Xiaochang Zhang & team introduce exon annotation for nonsense-mediated mRNA (EANMD) and report on alternatively spliced exons in the brain that trigger mRNA decay, noting modulation of such exons in disease-causal genes can potentially treat neurodevelopmental disorders.
Address correspondence to: Xiaochang Zhang, University of Chicago, Cummings Life Science Center 507A, 920 E. 58th St., Chicago, Illinois 60,637, USA. Phone: 773.834.5369; Email: [email protected].
Among adults with Prediabetes, vitamin D3 supplementation was associated with lower diabetes risk only in those with specific ApaI vitamin D receptor genotypes.
This genetic association analysis of the D2d study suggests that genetic variation in the VDR, specifically the ApaI polymorphism, is associated with diabetes risk at higher intratrial 25(OH)D levels and is associated with response to 4,000 IU/d of vitamin D3 supplementation among adults with prediabetes. Participants carrying the ApaI AA genotype did not experience a reduction in diabetes risk, either when achieving higher intratrial 25(OH)D concentrations or while being treated with 4,000 IU/d of vitamin D3. In contrast, those carrying the ApaI CC and AC genotypes, representing 71% of the D2d study population, had progressively lower risk of type 2 diabetes at intratrial 25(OH)D levels of 40 ng/mL or higher. Participants with these genotypes randomized to vitamin D3 had a 19% reduction in the risk of progression to diabetes compared with placebo, whereas those with ApaI AA alleles did not respond to treatment with vitamin D3. The BsmI polymorphism also appeared to play a role in the association between the achieved intratrial 25(OH)D level and diabetes risk, as expected given the high linkage disequilibrium of ApaI and BsmI (D’ = 1.0 and r2 = 1.0) among people of European ancestry.15 Because there was a near complete overlap between participants carrying the nonresponsive Bsml TT genotype and those carrying the nonresponsive ApaI AA genotype, knowing the ApaI genotype alone was sufficient to identify individuals who were likely—or unlikely—to respond to supplementation with 4,000 IU/d of vitamin D3. These exploratory genetic association findings support our hypothesis that a common VDR variant modulates the link between high intratrial 25(OH)D levels and diabetes risk, and the association between relatively high-dose vitamin D3 supplementation and diabetes risk among adults with prediabetes. The distributions of alleles of the 3 polymorphisms in the D2d study were similar to those reported in the UK Biobank of participants with prediabetes.5 Consistent with the UK Biobank study and other studies,5,16,17 the 25(OH)D levels achieved during the D2d trial did not differ significantly among participants with different VDR polymorphisms.
In the UK Biobank study, among adults with prediabetes and a median 25(OH)D level of 19.2 ng/mL (a value below our referent range of 20–29.9 ng/mL), there was a stepwise decrease in the risk of diabetes at 25(OH)D levels of lower than 10 (the study’s referent), 10 to 20, 20 to 30, and 30 ng/mL or higher.5 Risk reduction was present in all VDR genotypes of the 4 examined polymorphisms (ApaI, BsmI, TaqI, and FokI), but it was more prominent among those carrying the T allele of BsmI. There were too few participants in the D2d study with sufficiently low 25(OH)D levels to address this range of the 25(OH)D spectrum. Conversely, there were too few participants with sufficiently high 25(OH)D levels in the UK Biobank study to address the question posed in our study. To our knowledge, no other high-dose vitamin D trials among adults with prediabetes have examined how VDR polymorphisms may modify the effect of vitamin D supplementation on diabetes risk.
Our exploratory findings, if confirmed, hold promise for high-dose vitamin D3 as a targeted, personalized approach to reducing the risk of type 2 diabetes among selected adults with prediabetes. The magnitude of the observed risk reduction among participants with AC and CC alleles of the ApaI polymorphism, if confirmed in an independent clinical trial, would have clinical implications for the management of prediabetes. In the original report of the D2d trial,2 the HR for conversion to type 2 diabetes with vitamin D supplementation was 0.88 (95% CI, 0.72−1.04). The HR decreased to 0.81 (95% CI, 0.66−0.99) in our exploratory analysis when genetically nonresponsive participants (those with AA alleles of the ApaI polymorphism, comprising 29.5% of all participants) were excluded. If confirmed, a 19% risk reduction in conversion to type 2 diabetes with vitamin D3 supplementation would not be trivial. First, assessment of a single VDR polymorphism is inexpensive and now widely available.
For centuries, the inability to regrow lost body parts has been considered a defining limitation of humans and other mammals. While animals like salamanders can regenerate entire limbs, humans are left with scar tissue. But new research from the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) suggests that this limitation may not be permanent. Instead, the capacity for regeneration may still exist—hidden within the body’s normal healing process.
