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Structural basis for selective inhibition of human GABA transporter GAT3
Exceptionally selective voltage-sensor trapping of NaV1.5 channels by Mg-protoporphyrin impairs cancer cell migration
Abstract The human voltage-gated sodium channel hNa V 1.5 is essential for cardiac excitability. Though underrecognized, Na V 1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa V 1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle Na V channels. Here we identify Mg 2+ -protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa V 1.5 ( IC 50 of 1 nM). The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNa V 1.5, as no inhibition of other hNa V isoforms (hNa V 1.2, 1.4, 1.7, 1.8) was detected. A mutagenesis study and structural modeling reveals that MgPpIX stabilizes the domain-II voltage sensor in the deactivated conformation, with residues E795 and N803 being relevant determinants. MgPpIX also inhibits native Na V channels in breast cancer MDA-MB-231 and colorectal carcinoma SW-480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNa V 1.5 and may serve as a lead compound in anti-cancer drug development.
Investigation of the drug release modifying property of Pentadesma butyracea gum in diclofenac sodium matrix tablets
Background Natural gums have long served as essential excipients in pharmaceutical formulations, traditionally functioning as binders, disintegrants, suspending agents, and emulsifiers. Their role has expanded to include drug delivery carriers in advanced systems such as matrix formulations, gene therapy, and nanomedicine. Increasing attention has been given to natural gums over synthetic alternatives due to their non-toxicity, biodegradability, affordability, and availability. This study investigated the potential of Pentadesma butyracea gum as a matrix-forming agent for the extended release of diclofenac sodium. Methods The crude gum was harvested from the stem bark of Pentadesma butyracea and purified using ethanol precipitation. Fourier-transform infrared spectroscopy (FTIR) was employed to assess potential interactions between the gum, diclofenac sodium, and other excipients. Matrix tablets (PM01–PM05) containing varying concentrations (15–35% w / w ) of the purified gum were prepared via wet granulation, along with a control batch (PM06) lacking the gum. Additionally, the PM01 formulation was optimised by incorporating xanthan gum at concentrations of 10–20% w / w (PM01A–PM01C). All formulations were assessed for weight and dimensional uniformity, mechanical integrity, drug content, and in vitro release characteristics. Comparative dissolution profiles were assessed against an innovator brand using the similarity (f₂) and difference (f₁) factors. Drug release kinetics and mechanisms were analysed using appropriate mathematical models. Results All batches passed the uniformity of weight and dimensions tests, drug content (99.11–101.87%), friability (0.25–0.79%), hardness (7.74–8.83 Kgf), and tensile strength (1.29–1.49 MPa). The control batch (PM06) failed to meet dissolution criteria, releasing only 60.46% of diclofenac sodium within 45 minutes. In contrast, formulations containing P. butyracea gum exhibited a gradual, concentration-dependent, time-mediated release, with all test batches (PM01–PM05) releasing over 50% of the drug within 45 minutes. Among the optimised formulations, PM01C exhibited a modified release profile, with 19.90 ± 0.508% of the drug released at 2 hours and 100.26 ± 2.118% at 24 hours, consistent with the British Pharmacopoeia standards. The release profile of PM01C was comparable to the reference product (f₂ = 79.35; f₁ = 2.93) and followed zero-order kinetics. PM01A and PM01B exhibited Korsmeyer-Peppas release kinetics. Mechanistically, drug release occurred via non-Fickian diffusion for PM01C and Fickian diffusion for PM01A and PM01B. Conclusion A matrix system comprising 15% w / w P. butyracea gum and ≥ 20% w / w xanthan gum effectively extended the release of diclofenac sodium over 24 hours, demonstrating its potential application in extended-release formulations.
Coordinated gene family evolution shapes the genome of dimorphic Mucorales
Unveiling key genetic loci and candidate genes for brown spot disease resistance in rice based on QTL analysis
Abstract Rice brown spot, a widespread disease caused by the fungus Bipolaris oryzae (teleomorph: Cochliobolus miyabeanus ), significantly diminishes both grain yield and quality. Developing resistant rice cultivars remains the most sustainable and effective strategy for managing this disease. In this study, we conducted quantitative trait locus (QTL) analysis to identify genetic loci and candidate genes associated with brown spot resistance. A mapping population was generated from a cross between the resistant variety ‘Cheongcheong’ and the susceptible variety ‘Nagdong’. Disease evaluations were performed following inoculation with a mixture of six Cochliobolus miyabeanus isolates collected in 2023 to represent current field diversity, and disease severity was assessed seven days post-inoculation using a 0–9 scale. The QTL analysis revealed a new major locus on chromosome 3 linked to brown spot resistance, between markers RM15749 and RM15689. Within this genomic interval, 32 candidate genes were identified using qRT-PCR-based expression profiling. Among them, a gene designated OsRBSq3 ( Os03g0687400 ), encoding a ribosome-inactivating protein family member that plays a role in defense mechanisms against necrotrophic pathogens, exhibited notable differential expression between Cheongcheong and Nagdong. These results provide new insights into the genetic architecture underlying brown spot resistance in rice and highlight OsRBSq3 as a potential target for marker-assisted selection and functional studies.
