution 3D structure of such an effector from Pseudomonas protegens by cryo-electron microscopy. The effector protein, called RhsA, has a toxic component that sits unlocked and ready to be fired within a molecular cocoon sealed by a cork-like structure. Their findings will not only help in understanding how the T6SS machinery works, but will also promote the future development of antibacterial treatments and plant protection strategies.
The beneficial bacterium Pseudomonas protegens protects plants from fungi and bacteria. However, behind this seemingly selfless act lies a complex system by which the bacteria try to occupy a biological niche by eliminating their competitors. For this purpose, bacteria have developed a whole arsenal of poisons and a variety of injection systems to prepare them for battle.
Like a poison dart
One of the most widely-used injection machinery in Gram-negative bacteria is the type VI secretion system. When this machinery is activated, a nanotube is assembled in the cell interior, through which a poison dart with deadly toxic proteins on its tip is shot into a competitor. The 3D structure of one of these toxic proteins, the bacterial RhsA effector, has now been solved by the team of Stefan Raunser along with the team of John Whitney. The scientists found that the RhsA effector consists of three connecting pieces: the toxic weapon itself, a cocoon surrounding it, and a cork-like plug which seals the toxin encapsulating cocoon entirely.
Unlocking a bacterial weapon
“The cocoon protects the bacterium from its self-produced toxin,” Stefan Raunser says. “We already observed a very similar strategy in bacterial Tc toxins.” The scientists have shown that the effector protein itself cleaves the seal and the toxin from the rest of the protein, thereby unlocking the deadly weapon. However, the release of the toxic component is not yet possible since the seal keeps the cocoon secured. “We suspect that when the poison dart penetrates the enemy bacterium, mechanical force is generated to remove the cleaved seal, similar to when a champagne cork pops. This would ensure that the toxin is released in the right place at the right time” Stefan Raunser says.
In a series of earlier collaborative projects, the scientists have already gained a lot of knowledge about how the T6SS injection system works. They were able to reveal how effectors are transported inside the cell, how they are loaded on the poison dart and how the dart is then delivered into the host cell. “Our latest collaborative work now provides molecular insights into the arming process of Rhs effectors and its importance for toxin release. I am quite optimistic that our continued collaboration will uncover even more details of the T6SS machinery. This could one day allow for the engineering of bacteria with improved pathogen suppression capabilities useful for antibacterial and antifungal applications” John Whitney says.
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The solutions to many of humanity’s problems can be found within nature. For instance, who could have guessed that an antibiotic as powerful as penicillin would be found in a common mold, or that the drug aspirin would be derived from the bark of the willow tree?
Research into natural products has become a crucial part of drug discovery. Natural products have exhibited promising specificity and efficacy when used against a variety of pathogens, including viruses. For instance, an organic compound called neoechinulin B, isolated from the fungus Eurotium rubrum, has demonstrated antiviral activity against hepatitis C virus (HCV). However, the isolation of such compounds from natural sources can get quite tedious and expensive. Yet, the attempts to synthetically synthesize it seem to be very scarce.
Thus, a group of scientists from across Japan rose to the occasion and embarked on a mission: To discover a simple route for synthesizing neoechinulin B under laboratory conditions. The team included Prof. Kouji Kuramochi and Dr. Koichi Watashi from Tokyo University of Science, along with Dr. Hirofumi Ohashi, Dr. Shusuke Tomoshige, Dr. Kenji Ohgane, and Dr. Shinji Kamisuki from the National Institute of Infectious Diseases, Tohoku University, Ochanomizu University, and Azabu University, respectively. Their findings were recently published in the Journal of Natural Products.
Commenting on their strategy, Prof. Kuramochi, the lead author of the study, says: “We designed a streamlined two-step synthesis strategy to obtain diketopiperazine scaffold of neoechinulin B. The process involved the base-induced coupling of available piperazine-2,5-dione derivative was aldehydes. The coupled products were then treated with a commercial reagent called tetra-n-butylammonium fluoride (TBAF) which gave us neoechinulin B and its 16 other derivatives.”
