An experimental treatment produced improvements in cognitive function and language in patients with fragile X syndrome, according to study results published on April 29 in Nature Medicine. Fragile X syndrome (known as FXS for short) is the most common known genetic cause of autism and the most common cause of inherited intellectual disability.
“These results offer hope for patients with fragile X syndrome and their families,” said Elizabeth Berry-Kravis, MD, PhD, a pediatric neurologist at Rush University Medical Center and principal investigator of the study. “The majority of clinical outcome measures were in favor of the drug. These measures included performance-based assessments, biomarkers, and parent and physician-rated scales, which in combination, suggest a meaningful impact on the global FXS disease process.”
The study was a phase two clinical trial to assess the safety and efficacy of a drug known as BPN14770 in 30 men with between the ages of 18 and 41 years who have fragile X syndrome. BPN1477 inhibits the activity of an enzyme known as phosphodiesterase-4D (PDE4D), which controls the availability in the brain of cyclic adenosine monophosphate (cAMP), a molecule that is critically involved in memory formation. By inhibiting PDE4D, the drug increases the levels of cAMP in the brain. “It’s exciting that we have a drug that potentially addresses a core biochemical deficit in FXS, a deficiency of cAMP, that has been documented in patients, and which I discovered during my pediatric neurology fellowship 30 years ago,” Berry-Kravis said.
Participants in the study received daily oral doses of BPN14770 twice a day or a placebo for 12 weeks. Parents, caregivers and physician raters were kept unaware of whether the participants received the treatment or the placebo.
The study evaluated the participants using a version of the National Institutes of Health (NIH) Toolbox Cognitive Battery (a cognitive measure) that, in work performed in collaboration with Dr. David Hessl at the UC Davis MIND Institute, was modified to be effective in assessing people with intellectual disabilities. In addition, the study included scales on which parents’ rated improvements from the drug.
“This is the first time that the NIH Toolbox has been able to be used to demonstrate a cognitive change in a trial in people with intellectual disabilities,” Berry-Kravis said. “In just three months, we saw improvement specifically in the verbal subtests of the NIH Toolbox, coupled with parent rating of improvements, particularly in language.”
Cognitive assessments using the NIH Toolbox revealed significant benefit in oral reading recognition, picture vocabulary and the cognition crystallized composite score. Parent/caregiver ratings revealed benefit that was judged to be clinically significant in language and daily functioning.
After 12 weeks of treatment in the study, patients crossed over and took placebo if they had been taking drug, and drug if they had been taking placebo for another 12 weeks. The benefit of BPN14770 was found to persist up to 12 weeks after the crossover from drug to placebo. BPN14770 was very well tolerated, with few adverse events.
In laboratory studies, BPN14770 promoted the maturation of connections between neurons, (which is impaired in patients with fragile X syndrome). BPN14770 is being developed by Tetra Therapeutics for the treatment of fragile X syndrome. The drug’s mechanism of action also may have potential to improve cognitive and memory function in Alzheimer’s disease and other dementias, learning/developmental disabilities and schizophrenia. At this time, however, the U.S. Food and Drug Administration only has approved BPN14770 for investigational use, and it will be important to do larger controlled studies in fragile X syndrome to confirm the cognitive benefit of the drug.
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Materials provided by Rush University Medical Center. Original written by Nancy Difiore. Note: Content may be edited for style and length.

Researchers in Japan have compiled a first-of-its-kind genetic database for autoimmune and autoinflammatory diseases. This resource will allow experts to more deeply understand how immune disorders develop and plan future drug discovery projects. Scientists also hope this atlas of immune-related genome data may eventually be applied to investigations of infectious diseases like COVID-19.
“To understand diseases, a deep comprehension of the function of genetic variants is essential. With this data set, we can connect the data about changes to DNA sequence associated with a disease to genes and cell types that are important for disease pathogenesis,” said University of Tokyo Project Research Associate Mineto Ota, M.D., Ph.D., a clinical rheumatologist and expert in functional genomics. Ota is lead author of the study recently published in Cell. The project was completed with collaborators at RIKEN research institution and Chugai Pharmaceutical Co., Ltd.
