Search Results (1,199)

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

The two-parameter bathtub-shaped distribution is an important lifetime distribution. In this paper, we are interested in developing reliability inference and remaining useful life prediction methods for the two-parameter bathtub-shaped lifetime distribution under progressive type-II censoring. By constructing generalized pivotal quantities, the generalized confidence intervals for both model parameters and key reliability metrics, including quantiles, reliability functions, and remaining useful life are exploited. The proposed methods are further extended to accelerated life testing scenarios. The corresponding accelerated life testing model is constructed based on the two-parameter bathtub-shaped distribution. Furthermore, the generalized confidence intervals for model parameters, quantiles, reliability functions, and remaining useful life are also exploited under the designed stress level. Through comprehensive Monte Carlo simulations, and comparing our approach with Wald confidence intervals and bootstrap-p confidence intervals across moderate and large sample sizes, we confirm the superior coverage probability performance of the generalized confidence interval procedures. The practical applicability of our methodology is validated through two illustrative examples. Full article

The MADS-box transcription factor (TF) family constitutes a critical class of transcriptional regulators in plants, playing pivotal roles in diverse developmental processes. MIKC-type proteins represent Type II MADS-box TFs that widely function in regulating floral organ development and reproductive growth in plants. In this study, a total of 38 MIKC-type MADS TFs were identified from the sorghum genome, distributed across nine chromosomes. Based on sequence alignments and phylogenetic analysis, these 38 SbMIKC genes (SbMIKCs) were further classified into 10 distinct subfamilies. The expression profiling of these SbMIKCs across multiple tissues revealed five major patterns, among which SbMIKC17 exhibited relatively abundant transcript levels during grain development in sorghum. Further assays confirmed that the protein encoded by SbMIKC17 localizes to the nucleus without self-transactivation activity in yeast. Integrated results from DNA affinity purification sequencing (DAP-seq), dual-luciferase assays, and yeast one-hybrid experiments demonstrate that SbMIKC17 binds to the promoter of SbAGPS1 and activates its activity, as well as enhance the promoter activities of SbBt1, SbGBSSI, SbSSIIa, and SbISA1 simultaneously. Collectively, these findings suggest that the MIKC-type MADS member of SbMIKC17 serves as a potential transcriptional regulator in starch biosynthesis in sorghum. Full article

The black soldier fly, Hermetia illucens (Linnaeus, 1758), is a globally recognized resource insect for waste bioconversion and sustainable resource provision. Understanding its larval sensory system is key to explaining feeding and environmental perception behaviors. This study used scanning and transmission electron microscopy to analyze the types, distribution, ultrastructure, and developmental consistency of sensilla on larval cephalic appendages. Five sensilla types were found on antennae, sensilla basiconica I–II, sensilla twig basiconica I–II, and sensilla campaniformia, each type comprising 2–6 sensilla. Mouthparts harbored ten types, including sensilla twig basiconica III–V, sensilla placodea, sensilla ligulate, sensilla digitiformia, sensilla trichodea, and sensilla chaetica I–III, with 2–9 sensilla per type. All sensilla showed constant numbers and positions throughout larval development. Ten sensillum types with cuticle pores were innervated by 2–6 sensory neurons, primarily suggesting chemoreceptors; these were concentrated at the tips of antennae and maxillary palps. Sensilla digitiformia on the palps possessed a non-porous cuticle and a single sensory cell, indicative of a thermo-/hygroreceptive role. Sensilla chaetica and trichodea, with non-porous cuticles and no dendrites, were mechanosensory. These results reveal the morphofunctional basis of larval sensation, supporting chemoreception studies and optimizing rearing via behavioral modulation. Full article