“Why some animals can regenerate and others, particularly humans, can’t is a big question that has been asked since Aristotle,” said Dr. Ken Muneoka, a professor in the VMBS’ Department of Veterinary Physiology & Pharmacology (VTPP). “I’ve spent my career trying to understand that.”
In their study, published in Nature Communications, Muneoka and his colleagues detail a newly developed two-step treatment that led to the regeneration of bone, joint structures and ligaments. While the results were imperfect, the team believes this approach could be used more immediately to reduce scarring and improve tissue repair after amputations.
Daniel J. Drucker & team identify the vascular smooth muscle GLP-1 receptor as a key cellular target for the actions of GLP-1 medicines to lower blood pressure.
The figure: Renal GLP1R/Glp1r is expressed in human and murine vascular smooth muscle cells (VSMCs) and Glp1rVSM-/- mice have reduced Glp1r transcripts in renal tissues.
1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
2Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
Address correspondence to: Daniel J. Drucker, Mt. Sinai Hospital, 600 University Ave. Mailbox 39, Toronto, Ontario, Canada, M5G1X5. Phone: 416.361.2661; Email: [email protected].
Scientists build an atlas of the blood vessel in diabetes and decipher crosstalk between “foamy” phagocytes and endothelial cells, showing that TREM2 drives vessel dysfunction in peripheral artery disease.
Read more in Science TranslationalMedicine.
Diabetes-driven TREM2-endothelial cross-talk impairs vascular repair in peripheral arterial disease.
New research suggests that plasma phosphorylated tau 217 (pTau217) can detect Alzheimer’s disease pathology years before it appears on traditional PET scans. In longitudinal studies, elevated pTau217 levels accurately predicted future amyloid accumulation and cognitive decline in currently asymptomatic, healthy older adults. While not yet recommended for routine clinical screening, this biomarker offers a potential “clock” for estimating the onset of symptoms within a three to four year margin.
Participants who were amyloid-beta-negative and had very low pTau217 (below ~2.6% in this cohort) rarely became amyloid-beta-positive, suggesting this subgroup may be low risk and might not require amyloid-beta PET until pTau217 rises, the researchers said.
Higher baseline plasma %pTau217 also predicted tau accumulation in the brain — even when amyloid levels were still low, suggesting it captures very early disease processes.
In terms of cognition, across the full cohort, higher plasma pTau217 was associated with faster decline on a composite cognitive score. However, this relationship was largely driven by individuals who already had elevated amyloid; among amyloid-negative participants, pTau217 did not significantly predict cognitive decline over the follow-up period.
A new international study co-led by investigators from Mass General Brigham and the Eye & ENT Hospital of Fudan University shows that a gene therapy for a rare form of genetic deafness successfully restored hearing in most participants, with results lasting up to 2.5 years. The results, the largest clinical trial of gene therapy for inherited hearing loss to date and the longest follow-up reported so far, are published in Nature. According to the authors, these latest findings reinforce earlier trials that show gene therapy can be used to treat some forms of inherited deafness, helping guide future research and care.
“It’s remarkable to see patients go from complete deafness to being able to hear,” said the study’s corresponding author, Zheng-Yi Chen, DPhil, the Ines and Fredrick Yeatts Chair in Otolaryngology and an associate scientist at Mass Eye and Ear, a member of the Mass General Brigham healthcare system. “For many patients, that also means the ability to develop and use speech.”
Genetic mutations account for up to 60% of hearing loss present at birth. In this study, researchers used a gene therapy they developed to treat autosomal recessive deafness 9 (DFNB9), caused by mutations in the OTOF gene. The OTOF gene provides the body with instructions to make a protein called otoferlin, which is essential for hearing function. Without it, hair cells in the inner ear cannot pass sound signals to the brain, causing severe-to-complete deafness at birth. OTOF mutations account for about 2 to 8 in every 100 cases.
Gene therapies are designed to add a working version of mutated genes that lead to disease. Since a single faulty gene causes DFNB9, it is well-suited for gene therapy research. The treatment is a single injection into the inner ear that uses a harmless virus (AAV) to deliver a working copy of the OTOF gene to the cells needed for hearing.
This latest trial enrolled 42 participants across eight sites in China, ranging in age from infants to adults (0.8 to 32.3 years). Each participant received one of three doses of a single gene therapy treatment: 36 in one ear and six in both ears. The research team then followed participants for up to 2.5 years, to see if treatment remained safe, affected their hearing and speech recognition. The researchers also sought to better understand why some participants may respond better than others.
“These multicenter trial results validate the effectiveness of our OTOF gene therapy,” said Yilai Shu, MD, PhD, a professor from Eye & ENT Hospital of Fudan University, who led the study. “The procedure can be broadly implemented in hospital settings, ensuring consistent delivery for a larger patient population.”
Abstract: Multicentre gene therapy for OTOF-related deafness followed up to 2.5 years https://www.nature.com/articles/s41586-026-10393-y.