Browse Articles

Efficacy of probiotic supplementation in reducing primary dysmenorrhea: a double-blinded randomized controlled trial

Abstract Primary dysmenorrhea is painful menstruation in the absence of pelvic pathology, whereas secondary dysmenorrhea is menstrual pain attributable to an underlying pelvic disease (e.g., endometriosis). Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as first-line therapy. Recent evidence 18 suggests that modulation of the gut microbiota may influence menstrual pain through immunologic and neuroendocrine pathways. This double-blinded, randomized, placebo-controlled trial investigated the efficacy of daily multispecies probiotic supplementation in reducing menstrual pain severity in women aged 18–24 years diagnosed with moderate to severe primary dysmenorrhea. Forty-eight participants were randomized to receive either a probiotic supplement or placebo for three consecutive menstrual cycles, followed by a three-month observation period. The primary outcome was the change in pain severity, assessed using a 10 cm visual analog scale (VAS). At baseline, VAS scores were similar between groups (probiotic 6.1 ± 1.17 vs placebo 6.3 ± 1.26; p = 0.62). After three months of intervention, the probiotic group demonstrated a significantly greater reduction in pain scores compared to the placebo group (3.7 ± 1.84 vs 5.8 ± 2.14; p < 0.01). However, the effect was not sustained after discontinuation of supplementation. No serious adverse events were reported. These findings suggest that continuous intake of multispecies probiotics may be an effective non-hormonal adjunct therapy for primary dysmenorrhea. Clinical trial registration: Thai Clinical Trials Registry (TCTR20230326001), registered on 22 March 2023. https://thaiclinicaltrials.org/

Uniform bacterial genetic diversity along the gut

Abstract While environmental gradients are known to result in heterogeneous distributions of bacterial species along the gastrointestinal tract, the spatial distribution of genetic diversity within these species remains poorly understood. Because bacterial genetic variants influence host traits like inflammation and metabolism, understanding their distribution is critical. Here, we analyze ~30 common gut commensals in germ-free mice colonized with the same healthy human stool. Unexpectedly, we find that while species composition varied significantly across gut regions, genetic diversity within species remained remarkably uniform. This uniformity is driven by similar strain frequencies along the gut lumen, indicating that genetically divergent strains can coexist without spatial segregation. Furthermore, ~60 evolutionary adaptations arising within the mice tend to sweep globally throughout the gut, showing little region-specificity. We observe similar dynamics in conventional mice and humans, suggesting that uniform bacterial genetic diversity is a conserved, robust feature of mammalian gut ecosystems.

Reversibility and β-sheet formation are decoupled in tau condensate aging

Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer’s disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence for this pathway, the molecular basis by which reversible condensates evolve into irreversible, pathogenic aggregates has remained unclear. Here, we map the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging. Our results reveal that the two hallmark features of the pathological end state, β-sheet enrichment and irreversible aggregation, emerge at different rates and occupy distinct regions of the phase space, indicating that these properties are mechanistically uncoupled. Notably, we identify tau condensate phases that are β-sheet rich yet thermodynamically reversible, as well as irreversible intermediates that lack β-sheet structure. These findings expand the landscape of tau aggregate species beyond a simple linear progression toward fibrils and highlight a diverse array of intermediates with distinct structural and thermodynamic properties. This decoupling of structure and irreversibility has important implications for understanding tau aggregation mechanisms and may offer targets for therapeutic intervention.

A targeting lentiviral vector for generation of CAR-T cells in vivo

Abstract Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable therapeutic efficacy in treating cancer and autoimmune diseases. However, current CAR-T cell therapy requires ex vivo T cell engineering, which is both time-consuming and cost-prohibitive, adding complexity to the overall treatment. In this study, using an engineered Sindbis virus envelope, we developed a lentiviral vector system with high specificity for targeting human T cell line and primary T cells, but not targeting other immune cell subsets. Notably, this T cell-specific lentiviral vector does not require additional anti-CD3/CD28 stimulation for primary T cell activation during infection in vitro. Furthermore, the lentiviral vector successfully delivered a CD19-targeting CAR molecule to human primary T cells in vivo. The in vivo generated CD19-CAR-T cells efficiently mediated B cell lymphoma clearance. Overall, our study provides a promising tool for the development of in vivo T cell engineering approaches.

Origins and breadth of pairwise epistasis in an α-helix of β-lactamase TEM-1

Abstract The effect of mutations in a protein may depend on the presence of others—a phenomenon known as epistasis. Epistasis plays a key role in evolution and complicates predictions of mutational effects, as effects can be context-dependent. Yet, despite its importance, the mechanistic basis of epistasis remains poorly understood. To better characterize epistasis, we focused on an 11-residue α-helix in TEM-1 β-lactamase and constructed a comprehensive library of over 14,000 double mutants. Fitness and minimum inhibitory concentration, two contrasted measure of protein efficiency, reveal consistent widespread epistasis. A non-linear two-state protein stability model in which destabilizing, neutral, or stabilizing mutations contribute additively to the stability phenotype, largely explain the data. Most epistatic effects are consequently predictable from single-mutation effects. However, systematic deviations from the model occur when both mutated residues directly interact in the 3D structure—a fold conserved across distant TEM-1 homologs. We therefore investigated the predictive power of statistical models trained on distant homologous sequences and found that they could partially recover the observed epistatic interactions. Our results, built on a short structural element of a protein, shed light on multiple determinants of the epistatic landscape that have shaped the evolutionary trajectory of β-lactamase proteins over long timescales.