In this paper, a new probability model is suggested, known as the Unit Linear Failure Rate Distribution (ULFRD), which is used to analyse data expressed on a unit interval (0, 1), e.g., proportions, rates, and normalised indices. The proposed model is a transformation of the classical linear failure rate distribution to finite domains and gives us the opportunity to have shapes with a variety of shapes that can model any hazard rate behaviour, such as bathtub-shaped ones that are common in reliability research. Various fundamental statistical features of the distribution are obtained. The parameter estimation is analysed under Type-II censoring, where maximum likelihood and Bayesian estimations are used. Bayesian estimates are obtained under a symmetric and an asymmetric loss of a Metropolis–Hastings within a Gibbs approximation. The analyses of the estimates’ performance are performed via a simulation study of various sample sizes and censoring plans. Lastly, the generalisability of the proposed model is also demonstrated with two real datasets in the socioeconomic and reliability settings. The findings prove that the ULFRD offers a flexible and competitive alternative to model-bound data. Full article

The Lateral Organ Boundaries Domain (LBD) gene family encodes plant-specific transcription factors that play pivotal roles in growth, development, and stress responses. However, a comprehensive genome-wide analysis of the LBD family in watermelon (Citrullus lanatus) has not been conducted until now. In this study, we identified 39 ClLBD genes using the latest watermelon reference genome and systematically analyzed the function of ClLBD2 in root development. These ClLBDs are unevenly distributed across 10 chromosomes except Chr4. Evolutionary analysis grouped the gene family members into six subgroups: Class I (a–e) and Class II. Physicochemical properties and gene structure analysis showed that the ClLBD protein members are tightly conserved. In the promoter regions of ClLBD genes, we identified abundant cis-acting regulatory elements related to abiotic stress and hormone responses. Through RNA-seq analysis from a cucurbit database, we found that several ClLBD genes showed high relative expression in roots, with ClLBD2 being the most highly expressed. Since its subfamily includes AtLBD25, a known root development-related gene, we hypothesized that ClLBD2 might be involved in root development. To validate this, ClLBD2-edited roots were generated using the CRISPR-Cas9 system and Agrobacterium rhizogenes-mediated transformation. Compared to the wild type, the ClLBD2 edited roots exhibited significant reduction in taproot length and lateral root numbers, indicating that ClLBD2 may regulate root development. This study provides the first comprehensive analysis of the LBD gene family in watermelon, offering valuable insights for evolutionary and further functional studies of ClLBD genes. Full article

The neuromuscular junction (NMJ) is responsible for transmitting neural signals that trigger muscle contraction. Muscle injuries cause damage to cellular structures and trigger local inflammatory processes. In this context, eccentric contraction was used as an experimental model because it involves excessive stretching, generating mechanical stress. Twenty-five adult male Wistar rats were distributed into groups: Control (C) (n = 5) and Injury (I) (n = 20). The protocol was performed on a treadmill and consisted of 18 sets/5 min/16 m/min speed, with intervals, and with a negative incline (−16º). The analyses consisted of histochemical techniques, such as myofibrillar ATPase and immunofluorescence (calcium channels, synaptophysin and α-bungarotoxin). Group I-0H showed alterations in the presynaptic region and an increase in Type I fibers. I-24H presented disorganization in the postsynaptic region. In I-4D, we observed the reorganization of neuromuscular activity, while I-7D presented greater density and cross-sectional area (CSA) of Type II fibers. It is concluded that the protocol promotes changes in NMJ structure and fiber distribution, mainly in I-24H. In I-4d, a reorganization of neuromuscular activity is observed, and in I-7D, a structural indicator consistent with recovery demonstrates the skeletal muscle’s ability to adapt to injury. Full article

With the growing penetration of photovoltaic (PV) generation, robust uncertainty characterization is essential for secure operation, economic dispatch, and flexibility planning. This review surveys PV scenario generation from three perspectives: (i) explicit probabilistic approaches (distribution fitting, Copula-based dependence modeling, autoregressive moving average (ARMA)-type time-series methods, and clustering/dimensionality reduction), (ii) deep generative models (GANs, VAEs, and diffusion models), and (iii) hybrid Statistical Relational AI (SRAI) frameworks. We discuss the strengths of explicit models in interpretability and tractability, and their limitations in representing high-dimensional nonlinear, multimodal, and multiscale spatiotemporal dependencies. We also examine the ability of deep generative methods to synthesize diverse scenarios across meteorological regimes and multiple sites, while noting persistent challenges in interpretability, physical consistency, and deployment. To bridge these gaps, we outline an SRAI-oriented integration pathway that embeds statistical structure, meteorology–power relations, spatiotemporal coupling, and operational constraints into generative architectures. Finally, we highlight directions for future research, including unified evaluation protocols, cross-regional data collaboration, controllable extreme-scenario generation, and computationally efficient generative designs. Full article