Many prior research projects have compared the full genome sequences of patients with medical diagnoses to those of healthy people. Any DNA sequence variants identified in these genomewide association studies are then considered “associated” with the disease.
Many variants identified in association studies are not located in genes, the basic units of heredity, but rather in portions of DNA that regulate the “on” or “off” expression of genes. Most of the human genome is not genes, but this regulatory DNA. Experts might know that a portion of DNA is involved in gene regulation, but not understand exactly how or what it does or even what genes it regulates.
To uncover the function of regulatory DNA, a different type of genome study called expression quantitative trait loci (eQTL) analysis attempts to connect differences in DNA sequence to differences in gene expression. With eQTL data, researchers can make more informed guesses about the purpose of regulatory DNA sequences, how variants in the regulatory sequence might affect expression of the genes it regulates and how those differences in gene expression cause disease.
Other immune-focused eQTL studies have been performed, but prior research efforts included only healthy volunteers and examined a limited number of cell types.

Particularly sensitive to chemical modifications, messenger RNAs (mRNAs) are molecules responsible for transmitting the information encoded in our genome, allowing for the synthesis of proteins, which are necessary for the functioning of our cells. Two teams from the University of Geneva (UNIGE), Switzerland, in collaboration with the Norwegian University of Science and Technology (NTNU), have focused on a specific type of chemical modification — called methylation — of mRNA molecules in the small worm Caenorhabditis elegans. They found that methylation on a particular sequence of an mRNA leads to its degradation and that this control mechanism depends on the worm’s diet. These findings are to be read in the journal Cell.
Several steps take place before a DNA-encoded gene produces the corresponding protein. One of the two strands of DNA is first transcribed into RNA, which then undergoes several processes, including splicing, before being translated into a protein. This process removes unnecessary non-coding sequences (introns) from the gene, leaving only the protein-coding sequences (exons). This mature form of RNA is called messenger RNA (mRNA).
A “post-it” to block protein synthesis
In addition to these processes, RNA — but also DNA molecules — can undergo a chemical modification: methylation. This consists in adding a methyl group (CH3) which allows to modify the fate of these molecules without altering their sequence. Deposited on the RNA or DNA in very specific places like “post-its,” methyl groups indicate to the cell that a particular fate must be given to these molecules. Methylation of RNA is essential: mice without RNA methylation die at an early embryonic stage.
Two neighboring teams at the UNIGE, one working on RNA regulation and the other specializing in DNA organisation in the worm C. elegans, have studied the role of methylation in controlling gene expression. The laboratories of Ramesh Pillai and Florian Steiner, professors in the Department of Molecular Biology at the UNIGE Faculty of Science, have shown for the first time that methylation at the end of the intron of a particular gene blocks the splicing machinery. The intron cannot be removed and the protein is not produced.
Fine regulation to ensure a fair balance
This gene, whose mRNA is modified by methylation, encodes for the enzyme that produces the methyl donor. “It is therefore a self-regulating mechanism since the gene involved in producing a key factor required for methylation is itself regulated by methylation!,” explains Mateusz Mendel, a researcher in the Department of Molecular Biology at the UNIGE Faculty of Science, and the first author of this study.
Moreover, this modification is dependent on the quantity of nutrients received by the worms. “When nutrients are abundant, the mRNA is methylated, gene splicing is blocked, and the level of methyl donors decreases, which limits the number of possible methylation reactions. On the other hand, when there are few nutrients, there is no methylation of the particular RNA of this gene, so splicing is not blocked and the synthesis of methyl donors increases,” reports Kamila Delaney, a researcher in the Department of Molecular Biology at the UNIGE Faculty of Science. Elements present in the food provide the raw materials required for producing the methyl donor, so methylation-dependent splicing inhibition puts a brake on its production under conditions of a rich diet. “Aberrant methylation reactions — too much or too little — are the cause of many diseases. The cell has set up this very sophisticated regulatory system to ensure a fair balance of methylations in the cell,” summarizes Mateusz Mendel.
