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Breeding for cold tolerance in pepper (Capsicum annuum L.) is critical to mitigate yield losses caused by unpredictable temperature fluctuations associated with climate change. However, genetic improvement of this trait is hindered by challenges in accurate phenotyping, particularly at the adult stage, and by its complex genetic architecture involving numerous minor-effect loci. While genomic selection (GS) offers a promising solution to accelerate genetic gain, its predictive ability is often limited by statistical noise from uninformative markers within whole-genome marker sets. This study aimed to overcome this limitation by developing a robust phenotypic index and implementing a genome-wide association study (GWAS)-informed GS strategy. We phenotyped 192 pepper accessions from a core collection for cold tolerance using a visual survival score (Surv) and a newly developed composite cold-tolerance index (CTI). Both CTI (h2 = 0.55) and Surv (h2 = 0.53) showed moderate heritability, suggesting a substantial contribution from additive genetic variance to the phenotypic variation of cold tolerance in adult plants. GWAS identified 13 candidate genomic regions associated with cold tolerance; these regions included TRM9, CAP1, and PP2A-2, genes previously implicated in abiotic stress responses. For genomic prediction, we applied nested CV and LOOCV in which GWAS and marker selection were performed within the training set before fitting the prediction model, so that phenotypic information from the test individuals was not incorporated into the marker selection step. Compared with the full marker set of 73,502 markers, the best GWAS-selected marker sets achieved prediction accuracies of 0.237 for CTI and 0.197 for Surv in nested CV, and 0.349 for CTI and 0.294 for Surv in LOOCV. At the same marker numbers and model conditions, random marker sets showed lower accuracies of 0.205 and 0.166 for the nested CV, and 0.068 and - 0.064 for the LOOCV, respectively. Our study demonstrates that assessing cold tolerance via the CTI helps overcome the limitations of discrete survival scoring. By turning ordinal data into a continuous spectrum, the CTI can unmask hidden genetic variation. In addition, GWAS identified candidate genomic regions and genes associated with cold response, and nested CV and LOOCV showed that GWAS-selected marker sets could achieve higher prediction accuracy than the full marker set and random marker sets of the same marker number. This integrated framework offers a practical approach for interpreting the genetic basis of adult-stage cold tolerance in pepper and improving the efficiency of genomic prediction models for complex abiotic stress traits.

Complement 3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare glomerular diseases driven by dysregulation of the complement system, most commonly involving the alternative pathway. Recent advances in the understanding of disease pathogenesis have enabled the development of targeted complement therapies. The publication of pivotal phase 3 trials evaluating proximal complement inhibitors -iptacopan, a selective factor B inhibitor, and pegcetacoplan, a C3 inhibitor- marks a turning point in the management of C3G and IC-MPGN. Both agents demonstrated clinically meaningful reductions in proteinuria and stabilization of kidney function, establishing proof of efficacy. Despite these advances, important uncertainties remain. Key unresolved issues include optimal patient selection, timing and duration of therapy, treatment sequencing, monitoring strategies, and long-term kidney outcomes. Conventional immunosuppressive approaches provide inconsistent benefit and do not directly address complement dysregulation, while validated biomarkers to guide complement blockade are lacking. Additional challenges relate to treatment discontinuation, management of special populations, and health-system implementation. This review critically appraises the evidence from recent pivotal trials, highlighting both their transformative impact and the questions they raise. We emphasize the need for long-term outcome studies, precision-based therapeutic strategies, and pragmatic real-world data. Ultimately, the challenge ahead is not whether complement inhibition is effective but how best to deploy these therapies to maximize durable benefit, minimize risk, and ensure equitable access.