Differential seedling responses of chickpea varieties to hexavalent chromium (VI) stress under controlled conditions
Hexavalent chromium (Cr VI) contamination infiltration in soil due to industrial activities has become a sever threat to Pakistan’s agricultural productivity. Recent surveys report soil chromium concentrations in agricultural–industrial interfaces of Punjab and Khyber Pakhtunkhwa reaching 100 mg/kg, exceeding the WHO permissible limit (1.5 mg/kg) by more than 50-fold. Chickpea, a widely cultivated crop in Pakistan also faces productivity threats from Cr (VI). This study evaluates the differential seedling responses of two Pakistani chickpea varieties (CM-72 and CM-98) to hexavalent chromium stress (0µM to 100µM) under controlled conditions to address a critical research gap. A fully randomized experimental design (CRD) with five replicates per treatment was utilized, assessing germination metrics, root and shoot lengths, root collar diameter, and biomass over a period of 14 days. Statistical evaluations (ANOVA, Pearson correlation, PCA) indicated substantial varietal differences. Both varieties showed significant (p < 0.05) dose-dependent reductions in germination rates, growth, and biomass; however, CM-72 exhibited greater tolerance. At a concentration of 100 µM Cr VI, CM-72 achieved 90% germination (compared to 80% in CM-98), with moderate declines in root length (39% compared to 77% in CM-98), shoot length (76% compared to 90%), and biomass (34% dry weight loss in comparison to 59% in CM-98). Multivariate analysis revealed strong associations between growth inhibition and chromium stress, with PCA differentiating between structural (root collar diameter) and temporal (germination delay) effects. These results highlight the resilience of CM-72, likely attributable to metabolic and antioxidative adaptations, making it a potential candidate for cultivation in areas contaminated with chromium. The relative tolerance of CM-72 may relate to underlying physiological or biochemical traits that warrant investigation in future studies. This research offers essential insights into the responses of chickpea varieties to Cr VI stress, highlighting the necessity for biochemical and molecular studies to clarify tolerance mechanisms and support sustainable agricultural practices in regions impacted by heavy metals.
NR6A1 is essential for neural crest cell specification, formation and survival
Experimental study on the compaction deformation evolution and energy dissipation characteristics of graded broken rock mass
The mediating role of self-efficacy in the relationship between self-management and health-promoting behaviors in post-PCI patients
Background Coronary artery disease (CAD) has become one of the most prevalent diseases worldwide. Self-management and self-efficacy are critical for enhancing healthy lifestyles in patients with postoperative CAD and are strongly associated with health-promoting behaviors. However, the underlying mechanisms of this association remain unclear. Purpose To explore the mediating role of self-efficacy between self-management and health-promoting behaviors in patients following percutaneous coronary intervention (PCI). Methods From November 2024 to March 2025, 400 post-PCI patients were selected by convenience sampling from a tertiary first-class hospital in Xinjiang. Surveys were administered using a general information questionnaire, a self-management scale, a self-efficacy scale, and a health-promoting lifestyle scale. Structural equation modelling was employed to investigate the pathways of action among the three variables. Results The scores for self-management behaviour, self-efficacy, and health-promoting lifestyle were (96.66 ± 10.11) scores, (44.49 ± 6.10) scores, and (162.91 ± 12.24) scores, respectively, with positive correlations between each pair of items. Self-efficacy partially mediated the relationship between self-management and health-promoting behaviors, with a standardized indirect effect of 0.317, accounting for 61.3% of the total effect. Conclusions Self-efficacy plays a partial mediating role between self-management and health-promoting behaviors. Healthcare professionals should pay attention to the self-efficacy of patients post-PCI to enhance their awareness of personal health and strengthen self-management, thereby promoting proactive adoption of healthy lifestyles.
VSIG10L is a major determinant of esophageal homeostasis and inherited predisposition to Barrett’s esophagus
Sunscreen application substantially mitigates molecular perturbations induced by repetitive UV exposure and maintains healthy skin
Is the human chin a spandrel? Insights from an evolutionary analysis of ape craniomandibular form
Humans are unique among primates in possessing a chin, yet it is currently unclear whether the form of the symphyseal region of the mandible where the chin is located is the product of direct selection or a by-product of evolutionary pressures on other craniomandibular features. Here, we conduct an evolutionary analysis of hominoid craniomandibular traits to test three hypotheses: symphyseal mandibular traits evolved (1) neutrally due to genetic drift, (2) under direct selection, and (3) as a by-product (or “spandrel”) of selection on other craniomandibular traits. Evolutionary rates of morphological change, via Lande’s generalized genetic distance, were estimated along each branch of a fully-resolved hominoid phylogeny to reveal patterns of neutral, stabilizing and directional selection. Directional selection was detected along the branch between humans and the last common ancestor of chimpanzees and humans, against a backdrop of pervasive stabilizing selection and neutral evolution in hominoids. Significant directional selection was found on cranial traits reflecting increased basicranial flexion, neurocranial expansion, and reduction in lower facial prognathism, and on mandibular traits that generate a more parabolic-shaped, gracile mandible with a smaller ramus and shallower corpus. In contrast, of the nine mandibular “chin” traits, only three were under significant direct selection, while the other six were either under no selection or indirect selection. Thus, the results are consistent with the hypothesis that the symphyseal morphology that forms the human chin evolved largely as a by-product (i.e., spandrel) of direct selection for reduced anterior dental size and the craniofacial changes correlated with the evolution of bipedalism in hominins, rather than as a specific adaptation.