Methylation of mRNAs at these specific sequences was discovered in the 1970s by scientists, including Ueli Schibler, a former professor at the UNIGE, before being forgotten. It took 40 years before researchers rediscovered its importance in gene regulation in 2012. With this study, scientists from the Department of Molecular Biology highlight the crucial role of methylation in the control of splicing and in the response to environmental changes.
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Researchers at Karolinska Institutet in Sweden have discovered a mechanism through which meningitis-causing bacteria can evade our immune system. In laboratory tests, they found that Streptococcus pneumoniae and Haemophilus influenzae respond to increasing temperatures by producing safeguards that keep them from getting killed. This may prime their defenses against our immune system and increase their chances of survival, the researchers say. The findings are published in the journal PLoS Pathogens.
“This discovery helps to increase our understanding of the mechanisms these bacteria use to evade our normal immune defenses,” says co-corresponding author Edmund Loh, researcher in the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. “It could be an important piece of the puzzle in examining what turns this usually harmless bacterium into a lethal killer.”
Meningitis is an inflammation of the membranes surrounding the brain and the spinal cord. It can be caused by viruses, bacteria, fungi and parasites.
Bacterial meningitis is one of the most severe types and a major cause of death and disability in children worldwide. Several kinds of bacteria can cause the infection, including the respiratory pathogens Streptococcus pneumoniae and Haemophilus influenzae, which can be attributed to some 200,000 meningitis-caused deaths annually.
These two bacteria often reside in the nose and throat of healthy people without making them ill. In some cases they spread into the bloodstream and cause invasive diseases, but the reasons for this remain largely unknown.
In this study, the researchers set out to investigate the connection between temperature changes and survival of these bacteria in a laboratory setting. The experiments were prompted by another recent finding that linked the temperature sensing abilities of the bacterium N. meningitidis to invasive meningococcal disease.
One of the signs of an infection is elevated temperatures and fever, which typically boost our immune system’s ability to fight illness. In this study, however, the researchers found that both S. pneumoniae and H. influenzae activated stronger immune protections when challenged with higher temperatures.
They did so through mechanisms involving four specific so-called RNA thermosensors (RNATs), which are temperature-sensitive non-coding RNA molecules. These RNATs helped boost the production of bigger protective capsules and immune modulatory Factor H binding proteins, both of which help shield these bacteria from immune system attacks.
“Our results indicate that these temperature sensing RNATs create an additional layer of protection that helps the bacteria colonize their normal habitat in the nose and throat,” says the paper’s first author Hannes Eichner, PhD student at the same department. “Interestingly, we saw that these RNATs do not possess any sequence similarity, but all retain the same thermosensing ability, which indicates that these RNATs have evolved independently to sense the same temperature cue in the nasopharynx to avoid immune killing.”
More research is needed to understand exactly what triggers these pathogens to breach from the mucous membrane into the bloodstream and further into the brain. Future studies encompassing in vivo infection model are warranted to characterize the role of these RNATs during colonization and invasion, the researchers say.
The work was supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Stockholm County Council and Karolinska Institutet.
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Scientists have been able to track how a multi-drug resistant organism is able to evolve and spread widely among cystic fibrosis patients — showing that it can evolve rapidly within an individual during chronic infection. The researchers say their findings highlight the need to treat patients with Mycobacterium abscessus infection immediately, counter to current medical practice.
Around one in 2,500 children in the UK is born with cystic fibrosis, a hereditary condition that causes the lungs to become clogged up with thick, sticky mucus. The condition tends to decrease life expectancy among patients.