Methylation-associated mutagenesis underlies variation in the mutation spectrum across eukaryotes

Mutation spectra vary across genetic and environmental contexts, leading to differences between and within species. Most research on mutation spectrum has focused on trinucleotide (3-mer) mutation types in mammals, limiting the breadth and depth of variation surveyed. In this study, we use whole-genome resequencing data across 108 eukaryotic species—including mammals, fish, plants, and invertebrates—to characterize pentanucleotide (5-mer) noncoding mutation spectra using a Bayesian approach. Our findings reveal cytosine transition mutability at CpG sites and other sources of variation in the transition/transversion ratio as the main drivers of variation in mutation spectra across eukaryotes. We find that inferred CpG mutation rates almost perfectly predict genomic CpG depletion but are not predicted by genome-wide average CpG methylation levels. Together, our results illustrate the pivotal role of mutagenesis in shaping genome composition across eukaryotes and highlight a gap in knowledge about the mechanisms governing mutation rates.

IRX4204 sensitizes multiple myeloma to ferroptosis and improves lenalidomide efficacy through the HMOX1-GPX4 axis

Abstract Despite advances in therapy, multiple myeloma (MM) largely remains incurable, emphasizing the need for new strategies to overcome drug resistance. Ferroptosis is an iron-dependent cell death pathway that may present a therapeutic vulnerability in MM, but its transcriptional regulation remains poorly understood. Retinoid X receptors (RXRs) are ligand-activated nuclear transcription factors that regulate metabolism, redox homeostasis, and immune signaling. In this study, we demonstrate that RXR signaling regulates ferroptosis. The selective third-generation RXR agonist IRX4204 significantly increased MM cells’ susceptibility to ferroptotic stress and worked synergistically with ferroptosis inducers. Mechanistic studies showed that IRX4204 actively induces HMOX1 transcription via PPARα-RXRα binding and concurrently decreases GPX4 levels, leading to iron buildup, lipid peroxidation, and ferroptosis. Deleting HMOX1 using CRISPR abolished these effects, confirming HMOX1 as an essential effector. In vivo, IRX4204 enhanced lenalidomide’s effectiveness, reduced tumor burden, extended survival, and elevated ferroptosis markers without added toxicity. Clinically, high HMOX1 expression correlates with improved overall survival in MM patients. These findings reveal a new RXR–HMOX1–GPX4 regulatory axis, establish RXR activation as a method to boost ferroptosis sensitivity, and support combining RXR agonists with ferroptosis-based treatments in MM.

Quantifying the effects of response diversity dynamics on ecosystem stability

Maternal intake of inadequate dietary folate, and low serum folate levels during pregnancy are associated with increased risk of preterm birth in rural Ethiopia: a prospective cohort study

Massively parallel quantification of mutational impact on IAPP amyloid formation

Abstract Amyloid fibrils formed by the islet amyloid polypeptide cause pancreatic beta-cell damage, resulting in reduced insulin secretion and type 2 diabetes. Changes in the amino acid sequence of this peptide can influence its aggregation rate, and animals expressing variants that do not form amyloids do not develop type 2 diabetes. Conversely, specific single amino acid changes can accelerate the aggregation rate of this peptide. Here, we employ deep mutational scanning to measure the ability of 1916 islet amyloid polypeptide variants, including substitutions, insertions, truncations and deletions, to nucleate amyloids. Our results identify a continuous stretch of residues from 15 to 32 that is particularly sensitive to mutation. This region, which is likely structured in amyloids, matches the core of the early aggregated species formed by this peptide in vitro. Within this region, mutations in residues 21 to 27 have a substantial effect, suggesting tighter structural constraints. Finally, we compare the mutational atlas of the islet amyloid polypeptide to that of amyloid beta - the peptide that aggregates in Alzheimer’s disease - and find that mutations that slow down nucleation correlate between the two amyloids, but mutations that accelerate nucleation in one amyloid cannot be used to predict mutational effects in the other.

ODC1 restricts meningeal B cell age-associated-like phenotype and function in multiple sclerosis: A human and experimental study

Meningeal inflammation, as a clinical feature of multiple sclerosis (MS), is associated with worse clinical disease outcomes. In both relapsing and secondary progressive MS and the experimental autoimmune encephalomyelitis (EAE) MS model, the meninges have been found to contain ectopic lymphoid follicles enriched with B cells. The metabolic requirement of meningeal B cell function in MS or EAE is not well elucidated. Using 7-Tesla MRI brain scans of MS patients and leptomeningeal enhancement as a marker, we found a correlation between meningeal inflammation and metabolites of the arginine/polyamine pathway, a finding recapitulated in EAE. Ornithine Decarboxylase (ODC1), the rate limiting enzyme for polyamine biosynthesis, as well as polyamine metabolism was diminished in the dura meningeal B cells from mice with MOG 35-55 induced EAE mice as compared to naïve controls. Pharmacological inhibition of ODC1 restricted meningeal T cells but promoted meningeal B cell proliferation. B cell–specific deletion of ODC1 resulted in expansion of B cells with age-associated B cell–like phenotype (CD11c + CD21/35 − CD23 − IgD − ), an increase in MOG-specific IgG in the brain, reduction of hippocampal synaptic density, and exacerbated disease in the MOG 1-125 EAE model. Together, these findings demonstrate a divergent role of polyamines in regulating B and T cell responses in the meninges during autoimmunity.