Quantum magnetic J-oscillators
Abstract Zero-field nuclear magnetic resonance (NMR) offers magnet-free access to nuclear spin-spin (scalar J ) couplings, which define an intrinsic, molecule-specific frequency scale. However, the transient nature of zero-field NMR signals constrain spectral resolution and frequency stability. Here we introduce quantum J -oscillators that exploit J -couplings in molecules to produce phase-coherent continuous oscillations. Operated in zero magnetic field and driven by digital feedback, they generate sub-hertz to a few tens of hertz frequencies. In a proof-of-principle experiment on [ 15 N]-acetonitrile, the oscillator achieves a 340 μ Hz linewidth over 3600 s, more than two orders of magnitude narrower than in conventional zero-field NMR. This methodology may facilitate precision measurements of J -coupling constants and enables discrimination of molecules whose zero-field NMR spectra are otherwise difficult to resolve. In addition, the combination of strongly coupled spin systems and programmable feedback turns J -oscillators into a compact tabletop platform for exploring nonlinear spin dynamics, including chaos and dynamical phase transitions. By uniting high-resolution spectroscopy and controllable quantum dynamics in a single, magnet-free setup, J -oscillators open new opportunities for applications where ultraprecise frequency references or molecular fingerprints are required.
Multi-scale simulations of complexation behavior of lanthanides and actinides with soft-hard donor-based ligands
Exploring adverse events associated with vosoritide monotherapy: Insights from the FDA Adverse Event Reporting System
Background Dwarfism, a condition characterized by short stature, has been the focus of therapeutic advancements with the emergence of novel peptide drugs. Vosoritide, indicated for certain types of dwarfism, has shown therapeutic potential in clinical trials. However, a comprehensive safety profile is essential for its clinical application. The current literature lacks a detailed assessment of vosoritide’s safety, indicating a significant gap that this study aims to address. Methods We conducted a retrospective pharmacovigilance study by analyzing the FDA Adverse Event Reporting System (FAERS) database to evaluate adverse events (AEs) associated with vosoritide monotherapy. The study employed a case/non-case methodology and applied signal detection algorithms, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS), to identify AE signals related to vosoritide use. Results The study included 9319269 reports from the FAERS database, covering the period from 2022 to 2023, with 274 reports specifically citing vosoritide. A significant number of AEs were identified, with a notable incidence in the pediatric population. The most frequently reported AEs were related to endocrine disorders, including altered growth hormone levels and glucose homeostasis issues. Other affected system organ classes (SOCs) were infections and infestations, as well as skin and subcutaneous tissue disorders. Specific preferred terms (PTs) associated with vosoritide included “growth deceleration,” “glycemic dysregulation,” and “local injection site reactions.” Conclusion The findings from this study underscore the importance of close monitoring of vosoritide treatment, particularly in pediatric patients. The identification of both expected and unexpected AEs highlights the necessity for ongoing pharmacovigilance and further research to fully understand the safety profile of vosoritide in clinical practice. This study contributes to the broader field by emphasizing the critical need for patient safety considerations in the development of new therapeutic agents.
Technologies to give a clearer view of the lungs
Rochelle salt-based biodegradable piezoelectric devices for nerve regeneration and intestinal motility monitoring
Predicting postoperative delirium after lung cancer resection: the utility of synthetic data and LIME algorithm for model interpretation
Autonomous restart of information floating and dynamic control of transmittable area
Information floating (IF) is a method of delivering information to mobile nodes in a desired area while avoiding unnecessary communication and information dissemination by restricting direct wireless transmission to a transmittable area (TA). This restriction, however, also leads to the termination of IF, which is a longstanding problem that must be overcome. As a solution, methods have been developed to predetermine the optimal TA size based on environmental parameters such as node density. If the density changes over time, then the estimation of the density and the optimization of the TA must be repeated. Therefore, we previously proposed a method that guarantees that the IF never ends in principle, even if the node density changes over time, by dynamically controlling the TA size. However, this method is only applicable in a one-dimensional network. Here, we propose a method that guarantees, even in two-dimensional networks, that the IF never ends. To accomplish this, we introduce two key functions. The first autonomously restarts the IF even if it has temporarily terminated. The second function dynamically controls the TA size. We also highlight the necessity of introducing a lifetime for the TA generated by the dynamic control method if the density changes over time, and we improve the proposed method accordingly. We show the effectiveness of the proposed methods in terms of continuity and tracking performance through theoretical and simulation evaluations.