In recent years, M. abscessus, a species of multi-drug resistant bacteria, has emerged as a significant global threat to individuals with cystic fibrosis and other lung diseases. It can cause a severe pneumonia leading to accelerated inflammatory damage to the lungs, and may prevent safe lung transplantation. It is also extremely difficult to treat — fewer than one in three cases is treated successfully.
In a study published today in Science, a team led by scientists at the University of Cambridge examined whole genome data for 1,173 clinical M. abscessus samples taken from 526 patients to study how the organism has evolved — and continues to evolve. The samples were obtained from cystic fibrosis clinics in the UK, as well as centres in Europe, the USA and Australia.
The team found two key processes that play an important part in the organism’s evolution. The first is known as horizontal gene transfer — a process whereby the bacteria pick up genes or sections of DNA from other bacteria in the environment. Unlike classical evolution, which is a slow, incremental process, horizontal gene transfer can lead to big jumps in the pathogen’s evolution, potentially allowing it to become suddenly much more virulent.
The second process is within-host evolution. As a consequence of the shape of the lung, multiple versions of the bacteria can evolve in parallel — and the longer the infection exists, the more opportunities they have to evolve, with the fittest variants eventually winning out. Similar phenomena have been seen in the evolution of new SARS-CoV-2 variants in immunocompromised patients.

Researchers at University of California San Diego School of Medicine have discovered one way in which SARS-CoV-2, the coronavirus that causes COVID-19, hijacks human cell machinery to blunt the immune response, allowing it to establish infection, replicate and cause disease.
In short, the virus’ genome gets tagged with a special marker by a human enzyme that tells the immune system to stand down, while at the same time ramping up production of the surface proteins that SARS-CoV-2 uses as a “doorknob” to enter cells.
The study, published April 22, 2021 in Cell Reports, helps lay the groundwork for new anti-viral immunotherapies — treatments that work by boosting a patient’s immune system, rather than directly killing the virus.
“It’s very smart of this virus to use host machinery to simultaneously go into stealth mode and get inside more cells,” said Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center. “The more we know about how the virus establishes itself in the body, the better equipped we are to disrupt it.”
In human cells, genes (DNA) are transcribed into RNA, which is then translated into proteins, the molecules that make up the majority of cells. But it’s not always so straightforward. Cells can chemically modify RNA to influence protein production. One of these modifications is the addition of methyl groups to adenosine, one of the building blocks that make up RNA. Known as N6-methyladenosine (m6A), this modification is common in humans and other organisms, including viruses.
In contrast to humans, the entire genomes of some viruses, including SARS-CoV-2, are made up of RNA instead of DNA. And rather than carry around the machinery to translate that into proteins, the coronavirus gets human cells to do the work.

A third of children and adolescents develop a mental health problem after a concussion, which could persist for several years post-injury, according to a new literature review.
The research, led by the Murdoch Children’s Research Institute (MCRI) and published in the British Journal of Sports Medicine, found mental health should be evaluated as part of standard pediatric concussion assessment and management.
MCRI researcher and Monash University PhD candidate Alice Gornall said despite many post-concussion and mental health symptoms overlapping, the relationship between delayed recovery and mental health had remained poorly understood until this literature review.
The review of 69 articles published between 1980 to June 2020, involved almost 90,000 children, aged 0-18 years, from nine countries including Australia, US, Canada and New Zealand, who had a concussion. Falls (42.3 per cent) and sporting injuries (29.5 per cent) were the most common cause of injury, followed by car accidents (15.5 per cent).
It found up to 36.7 per cent experienced significantly high levels of internalising problems such as withdrawing, anxiety, depression and post-traumatic stress and 20 per cent externalising problems such as aggression, attention problems and hyperactivity after concussion compared with healthy children or children who sustained other injuries such as an arm fracture.
Pre-existing mental health problems were a strong predictor of post-concussion mental health issues. The review stated 29 per cent of children with a pre-injury mental health diagnoses received a new mental health diagnosis post-concussion. Up to 26 per cent without prior mental health problems went onto develop symptoms.

