Search Results (171)

Background/Objectives: Carfilzomib (CFZ) and bortezomib (BTZ) are proteasome inhibitors used as the first-line therapy for relapsed or refractory multiple myeloma (MM) but are associated with cardiovascular adverse events (CVAEs). This study aims to identify differentially methylated positions (DMPs) and regions (DMRs), and enriched pathways associated with CVAEs related to CFZ or BTZ-based treatment. Methods: Baseline germline DNA methylation profiles from 79 MM patients (49 on CFZ and 30 on BTZ) in the Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy (PROTECT) were analyzed. Epigenome-wide analyses were performed within each group, followed by meta-analyses to identify signals common to CVAEs associated with both medicines. Results: Four DMPs were significantly associated with CFZ-CVAEs, including cg15144237 within ENSG00000224400 (p = 9.45 × 10⁻¹⁰), cg00927646 within TBX3 (p = 9.78 × 10⁻⁸), and cg10965131 within WDR86 (p = 1.00 × 10⁻⁷). One DMR was identified in the FAM166B region (p = 5.46 × 10⁻⁷). There was no evidence of any DMPs in BTZ-treated patients, however two DMPs and one DMR reached a suggestive level of significance (p < 1.00 × 10⁻⁵): cg09666417 in DNAJC18 (p = 3.41 × 10⁻⁷) and cg12987761 in USP18 (p = 5.00 × 10⁻⁷), and a DMR mapped to the WDR86/WDR86-AS1 region (p = 8.11 × 10⁻⁸). Meta-analysis did not find any significant DMPs, with the top CpG being cg17933807 in GNL2 (p = 7.38 × 10⁻⁵). Pathway enrichment analyses identified peroxisome, MAPK, Rap1, adherens junction, phospholipase D, autophagy, and aldosterone-related pathways to be implicated in CVAEs. Conclusions: Our study identified distinct DMPs, DMRs, and pathways enrichment associated with CVAE, suggesting epigenetic contributors to CVAEs and supporting the need for larger validation studies. Full article

Previous in vivo studies have clearly demonstrated that the intravenous administration of the carotenoid astaxanthin (AST) suppresses the excitability of rat trigeminal spinal nucleus caudalis (SpVc) neurons. This action is hypothesized to be mediated through the inhibition of both voltage-gated Ca²⁺ (Cav) channels and excitatory glutamate receptor transmission. The objective of this study was to determine whether acute intravenous administration of AST alleviates the hyperexcitability of SpVc wide dynamic range (WDR) neurons in a rat model of inflammation. Neuronal responses to both nociceptive and non-nociceptive mechanical stimulation were evaluated using an in vivo electrophysiological model. One day following inflammation induced by Complete Freund’s Adjuvant (CFA), the mechanical escape threshold was significantly reduced compared to pre-injection baseline values. Subsequently, extracellular single-unit recordings were performed on SpVc WDR neurons in anesthetized, inflamed rats. The neuronal responses to both non-noxious and noxious orofacial mechanical stimuli were then analyzed. Acute intravenous administration of AST at 1 and 5 mM elicited a dose-dependent reduction in the mean firing frequency of SpVc WDR neurons in response to noxious mechanical stimuli. This inhibition peaked within 10 min and was fully reversed after approximately 25 min. Importantly, AST preferentially inhibited the discharge frequency of SpVc WDR neurons in response to noxious stimulation, exhibiting a significantly greater effect than on the response evoked by non-noxious stimulation (41.5 ± 3.0% vs. 20.7 ± 4.2%, p < 0.05). Collectively, these findings demonstrate that acute intravenous administration of AST effectively suppresses noxious synaptic transmission within the SpVc during inflammation. We propose that this suppressive effect is mediated by the inhibition of upregulated Cav channels and glutamate receptors. Consequently, AST is implicated as a promising therapeutic candidate for the management of trigeminal inflammatory pain, given its potential for a favorable safety profile compared to conventional treatments. Full article

Advances in CMOS image sensors (CISs) have led to utilization in various industrial fields, including machine vision, medical, surveillance, the automotive industry, and the Internet of Things (IoT). One critical metric for CISs is the dynamic range (DR), which indicates the range of light intensity that can clearly capture images. As the technology evolves, wide dynamic range (WDR) becomes increasingly required for more diverse applications. To further advance these industries, this paper presents the active-pixel-type CIS design techniques and architectures developed to achieve WDR. These include the following: the basic concepts of the active pixel sensor, readout mechanism, and DR of the CIS; multiple exposure and dual conversion gain (DCG) schemes that are conventionally used to address a trade-off in the CIS; lateral overflow integration capacitor (LOFIC) and dual photodiode (PD) architectures that can improve the DR by utilizing trade-offs in the DR and exposure mechanism; CISs with logarithmic and linear–logarithmic (Lin-Log) responses to enable non-linear characteristics; and techniques that can be employed for higher sensitivity in dark conditions. This comprehensive study of various techniques and architectures can also be utilized for cutting-edge tech advances and future research, including neuromorphic array architecture. Full article