Background/Objectives: Eliglustat is an oral therapy for Gaucher disease type 1 (GD1) that may reduce infusion-related logistical burden, particularly in resource-constrained settings. Post-approval evidence from routine clinical practice in China remains limited. This study evaluated its real-world effectiveness and safety in Chinese adults with GD1. Methods: This retrospective, multicenter study included adults with GD1 receiving eliglustat monotherapy for ≥6 months. Outcomes included plasma glucosylsphingosine (lyso-Gb1), hemoglobin (HGB), platelet count (PLT), liver and spleen volumes, and adverse events (AEs). Depending on distribution, paired changes were analyzed using paired t tests or Wilcoxon signed-rank tests. p < 0.05 was considered statistically significant. Results: Nineteen patients were included in the effectiveness analysis, with a median follow-up of 7 months (range, 6–9). Lyso-Gb1 decreased from 468 to 210 ng/mL (p < 0.0001). HGB increased from 123 to 131 g/L (p = 0.147); among six patients with baseline anemia, 83.3% improved and 33.3% normalized. PLT increased from 109 to 132 × 10⁹/L (p = 0.019); among 12 patients with baseline thrombocytopenia, 58.3% improved. Liver volume decreased from 1808 to 1747 mL (p = 0.016) (1.22 to 1.01 multiples of normal; p < 0.001). Spleen volume decreased from 473 to 452 mL (p = 0.016) (4.69 to 5.17 multiples of normal; p = 0.015). Lyso-Gb1 reduction was greater in patients without prior enzyme replacement therapy (ERT) exposure than in those with prior ERT exposure (−55.1% vs. −43.1%; p = 0.049). In the safety analysis group (n = 90), suspected drug-related AEs occurred in 27.8% of patients, mainly gastrointestinal or skin-related, and were limited to grade I/II. No serious AE or treatment discontinuation occurred. Conclusions: In routine clinical practice in China, eliglustat was associated with rapid substantial reductions in plasma lyso-Gb1, early improvements in hematologic and visceral parameters, and favorable short-term tolerability in adults with GD1. Full article

This study is a detailed study of unit J-shaped distributions which establishes and examines the unit Topp–Leone distribution. The proposed study presents a mathematically tractable model of bounded data with strong skewness and boundary effects. Various basic distributional properties, such as moments, entropy measures, order statistics, and L-moments, are obtained in explicit form, which provides a full analytic description of the model. Type-II censoring is applied to develop some statistical inferential methods. The usefulness of the suggested distribution is illustrated by the application to the normalized water use efficiency indicators and censored survival time data. The findings are useful to the theory of unit distributions, as they introduce new analytics that have been demonstrated to be beneficial in practice and demonstrate that the theory is effective in applications with limited and censored data. Full article