To ascertain the efficacy of their products, the team tested the antiviral activity of neoechinulin B and its derivatives against different positive-strand RNA viruses, such as HCV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They found that some derivatives showed anti-HCV activity with minimal cell toxicity, while others showed anti-SARS-CoV-2. Moreover, six derivatives exhibited both strong anti-HCV and SARS-CoV-2.
Further studies by the research team uncovered that neoechinulin B and one derivative can reduced the transcriptional activity of liver X receptors (LXRs). This subsequently disrupts the formation of double-membrane vesicles (DMV), which are the sites where viral RNA replication occur. This process results in reduced viral replication in the infected cells.
Along with the 17 active compounds, the scientists also produced three other compounds which, while structurally related to the others, possessed none of the antiviral properties. Further investigation into their molecular structure revealed that inactive compounds were missing the exomethylene moiety which is the key to the antiviral activities of neoechinulin B and its 16 derivatives against HCV and SARS-CoV-2.
The team believes that the insights from this research could be used as a framework for the development of new broad-spectrum antiviral drugs. The study also solidifies the fact that natural products can act as promising lead compounds for the development of antiviral drugs. “The skeleton of neoechinulin B is simple, but only one chemical synthesis method has been reported in the past. Our research presented a simple and viable method for obtaining promising antiviral compounds bringing us one step closer to its practical application,” concludes Prof. Kuramochi.
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Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.

As a 10-year journey comes to fruition, MUSC Hollings Cancer Center researcher John O’Bryan, Ph.D., and colleagues have demonstrated a new therapeutic way to block a protein that is frequently mutated in cancers. These proof-of-principle findings were published on Feb. 8 in Cell Reports. This work, which involves inhibiting the oncogenic protein RAS using small molecules, lays a strong foundation for the development of clinical anti-cancer therapies.
The American Cancer Society estimates that 1.9 million new cancer cases will be diagnosed this year. Based on the urgent need for more effective therapies, researchers are always on the search for elusive treatments that can affect many cancers.
O’Bryan, who is a professor in the Department of Cell and Molecular Pharmacology and Experimental Therapeutics at the Medical University of South Carolina, said, “RAS is one of the most central and critical regulators of cell proliferation, and it is also the most mutated in cancers. Mutated RAS drives the growth of tumors. This makes it an attractive therapeutic target.”
The RAS family of proteins are mutated in nearly 20% of human tumors; however, there has been little progress in drug development for this target. “Think of RAS as a slick ball that does not let anything bind to it. Until recently, it was thought that mutant RAS could not be targeted with drugs. Now there is one FDA-approved drug for mutant RAS in lung cancer, which demonstrates that it is possible to target mutant RAS in some cases,” said O’Bryan.
The new drug sotorasib targets a mutant form of RAS that only occurs in less than 3% of all human cancers, so the new drug is not very useful across multiple types of cancers, O’Bryan said. His new method of therapeutically targeting mutant RAS is more promising because it has the potential to work with numerous mutant forms of RAS in multiple cancers.
“Pancreatic, lung and colorectal cancers are three of the four most deadly cancers, and their growth is driven by mutations in RAS proteins. Therefore, successfully targeting mutant RAS has big implications for patients,” said O’Bryan.

It’s already well known that prunes are good for your gut, but new Penn State research suggests they may be good for bone health, too.
In a research review, the researchers found that prunes can help prevent or delay bone loss in postmenopausal women, possibly due to their ability to reduce inflammation and oxidative stress, both of which contribute to bone loss.
“In postmenopausal women, lower levels of estrogen can trigger a rise of oxidative stress and inflammation, increasing the risk of weakening bones that may lead to fractures,” said Connie Rogers, associate professor of nutritional sciences and physiology. “Incorporating prunes into the diet may help protect bones by slowing or reversing this process.”
The review was recently published in the journal Advances in Nutrition.
Osteoporosis is a condition in which bones become weak or brittle that can happen to anyone at any age, but according to the researchers is most common among women over the age of 50. The condition affects more than 200 million women worldwide, causing almost nine million fractures each year.
While medications exist to treat osteoporosis, the researchers said there is a growing interest for ways to treat the condition with nutrition.