Three new species of Microlaimidae are described from the sand coast of the Sea of Japan (Russian coast). Among previously discovered free-living nematodes, the genera Microlaimus and Bolbolaimus are recorded for the first time. Bolbolaimus mirandussp. nov. is characterised by anterior cephalic region set off from the body, large cuticularised buccal cavity with one strong dorsal tooth and two noticeable subventral teeth, muscular anterior and posterior pharyngeal bulbs, curved not cephalated spicules, short and simple gubernaculum, and short and conical tail. Bolbolaimus selinaesp. nov. has an annulated cuticle with very close and fine longitudinal bars; anterior and posterior pharyngeal bulb; large buccal cavity with one large dorsal tooth, two small subventral teeth in the anterior part, and transversal rows of protrusions in the posterior part; amphidial fovea oval shaped in males and circular shaped in females. Microlaimus asiaticus sp. nov. is characterised by monospiral amphidial fovea turning ventrally at the level of posterior part of cup-shaped buccal cavity, weakly conspicuous dorsal tooth and two small subventral protrusions; small circular pharyngeal bulb; four conical precloacal supplements in male, and conical tail. These findings expand the taxonomic knowledge and geographic distribution of Microlaimidae in the Pacific region.

Herbaria are invaluable repositories for documenting past and present biodiversity and, beyond their botanical focus, provide historical snapshots of microhabitats that support diverse microfauna such as tardigrades. Bryophyte collections are particularly important in this regard, offering material for the discovery and characterisation of species. The genus Macrobiotus is taxonomically challenging due to high phenotypic variability, making species identification difficult and rendering several historical Mexican records doubtful under current integrative standards. In this study, we integratively describe two new species, Macrobiotusexcelsussp. nov. (within the hufelandi morphogroup), and Macrobiotusignifersp. nov. (within the persimilis morphogroup) and record Macrobiotus olgae for the first time in Mexico from moss samples from the Trans-Mexican Volcanic Belt housed in the National Herbarium of Mexico; M. excelsussp. nov. represents the first documented tardigrade species from Veracruz. Morphological analyses using phase contrast microscopy and scanning electron microscopy, together with DNA sequencing, provided robust evidence for species delimitation. These findings represent a turning point in clarifying the taxonomy and phylogeny of Macrobiotus in Mexico and underscore the need to re-evaluate historical records using modern criteria. At the same time, they highlight the essential role of herbaria as key resources for discovering and characterising tardigrade diversity.

Proteolysis-targeting chimeras (PROTACs) have become a game-changing mode of therapeutic intervention capable of turning off disease-driving proteins by using the ubiquitinproteasome system. In contrast to conventional inhibitors, PROTACs act through event-driven pharmacology and, by providing comprehensive clearance of targeted proteins, they promise to address resistance mechanisms that plague conventional therapies. This review discusses the paradigm- shifting potential of PROTACs to degrade poly (ADP-ribose) polymerases (PARPs), key regulatory enzymes in the DNA damage response whose inhibition has been clinically validated in BRCA-mutant cancers. Nevertheless, resistance to PARP inhibitors has led to the need for alternative approaches, and PROTACs have become a potent strategy to degrade PARP via the proteasome. A key component of this strategy is Cereblon (CRBN), which is a commonly utilized E3 ligase in the design of PROTACs and is considered highly druggable and expressed. We unravel the molecular actions that are the basis of CRBN-directed protein degradation and address the existing issues, such as ligase saturation, resistance through mutations, and off-target signatures, as well as translational challenges of PROTAC technology, such as pharmacokinetics, cell permeability, and potential toxicity. Moreover, we demonstrate emerging technologies such as dual-ligase PROTACs, AI-based ligand optimization, and deep mutational scanning as methods to enhance degrader space and target efficacy. This review combines insights on the mechanisms with upcoming technologies to propose important prospects and future research gaps in E3 ligase selection, degrader specificity, and resistance management. Together, we introduce PARP-targeting PROTACs, in collaboration with CRBN, as a promising area of precision drug development and oncology.