A new, rapid screening approach uses CRISPR/Cas9 technology to identify immune system-related genes that play a crucial role in repairing zebrafish spinal cord injuries. Marcus Keatinge and Themistoklis Tsarouchas of the University of Edinburgh, U.K., and colleagues present these findings in the open-access journal PLOS Genetics.
In humans and other mammals, severed spinal-cord nerve connections do not heal, so a spinal cord injury may lead to permanent paralysis. In contrast, zebrafish are capable of recovering from spinal cord injury in a process that involves inflammation controlled by macrophages — a type of immune system cell. However, the precise process by which macrophages aid spinal cord regeneration in zebrafish remains mysterious.
To help clarify this process, Keatinge, Tsarouchas and colleagues developed a new method for rapidly identifying macrophage-related genes that are involved in zebrafish spinal cord regeneration. The strategy employs CRISPR/Cas9 technology, which enables researchers to target and disrupt specific genes, thereby revealing their function. Molecules known as synthetic RNA Oligo CRISPR guide RNAs (sCrRNAs) enable this gene-specific targeting.
The researchers applied the new method to study spinal cord regeneration in larval zebrafish. Key to the method was a prescreening step in which they tested over 350 sCrRNAs that target genes already known to potentially play an important role in inflammation-related spinal cord regeneration. Introducing these sCrRNAs to the zebrafish enabled identification 10 genes that, when disrupted, impaired recovery from spinal cord injury.
Further analysis narrowed the list to four genes that appear to be crucial for repair of severed spinal nerve connections, validating the novel method. One gene in particular, tgfb1, appears to play an essential signaling role in controlling inflammation during the recovery process.
The new method and findings could help deepen understanding of spinal cord regeneration in zebrafish. The researchers also say the method could be adapted to screen for genes that play important roles in other biological processes, as well.
The authors add, “Zebrafish can fully regenerate their spinal cords after injury. Using a new and very rapid screening platform, we discover genes of the immune system that are essential for regeneration. We envision our findings to lead to new insights into the inability of mammals to regenerate and our versatile screening platform to be adapted to other disease or injury models in zebrafish.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

In recent weeks, people who oppose Covid vaccinations have spread a claim that is not only false but defies the rules of biology: that being near someone who has received a vaccine can disrupt a woman’s menstrual cycle or cause a miscarriage.The idea, promoted on social media by accounts with hundreds of thousands of followers, is that vaccinated people might shed vaccine material, affecting people around them as though it were secondhand smoke. This month, a private school in Florida told employees that if they got vaccinated, they could not interact with students because “we have at least three women with menstrual cycles impacted after having spent time with a vaccinated person.”In reality, it is impossible to experience any effects from being near a vaccinated person, because none of the vaccine ingredients are capable of leaving the body they were injected into.The vaccines currently authorized for use in the United States instruct your cells to make a version of the spike protein found on the coronavirus, so your immune system can learn to recognize it. Different vaccines use different vehicles to deliver the instructions — for Moderna and Pfizer, messenger RNA, or mRNA; for Johnson & Johnson, an adenovirus genetically modified to be inactive and harmless — but the instructions are similar.“It’s not like it’s a piece of the virus or it does things that the virus does — it’s just a protein that’s the same shape,” said Emily Martin, an infectious disease epidemiologist at the University of Michigan School of Public Health. “Transferring anything from the vaccine from one person to another is not possible. It’s just not biologically possible.”Microorganisms spread from person to person by replicating. The vaccine ingredients and the protein can’t replicate, which means they can’t spread. They don’t even spread through your own body, much less to anybody else’s.