Cable online partial discharge detection and state evaluation based on deep belief network and swarm intelligence optimization algorithm

Meta-analysis shows that plant mixtures reduce pathogens and invertebrate herbivores and increase plant productivity

Non-Fickian diffusion within assemblies of the intrinsically disordered protein β-casein

The molecular mechanisms governing internal fluctuations in intrinsically disordered protein (IDP) assemblies are crucial to the stability and dynamics of both regulated and aberrant toxic cellular aggregates, but remain poorly understood. By comprehensively combining high-resolution quasi-elastic neutron scattering with all-atom molecular dynamics simulations, we probe the motions of β -casein, a model IDP, inside its assemblies. We uncover a previously unresolved slow relaxation process with phenomenological characteristics of anomalous non-Fickian diffusion. This anomalous signature emerges from a continuous mobility gradient governed by density and crowding within the assemblies; the core is denser and more compact, and mobility increases progressively toward the exterior. This dynamical heterogeneity underlies the non-Gaussian behavior and accounts for the observed spectral broadening. Our findings provide insight into how disorder and extreme local crowding within IDP assemblies can result in a fundamentally different behavior compared to, e.g., clusters of well-folded proteins. The deviations from Fickian diffusion arise from dynamic heterogeneity and can be captured within the framework by a model typically used for the jump diffusion observed in liquids, thereby extending its applicability.

Distribution of extended red blood cell phenotypes among blood donors: experience from a low- and middle-income country

A mouse-adapted Yezo virus model for antiviral testing in immunocompetent mice

A global analysis of patterns of tuberculosis exposure and transmission

Tuberculosis (TB) is a major public health concern and the leading infectious cause of mortality globally. The disease exhibits strong prevalence patterns by age and sex, but the implications of these patterns for likely TB exposure and transmission have not previously been systematically assessed. We combined estimates of social mixing patterns and TB prevalence for 177 countries to estimate the proportion of TB exposure to and transmission from age groups and sexes. We found that a majority of TB transmission, in both sexes, and for both children and adults, is attributable to contact with adult men. Across age groups, TB exposure typically peaked in adolescence, whereas contributions to TB transmission was flatter or increasing with age, and more variable across regions. Our analysis highlights an important and under-appreciated contribution to transmission in some settings from older adults, who may face particular barriers to healthcare access. More systematic analyses focusing on understanding the epidemiology of TB transmission should be used to inform context-specific prioritization of interventions.

Carbon price fluctuation forecasting using an adaptive dual-channel residual attention neural network optimized with white shark optimizer and blockchain-based data provenance

The Kananaskis Wildfire Charter: a good start

Anion-mediated solvation structures and intercalation chemistry of aqueous zinc-ion electrolytes

Understanding solvent/solute-borne coordination structures and their impact on electrode intercalation chemistry is crucial for the rational design of high-performance electrolytes. Nevertheless, the anion coordination mechanisms governing solvation structures and their influence on electrochemical properties within aqueous zinc-ion electrolytes remain insufficiently explored. In this work, we systematically elucidate the Zn 2+ coordination environments in dilute aqueous zinc-ion electrolytes containing three different Zn salts (Zn(OTf) 2 , ZnCl 2 , and Zn(Ac) 2 ) using X-ray absorption fine structure (XAFS) spectroscopy and metadynamics simulations. Our results identify distinct average Zn 2+ coordination species: [Zn(H 2 O) 6 ] 2+ in Zn(OTf) 2 , [Zn(H 2 O) 5 Cl] + in ZnCl 2 , and [Zn(H 2 O) 4 (Ac)] + in Zn(Ac) 2 . Further employing synchrotron-based spectroscopy and in situ synchrotron radiation X-ray diffraction (SRXRD), we reveal that the electrode operating in Zn(OTf) 2 electrolyte exhibits minimal crystal lattice distortion upon Zn 2+ de/intercalation cycling, thereby delivering highly reversible electronic structure evolution and zinc-ion electrochemistry. In stark contrast, pronounced structural shape-shifting is observed in ZnCl 2 and Zn(Ac) 2 electrolytes, attributed to electrode dissolution and acetate anion coinsertion, respectively. These processes induce significant structural deterioration during cycling and compromise electrochemical reversibility. This study provides critical insights into the anion coordination chemistry within aqueous electrolytes and its profound influence on electrode intercalation behaviors, offering essential guidance for developing advanced high-performance aqueous batteries.