Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and beta-secretase 1 (BACE1) remains a high-priority target for reducing amyloid-beta production. Nobiletin, a polymethoxylated flavonoid from citrus peel, has reported neuroprotective and amyloid-lowering effects in AD models, and previous enzymatic work suggested weak BACE1 inhibition; however, its replica-level binding stability and residue-level energetic determinants remain unresolved. Here, we analyzed the nobiletin-BACE1 complex using ChEMBL-based chemical-space contextualization, qualitative QSAR uncertainty assessment, molecular docking, triplicate 200-ns all-atom molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) end-point scoring, residue-level decomposition, ProLIF interaction fingerprints, electrostatic surface analysis, and a same-protocol OM99-2 structural control. The ligand remained locally accommodated within the BACE1 cleft across the sampled trajectories, with a mean internal MM-GBSA score (DeltaG_bind) of - 15.71 +/- 0.76 kcal/mol (n = 3: - 14.20, - 16.35, and - 16.57 kcal/mol). Residue-level decomposition identified ARG128 as the dominant computed hotspot (total mean = - 11.13 +/- 0.38 kcal/mol), with favorable van der Waals (VDW mean = - 6.88 +/- 0.21 kcal/mol) and Coulombic (Coulomb mean = - 4.25 +/- 0.53 kcal/mol) components. Additional hydrophobic/aromatic packing involved VAL69, TYR71, PRO70, PHE38, and PRO129, while ASP32/ASP228 were positioned outside the dominant nobiletin contact pattern. Together, these results support a putative ARG128-associated, non-dyad-dominant catalytic-cleft recognition model that should be interpreted as a hypothesis-generating computational framework for future biochemical testing and scaffold optimization.

Echolocating big brown bats broadcast downward-sweeping, frequency-modulated (FM) biosonar sounds and process the returning echoes to track and capture flying insects. Neurons in the inferior colliculus are tuned to different frequencies along the FM sweep and form a representation of target azimuth largely on the basis of sensitivity to interaural differences in intensity, with canonical interaural time difference cues by themselves less reliable. Here, we reanalyze neurophysiological data on binaural sensitivity of inferior colliculus neurons consistent with a signal-processing model used in engineered sonar for generating directional beams. Model inputs are the times-of-occurrence of phasic-on responses to FM sweeps presented at a range of interaural intensities and azimuths. Tuning curves for interaural intensity were computed, and the slopes of these tuning curves plotted against neuronal best frequency and sound azimuth. The resulting aggregate plots suggest that the bat forms two distinct beams, one encompassing the entire FM sweep for a narrow zone of azimuths straight ahead and the other restricted to lower frequencies and offside to the left and the right. When interpreted with respect to psychophysical data, these analyses suggest that the forward beam allows for acute target perception, while the offside beams allow for perception of multiple objects that constitute clutter. The distribution of azimuths further suggests the formation of numerous detailed offside beams pointing in different directions to accommodate the width of the spatial arrangement of the clutter.

Bivariate first-event outcomes arise in longitudinal biomedical studies when two clinically related events are assessed on a shared visit schedule. We propose a Bayesian local Gaussian-copula allocation model for bivariate discrete-time first-event data with baseline and time-dependent covariates. Two outcome-specific working discrete-time decrement models define interval-specific working decrement probabilities and thereby generate marginal survival coordinates on the common interval grid. Among subjects jointly at risk at the start of an interval, a Gaussian copula is used locally to allocate probability mass across four terminal outcomes: no event, event 1 only, event 2 only, and same-interval co-occurrence. The Gaussian copula accommodates negative local dependence, independence, and positive local dependence. We consider constant, unstructured interval-specific, and hierarchical shrinkage specifications for the dependence parameter, and compare them with frequentist and Bayesian odds-ratio benchmarks on the observed-probability scale. Because the native copula-model coefficients act on the working decrement scale, observed-scale covariate effects are summarized by Kullback-Leibler projection. In simulations, the Gaussian-copula models were competitive with odds-ratio benchmarks for observed-scale covariate-effect estimation; the hierarchical model provided a regularized alternative to unstructured interval-specific dependence. We illustrate the method using National Health and Aging Trends Study data on first onset of mobility help and self-care help. The application gave broadly similar observed-scale covariate-effect conclusions across the odds-ratio, constant Gaussian-copula, and hierarchical Gaussian-copula models.