To explore the association between high-density lipoprotein cholesterol ratio (NHR) and the prevalence of heart failure (HF). Data from National Health and Nutrition Examination Survey (1999-2018) were downloaded. Unweighted multivariate logistic regression model evaluated whether NHR levels were independently related to HF, adjusting for demographics and clinical variables. Subgroup analyses examined consistency across populations. The nonlinear relation between NHR and HF was appraised by restricted cubic spline (RCS), with inflection point identified by two-piece linear regression. The study included 41,449 participants, of whom 1322 (3.19%) were diagnosed with HF. Analyzing NHR as a continuous variable, multivariable-adjusted logistic regression analysis demonstrated a significant independent relationship between elevated NHR levels and HF risk (OR&#x2009;=&#x2009;1.08; 95% CI: 1.04-1.12; p&#x2009;<&#x2009;0.001). When NHR was stratified by quartiles, the risk of HF was 1.94 times higher (95% CI: 1.56-2.41; p&#x2009;<&#x2009;0.001) for individuals in the highest NHR quartile compared to those in the lowest quartile. RCS analysis indicated a notable nonlinear relationship (p-nonlinear <&#x2009;0.001), with a threshold effect identified at an NHR of 6.39. A 21% higher risk of HF was associated with each unit increase in NHR below this turning point. In subgroup analyses, it was shown that the connection between NHR and HF was noticeable across both males and females, in participants with and without hypertension, in those with and without diabetes, and certain racial groups (Non-Hispanic Whites, Non-Hispanic Blacks, and other races). The increased NHR was correlated with a heightened prevalence of HF.

This study presents the design and development of a lever-propelled wheelchair with a novel propulsion system aimed at reducing user effort and fatigue by improving propulsion efficiency and ergonomics. A cost-effective and user-friendly prototype was developed to benefit individuals with lower limb disabilities, particularly those in low-income settings. A descriptive review of the literature and patents was conducted to identify the current advancements in wheelchair design and features. Essential features from the tricycle and lever-propelled wheelchairs are considered in the prototype design, in adherence to the WHO wheelchair standards. A CAD model was designed based on these standards and considering the low-cost manufacturing process to match the low-resource setting. The prototype was then fabricated using the standard manufacturing process. Trials were conducted with 25 unimpaired participants following a brief familiarisation and training session. Participants performed repeated propulsion trials along a predefined outdoor course involving straight-line motion, turning, and braking. User feedback on ease of use, comfort, safety, and propulsion effectiveness was collected using the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0). Based on the participants trials, received positive feedback, which provides preliminary support for the developed wheelchairs propulsion mechanism, stability, and overall build quality. The user provides feedback on ease of use because of the dual-power stroke mechanism, which reduces a significant amount of user effort in propelling the wheelchair, manufactured in limited-resource settings. The dual-power stroke mechanism improves propulsion efficiency and decreases everyday upper limb fatigue.The simplified mechanical design makes it suitable for use in a limited-resource setting.Adjustable lever height enables use by a broad range of users with different anthropometric characteristics.The design can support community-based rehabilitation programs, especially in rural areas.High user satisfaction scores indicate that the proposed wheelchair has the potential to be considered for prescription as an assistive technology.

Clear cell renal cell carcinoma poses unique challenges for immunotherapy, particularly with immune checkpoint inhibitors. Many ccRCC tumors exhibit an "immune-cold" tumor immunosuppressive microenvironment (TIME), characterized by poor T cell infiltration and multiple immunosuppressive barriers, leading to primary or acquired resistance to ICIs. Approaches to convert these tumors into "immune-hot" (T cell-inflamed) states are critical for improving therapeutic outcomes. Nanomedicine offers promising solutions by modulating the broader tumor microenvironment (TME) and enabling precision delivery of immune-modulatory agents. In this review, we highlight how nanotechnology-based platforms can alleviate hypoxia and acidity in the TME, reprogram suppressive myeloid cells within the TIME (e.g., myeloid-derived suppressor cells and tumor-associated macrophages), and synergize with ICIs and targeted therapies. We summarize recent advances in ccRCC and ccRCC-relevant preclinical models, distinguishing direct RCC evidence from hypothesis-generating findings derived from other solid tumors. These integrative nano-immunotherapy approaches aim to overcome immunoresistance in ccRCC, turning immunologically "cold" tumors "hot" and improving the depth and durability of anti-tumor immune responses.