Heavy metals in agricultural systems pose a significant challenge to food security, especially in regions with long-term intensive land use. While the Pannonian Plain represents Croatia’s primary breadbasket, accounting for a significant portion of the nation’s cereal production, data on the soil-to-grain transfer of heavy metals and the associated human exposure risk are limited. The objective of this study was (i) to determine the concentrations of arsenic (As), cadmium (Cd), and lead (Pb) in agricultural soils and corresponding grains (wheat, barley, and maize) across four principal counties within the Pannonian region of Croatia; (ii) to evaluate the soil-to-grain transfer factors that varied regionally and among cereal types; and (iii) to assess the potential non-carcinogenic health risks for both adults and children highlighting differences in exposure due to body weight and consumption patterns. Soil and cereal grain samples were collected in 2019 and 2020, and metal concentrations were determined by ICP-MS after microwave acid digestion. The transfer of metals from soil to grain was estimated using the transfer factor (TF), while exposure assessment was conducted by calculating the estimated daily intake (EDI), hazard quotient (HQ), and hazard index (HI). Due to the nonlinear distribution of the data and the lack of strictly matched soil and grain samples, median metal concentrations pooled across all studied regions were used for exposure assessment. For As, a conservative approach was applied, assuming that 50% of the total As is in inorganic form. Additionally, a probabilistic risk assessment using Monte Carlo simulations was conducted to account for variability in body weight and cereal intake, providing a more comprehensive evaluation of potential exposure. The results showed differences in metal accumulation among cereal species, with wheat and barley tending to accumulate more Cd than maize, while As and Pb concentrations in grains were low for all crops studied. Although soil metal concentrations in Međimurje County were generally low, elevated TF values for As and Pb were observed, indicating enhanced soil-to-plant transfer under specific local soil conditions. In contrast, high soil metal concentrations in Slavonski Brod–Posavina County were associated with low TF values, suggesting limited bioavailability and restricted transfer to cereal grains. Both deterministic and probabilistic assessments indicated that the HQ and HI for adults and children were below 1, suggesting low non-carcinogenic risk from cereal consumption. These findings highlight pronounced regional and crop-specific differences in soil-to-plant metal transfer and confirm that low soil contamination does not necessarily imply low transfer potential, emphasizing the importance of integrated soil–plant–grain monitoring for food safety assessment. Full article

This study investigated the impact of the pretreatment of pea plants (Pisum sativum L. Ran 1) for five days by three times higher light intensity (360 μmol m⁻² s⁻¹) than the intensity for their cultivation (120 μmol m⁻² s⁻¹) on the photosynthetic apparatus’s ability to withstand moderately high temperatures. Photosystem II (PSII) performance was assessed by pulse amplitude-modulated (PAM) fluorometry—evaluation of F_v/F_m, Chl fluorescence decrease ratio—R_Fd, excitation pressure on PSII (1 − qP), non-photochemical quenching (NPQ) analysis, and PsbA (D1) abundance. The redox state of P700 was used to examine photosystem I (PSI), and the redox kinetics of P700 was evaluated as an estimate of cyclic electron flow (CEF). The energy distribution and interaction between the two photosystems were assessed by 77 K chlorophyll fluorescence. Diphenylhexatriene (DPH) fluorescence polarization and PsbS accumulation were followed to estimate alterations in thylakoid membrane characteristics. Our data show that pea plants pretreated with a higher level of light intensity showed higher resistance to temperature increase, maintaining R_Fd values similar to control plants, and the effect of high temperature on PSII excitation pressure (1 − qP) was mitigated. A significant difference between the two groups of plants was observed in terms of quantum yields in both types of non-photochemical quenching, with light pretreated plants showing no change in the energy partitioning ratio while the exposure of non-high light pretreated plants to elevated temperatures led to a more significant increase in quantum yield of constitutive non-photochemical quenching. When plants were exposed to higher temperature, the accumulation of PsbS, induced by high light treatment, was accelerated, and stabilization of thylakoid membrane also occurred. A complex mechanism behind the enhanced tolerance to higher temperature includes the reorganization of membrane pigment–protein complexes, which is regulated by the buildup of PsbS and the accompanying redistribution of excitation energy. Full article