Protein folding by the bacterial chaperonin GroEL/ES relies on ATP-driven conformational cycles that promote substrate encapsulation and folding. Under oxidative stress, the redox-active co-chaperone CnoX protects oxidized proteins and associates with GroEL, yet the structural basis of its interaction with the GroEL/ES remains incompletely understood. Using single-particle cryo-electron microscopy, we resolved four distinct nucleotide-bound conformational states of CnoX-associated GroEL/ES complexes. CnoX remains tethered to GroEL through its C-terminal TPR domain despite substantial rearrangements of the GroEL apical domains. We further captured a GroEL/ES-CnoX ternary assembly in which CnoX and GroES simultaneously occupy the same GroEL ring, demonstrating that their binding sites are structurally distinct and non-overlapping. Comparison of two GroES-bound states reveals how apical-domain compaction occludes the CnoX-binding surface and coincides with loss of CnoX from the cis-ring. Together, these structures define how CnoX is accommodated and excluded across distinct GroEL/ES conformations and provide a structural framework for understanding the interplay between redox co-chaperones and chaperonin assemblies.

Subcutaneous (SC) delivery of biologics is evolving to accommodate the greater volumes and doses required for efficacy. Conventional handheld auto-injectors are constrained by volume and speed limitations, prompting the development of high-volume auto-injectors (HVAIs) and wearable on-body injectors (OBI). A Near-Body Injector (NBI) system offers a novel approach by combining the benefits of high-volume delivery with hands-free operation, without the need for adhesive attachment associated with OBI's by using a standard winged infusion set and a mechanical priming mechanism incorporated into the device. This study evaluated the feasibility of a NBI system in a porcine model, delivering SC immunoglobulin alone and in combination with recombinant human hyaluronidase PH20 (rHuPH20), an enzyme known to enhance SC dispersion and absorption.Results demonstrated that the NBI system was easily primed and effectively delivered 10 mL SC. Co-formulation with rHuPH20 significantly improved injection performance, reducing delivery time by ∼13%, eliminating back-leakage, and decreasing swelling volume and induration at the injection site. These findings support the clinical potential of NBI systems for hands-free high-volume, high-dose biologic administration, offering an alternative to conventional SC delivery methods.

Hantaviruses are emerging rodent borne zoonotic pathogens of increasing global public health concern because of their high mortality, expanding ecological distribution, and potential for international dissemination. Although traditionally associated with sporadic rural outbreaks, recent ecological disruption, climate variability, urbanization, and increased global mobility have heightened concerns regarding hantavirus risks in mass gathering settings. This review critically examines the epidemiology, transmission uncertainty, diagnostic and surveillance challenges, and preparedness strategies related to hantavirus infections in the context of mass gatherings, including religious events, refugee settlements, cruise tourism, sporting events, and temporary accommodations. Particular emphasis is placed on the 2026 multinational cruise ship associated outbreak linked to the MV Hondius, which highlighted vulnerabilities related to delayed diagnosis, international passenger dispersal, and uncertainties surrounding possible human to human transmission of Andes virus. Current evidence indicates that hantavirus transmission occurs primarily through inhalation of aerosolized rodent excreta; however, controversies regarding limited interpersonal transmission, environmental persistence, and asymptomatic infections continue to complicate risk assessment and outbreak preparedness. Diagnostic limitations, underreporting, insufficient environmental surveillance, and lack of mass gathering specific preparedness frameworks remain major public health challenges, especially in resource limited settings. Strengthening proactive preparedness through integrated One Health approaches, ecological surveillance, genomic monitoring, AI driven epidemic intelligence, and coordinated international response systems is essential for mitigating future risks. The review emphasizes the urgent need for multidisciplinary research and evidence based policy development to improve global preparedness against emerging hantavirus associated threats in increasingly interconnected mass gathering environments.