“They’re injected into your arm, and that’s where they stay,” Jennifer Nuzzo, an epidemiologist at Johns Hopkins, said of the vaccines. “mRNA is taken up by your muscle cells near the site of injection, the cells use it to make that protein, the immune system learns about the spike protein and gets rid of those cells. It’s not something that circulates.”It’s also not something that sticks around. Messenger RNA is extremely fragile, which is one reason we’ve never had an mRNA-based vaccine before: It took a long time for scientists to figure out how to keep it intact for even the brief period needed to deliver its instructions. It disintegrates within a couple days of vaccination.Vaccinated people can’t shed anything because “there’s nothing to be shedding,” said Dr. Céline Gounder, an infectious disease specialist at Bellevue Hospital Center and a member of President Biden’s transition advisory team on the coronavirus. “The people who shed virus are people who have Covid. So if you want to prevent yourself or others from shedding virus, the best way to do that is to get vaccinated so you don’t get Covid.”This brings us to the reports of women having abnormal periods after being near vaccinated people. Because one person’s vaccine can’t affect anybody else, it is impossible for these two events to be connected. Many things, like stress and infections, can disrupt menstrual cycles.The shedding claims are “a conspiracy that has been created to weaken trust in a series of vaccines that have been demonstrated in clinical trials to be safe and effective,” Dr. Christopher M. Zahn, vice president of practice activities at the American College of Obstetricians and Gynecologists, said in a statement. “Such conspiracies and false narratives are dangerous and have nothing to do with science.”Some women have expressed a related concern that getting vaccinated themselves could affect their menstrual cycles. Unlike secondhand effects, this is theoretically possible, and research is ongoing — but anecdotal reports could be explained by other factors, and no study has found a connection between the vaccine and menstrual changes.“There’s no evidence that the vaccine affects your menstrual cycle in any way,” Dr. Gounder said. “That’s like saying just because I got vaccinated today, we’re going to have a full moon tonight.”

In one of the first studies of its kind, medical and engineering researchers have shown wearable devices that continuously monitor blood sugar provide new insights into the progression of Type 2 diabetes among at-risk Hispanic/Latino adults.
The findings by researchers from Sansum Diabetes Research Institute (SDRI) and Rice University are available online this week in EClinicalMedicine, an open-access clinical journal published by The Lancet.
“The fresh look at the glucose data sheds new light on disease progression, which could have a direct impact on better management,” said Rice study co-author Ashutosh Sabharwal, professor and department chair in electrical and computer engineering and founder of Rice’s Scalable Health Labs. “An important aspect of our analysis is that the results are clinically interpretable and point to new directions for improved Type 2 diabetes care.”
The study builds on SDRI’s groundbreaking research to address Type 2 diabetes in underserved Hispanic/Latino communities. SDRI’s Farming for Life initiative assesses the physical and mental health benefits of providing medical prescriptions for locally sourced fresh vegetables to people with or at risk of Type 2 diabetes, with a focus on the Hispanic/Latino community. SDRI recently added a digital health technology called continuous glucose monitoring to this research.
Continuous glucose monitors track blood sugar levels around-the-clock and allow trends in blood glucose to be displayed and analyzed over time. The devices typically consist of two parts, a small electrode sensor affixed to the skin with an adhesive patch and a receiver that gathers data from the sensor.
“We found that the use of this technology is both feasible and acceptable for this population, predominantly Mexican American adults,” said study co-author David Kerr, SDRI’s director of research and innovation. “The results also provided new insights into measurable differences in the glucose profiles for individuals at risk of as well as with noninsulin-treated Type 2 diabetes. These findings could facilitate novel therapeutic approaches to reduce the risk of progression of Type 2 diabetes for this underserved population.”
Sabharwal, who is also a co-investigator of the Precise Advanced Technologies and Health Systems for Underserved Populations (PATHS-UP) engineering research center, said, “The collaboration with SDRI aligns with our mission to use technology as an important building block to reduce health care disparities.”
“We are excited about the application of digital health technologies for underserved populations as a way to eliminate health disparities and improve health equity,” Kerr said. “This opens up potential for a larger number of collaborations to support SDRI’s evolving focus on precision nutrition and also the expanded use of digital health technologies for both the prevention and management of all forms of diabetes.”
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Materials provided by Rice University. Original written by Jade Boyd. Note: Content may be edited for style and length.