PANoptosis, a collective form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, is turning out to be a key player in the neuroimmune activation and sustaining chronic neuroinflammation in the nervous system. PANoptosis, in contrast to single cell death mechanisms, is a web of events coordinating neuronal death, glial cell changes, and inflammatory signals, being implicated in the initiation and progression of neurodegenerative and neuroinflammatory diseases. This review compiles current knowledge of the molecular pathways of PANoptotic signaling, its interaction with autophagy and immune pathways, and the in vivo models utilized for its pathogenic role in the central nervous system. We also tackle translational hurdles such as biomarker identification, therapeutic safety, disease, stage precision, and patient heterogeneity, which all point to the necessity of highly accurate interventions. Moreover, novel techniques combining systems biology, AI-based target identification, and personalized neuroimmunomodulation may effectively harness PANoptosis regulation to be both controlled and disease-specific. Through bridging the gap between the mechanistic insights and the translational perspectives, this review points out that PANoptosis provides a comprehensive basis for neuroimmune-associated pathology and represents a viable target for novel therapeutic approaches to counteract both chronic neuroinflammation and neurodegeneration.

The purpose of this study was to explore why and how medical students use non-traditional learning resources relative to the formal curriculum, to inform curriculum development efforts, and support self&#x2011;directed learning. A qualitative study grounded in a pragmatic research approach was conducted using semi structured interviews with medical students at the University of Ottawa. Participant recruitment occurred via email/social media, and a pre survey was used to ensure sampling of both low- and high-level resource users. Transcripts were analyzed using reflexive thematic analysis in NVivo. Analysis was both deductive, guided by self-regulated learning (motivation, goal setting, feedback, self-monitoring), and inductive to capture unanticipated themes. Twenty-nine students participated (18 pre-clerkship; 11 clerkship). Four themes were developed: two addressing motivations&#xa0; for using non&#x2011;traditional resources-the traditional curriculum is repetitive and inflexible and non&#x2011;traditional resources are high&#x2011;yield and flexible; one addressing goal setting-studying for today's exam or tomorrow's patient; and one addressing how students engage with resources, captured through three archetypes-the Traditionalist, the Supplementer, and the Reformer. This study demonstrates how medical students navigate learning by turning to non-traditional resources, shaped by their motivations, goal orientations, and distinct engagement patterns. These insights highlight opportunities to streamline and modernize curricula, integrate vetted high yield resources, and strengthen students' self-regulated learning skills. Leveraging the three learner archetypes can further guide curriculum planning by recognizing diverse learning approaches, engaging Supplementers as indicators of curricular gaps, supporting Traditionalists with structured pathways, and viewing Reformers' non-attendance as an expression of SRL rather than disengagement.

Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioception's contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.

Metabolic, neurodegenerative, and stress-related disorders are frequently accompanied by altered locomotion, impaired decision-making, and reduced behavioral flexibility. However, accessible multimodal behavioral frameworks for quantifying these phenotypes in Drosophila melanogaster remain limited. Here, a protocol integrating forced swim exposure, Y-maze turning behavior and handedness, phototaxis, and activity assessment in the FlyVac system, open-field exploration, and long-term locomotor monitoring using the Drosophila Activity Monitor is presented. These complementary assays capture multiple dimensions of behavior, including motor output, motivation, decision structure, and behavioral variability, as functional readouts of neural and metabolic states. The pipeline is scalable, reproducible, and adaptable to pharmacological, genetic, and environmental manipulations, providing a versatile framework for detecting stress-, metabolic-, and neurodegeneration-related behavioral phenotypes in Drosophila.

Accurate force fields are essential for reliable molecular simulations. These models are refined against quantum mechanical calculations and experimental measurements, which are subject to random and systematic errors. Bayesian Inference of Conformational Populations (BICePs) is a reweighting algorithm that reconciles simulated ensembles with sparse or noisy observables by sampling the full posterior distribution of conformational populations and experimental uncertainty. In this method, a metric called the BICePs score is used to perform model selection, by calculating the free energy of "turning on" the conformational populations under experimental restraints. This approach, when used with improved likelihood functions to deal with experimental outliers, can be used for force field validation (Raddi et al. 2025). Here, we extend the BICePs approach to perform automated force field refinement while simultaneously sampling the full distribution of uncertainties, using a variational method to minimize the BICePs score. To demonstrate the utility of this method, we refine multiple interaction parameters for a 12-mer HP lattice model using ensemble-averaged distance measurements as restraints. To illustrate the resilience of BICePs in the presence of unknown random and systematic errors, we assess the performance of our algorithm through repeated optimizations and under various extents of experimental error. Our results suggest that variational optimization of the BICePs score is a promising direction for robust and automatic parameterization of molecular potentials.