This study examined whether direct expert elicitation of gambling harm severity, applied to blinded first-hand narrative accounts, produces ordered and consistent estimates with respect to quantitative self-reports. As such, this represented independent convergent validation evidence of the Gambling Harms Scales (GHS) instruments for people who gamble and affected others (AOs). Six experts with significant research or clinical expertise in the gambling field evaluated 60 transcripts from people who gamble and AOs experiencing varying levels of gambling-related harm (no-harm, low-harm, moderate-harm, and high-harm). Each transcript was evaluated using four protocols (visual analogue scale, rank ordering, time trade-off, and standard gamble). Narratives from participants with higher levels of harm (as assessed by the GHS) were associated with significantly higher expert-elicited health disutility. Disutility increased monotonically with GHS harm bands, and this pattern was consistent across all four elicitation protocols and all six expert raters. Pooled disutility estimates were 0.084 for low-harm, 0.187 for moderate-harm, and 0.221 for high-harm. Harm severity elicited by interviews and expert assessment was consistent with harm severity as assessed by the brief GHS measures. Expert evaluation of blinded narrative accounts provides independent external evidence supporting the GHS suite of instruments as measures of gambling-related harm.

Electrophilic dihalogenation of alkenes is a powerful strategy for the construction of configurationally defined vicinal dihalides. However, because of its inherent anti-stereospecificity, the practical synthetic access has been largely restricted to only half of the diastereochemical space. Although recent advances enabled complementary syn-dihalogenations through sequences involving anti-addition followed by stereoinversion, these approaches often suffer from limitations when applied to aryl-substituted alkenes that are prone to loss of stereochemical integrity during electrophilic activation via stable benzylic cation formation. Our group previously reported an efficient syn-dichlorination of N-protected allylic amines by exploiting an internal assistance mechanism of a systematically identified stereodirecting group, which notably accommodated aryl alkenes. We present here a full account describing the detailed course of our study, including further efforts to expand the substrate and halogen scopes.

Scorpion envenomation is a major public health concern in Mexico. Although Q9 most of the approximately 300,000 annual cases are resolved without complications, a subset present with moderate or severe manifestations, and around 35 deaths are reported each year. Identifying factors associated with greater clinical severity may improve clinical assessment and management. Our objective was to evaluate factors associated with clinical severity among scorpion envenomated patients in western Mexico.

A new leafhopper genus, Mencius gen. nov., is established to accommodate Mencius quinquespinosus comb. nov. and Mencius simprocessus sp. nov., the latter described from southern China. The new genus is compared with the similar genera Petalocephala Stål and Platycephala Kuoh. A key to distinguish Mencius from these genera is provided. Morphological descriptions, illustrations, and distribution data for the new taxa are presented.

Linvoseltamab, a human B-cell maturation antigen × CD3 bispecific antibody, showed high efficacy and a generally manageable safety profile in 117 patients with relapsed/refractory multiple myeloma (R/RMM) over a median follow-up of 21.3 months in the LINKER-MM1 trial. Patient-reported health-related quality of life (HRQoL) was assessed at baseline, week 4, and then every 4 weeks, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30); the 20-item MM module (QLQ-MY20); and the EuroQol 5-dimension, 3-level (EQ-5D-3L) questionnaire. Changes from baseline were estimated overall and at each assessment using mixed models for repeated-measures analysis; clinically meaningful change thresholds were based on previous literature. Results were evaluated by objective response status (at least partial response). Nominal statistically significant improvements from baseline on all QLQ-C30/QLQ-MY20 scales and the EQ-5D-3L visual analog scale were observed overall and at multiple assessments. Improvements in QLQ-C30 Global Health Status/quality of life, fatigue, and pain observed by week 16 were maintained at most subsequent assessments; pain improvement reached the clinically meaningful threshold at week 20 and was generally maintained through week 104. Among 83 treatment responders, nominal statistically significant overall improvements were observed on all scales; nonresponders (n = 34) reported numerical worsening on most scales. Through treatment week 104, improvements in HRQoL measures, including pain, fatigue, and functioning, were reported in patients with triple-class-exposed R/RMM receiving linvoseltamab. Patient-reported benefits were consistent with clinical response, supporting linvoseltamab's favorable benefit-risk profile. This trial was registered at www.clinicaltrials.gov as NCT03761108.