With the deepening of deep mineral exploration, traditional methods face bottlenecks in identifying concealed orebodies, making the establishment of a mineralogical exploration indicator system for collision-type porphyry deposits imperative. This study investigates chlorite from the Cimabanshuo Porphyry Copper Deposit in the Zhunuo Ore Concentration Area of the Western Gangdese via systematic petrographic and in situ geochemical analyses, to elucidate the spatial evolution of its trace element compositions and assess the validity and applicability of different trace elements for hydrothermal center indication. Based on micropetrographic observations, chlorite is classified into three types: biotite-altered (Chl-1), amphibole-altered (Chl-2) and vein-type (Chl-3), with Chl-1 and Chl-2 significantly affected by primary mineral compositions. Trace element results show that spatial variations in Ti, Li, Ni, Co, Mn, and Sr contents and Li/Mn and Ti/Sr ratios in chlorite can clearly indicate the mineralization center—Ti, Li, Ni and Co are systematically enriched in the proximal ore zone by temperature and fluid compositional effects, while Mn and Sr are enriched in the distal ore zone due to elemental redistribution during fluid migration. Fitting analysis of chlorite elemental ratios against the distance from sampling points to the mineralization center indicates the Li/Mn ratio decreases with increasing distance (R² = 0.4665), consistent with elemental distribution and showing a certain correlation; in contrast, the Ti/Sr ratio has a fitting coefficient of determination of only 0.0581, which cannot serve as an effective analysis indicator for this study because the deposit’s plate collision metallogenic setting causes elemental migration to be disturbed by local geological factors. In addition, chlorite in the zones 0–500 m from the Cu I, Cu II, and Cu III orebodies and 1–1.5 km to the north is characterized by significant enrichment of Ti, Li, Ni, and Co, depletion of Mn and Sr and high Li/Mn ratios. Accordingly, a concealed hydrothermal center is inferred in the northern part of the Cimabanshuo Deposit beyond the proven orebodies. Comprehensive studies confirm that the spatial variation characteristics of trace elements in chlorite from the Cimabanshuo Porphyry Copper Deposit have high applicability for indicating hydrothermal mineralization centers. Full article

Background: Mass spectrometry (MS)-based immunopeptidomics has emerged as the gold standard for profiling HLA-bound peptides, yet detection remains challenging due to their non-tryptic nature, variable lengths, and lack of basic residues, which limit ionisation and fragmentation efficiency. Methods: To address these limitations, we investigated the impact of incorporating 5% dimethyl sulfoxide (DMSO) into LC-MS/MS mobile-phase buffers on immunopeptidomic workflows. Using B-lymphoblastoid cell lines expressing HLA class I and II alleles and elastase-digested HeLa lysates as a surrogate for non-tryptic peptides, we assessed peptide identification, ionisation efficiency, charge state distribution, and fragmentation quality. Results: DMSO significantly increased peptide identifications across all sample types, with gains of ~1.33 folds for HLA class I, ~1.55 folds for HLA class II, and ~1.24 folds for elastase digests. Improvements were systematic and reproducible, driven by enhanced electrospray ionisation, higher charge states, and superior MS2 spectral quality, evidenced by ~2-fold increase in b- and y-ion intensities. Importantly, DMSO did not introduce major sequence bias, preserving motif integrity and predicted binding characteristics. Conclusions: Overall, these findings establish DMSO as a robust additive for improving sensitivity and reliability in immunopeptidomics, particularly for low-input or clinically derived samples. Full article

The MADS-box gene family encodes a critical class of transcription factors that regulate diverse developmental processes in plants. However, its role in abiotic stress responses remains poorly characterized in Lilium davidii var. unicolor (Lanzhou lily). In this study, we identified 62 LdMADS genes in the Lanzhou lily genome, classifying them into 17 Type I and 45 Type II members. Notably, the SOC1 subfamily exhibited a pronounced expansion. These LdMADS members were distributed across all twelve chromosomes and displayed considerable structural variation, with some genes harboring exceptionally long introns. Tissue-specific expression profiling revealed that M-type and MIKC* genes were predominantly and specifically expressed in ovaries and anthers, whereas MIKC^C members exhibited complex and diverse expression patterns across multiple tissues. The selection of candidate LdMADS genes for abiotic stress response was based on their transcript abundance in leaf and root tissues, together with the enrichment of their cis-acting elements. The expression of these LdMADS genes under drought, heat, and cold stresses was further examined by qRT-PCR. Among them, LdMADS4 and LdMADS14 from the SEP subfamily, as well as LdMADS25 and LdMADS26 from the SOC1 subfamily, responded to multiple stress conditions. This study provides functional clues for the roles of MADS-box genes in the development and stress responses of Lanzhou Lily. Full article