This study identified genomic regions associated with carcass traits and primal cut yields in Hanwoo cattle using weighted single-step genome-wide association study (WssGWAS). A total of 50,227 carcass records and genomic data from 23,573 animals with 45,057 single-nucleotide polymorphisms were analyzed. Heritability estimates were 0.24 for carcass weight, 0.22 for eye muscle area, 0.31 for backfat thickness, and 0.36 for marbling score, while those for primal cut yields ranged from 0.02 to 0.26. For carcass traits, candidate genes were identified for carcass weight (XKR4 2.35%, COBL 1.26%), eye muscle area (LCORL 1.56%, TGFBR2 1.49%), backfat thickness (ATG7 1.27%, MYPN 1.33%), and marbling score (TWIST2 1.16%, BMP4 1.14%). For primal cut yields, the chromosome 6 region containing WDR1 was commonly identified across six traits and the chromosome 4 region containing CACNA2D1 across five traits; the chromosome 28 region containing SIRT1 explained the highest genetic variance (6.46%) for striploin. These pleiotropic regions are potential targets for genomic selection to improve production efficiency and carcass value in Hanwoo. Full article

High penetration of renewable energy sources (RES) in power systems introduces substantial source-load uncertainty and flexibility challenges, leading to misalignments between economic optimization and environmental sustainability. An edge-side electricity-carbon coordinated hybrid trading mechanism was proposed to enhance flexibility in microgrid clusters. A three-layer time-varying carbon emission factor (CEF) model is developed to quantify negative emissions as tradable Chinese Certified Emission Reductions (CCERs). An endogenous economic equilibrium point enables dynamic switching between Incentive-Based Demand Response during high-carbon periods and Price-Based Demand Response during low-carbon periods, based on marginal profit comparisons. A Wasserstein distance-based distributionally robust CVaR (WDR-CVaR) strategy constructs a data-driven ambiguity set to optimize decisions under worst-case distributional shifts in edge-side data. Simulations on a modified IEEE 33-bus system show that the mechanism increases the Multi-Energy Aggregator’s (MEA) expected profit by 12.3%, reduces carbon emissions by 17.6%, with WDR-CVaR demonstrating superior out-of-sample performance compared to sample average approximation methods. The approach internalizes environmental values through carbon-electricity coupling and edge intelligence, providing a resilient framework for low-carbon distribution network operations. Full article

Background: Major Depressive Disorder (MDD) is more common in patients with Inflammatory Bowel Disease (IBD) than in the general population, suggesting a shared but unclear pathogenesis. Autophagy, a conserved intracellular cleaning process, maintains cellular health by removing debris and recycling nutrients. Given the limited research on autophagy in this comorbidity, this study investigated the role of autophagy-related genes in both disorders. Aim: This study aimed to identify shared autophagy-related mechanisms between IBD and MDD and to explore potential therapeutic strategies. Methods: We identified differentially expressed autophagy-related genes (DE-ARGs) in diseased versus normal tissues. Shared DE-ARGs between IBD and MDD were designated Co-DEGs. We analyzed correlations among Co-DEGs and their association with immune cell infiltration. Four machine-learning algorithms were used to pinpoint key biomarkers. Potential therapeutic agents were predicted and validated via molecular docking. Results: We identified 47 shared Co-DEGs. Among these, CASP1 emerged as a cross-disease shared susceptibility-associated gene (SSAG), consistently selected by all machine-learning models. Drug-gene interaction analysis and molecular docking identified compounds that could regulate CASP1. Single-cell analysis suggested CASP1 helps reshape the immune microenvironment in Crohn’s disease. Furthermore, Mendelian randomization identified WDR6 as a shared genetic risk factor for both conditions. Conclusions: Our findings illuminate autophagy-mediated mechanisms linking gut and brain disorders. The identification of CASP1 as a SSAG, along with candidate therapeutics, provides a foundation for future research and targeted treatments for IBD and MDD comorbidity. Full article

Wind-driven rain (WDR) is recognized as a primary source of moisture intrusion in exterior wall assemblies. However, China’s national code for thermal design of wall assemblies predominantly relies on temperature criteria classified by thermal zones, with humidity-related impacts on building thermal performance remaining unconsidered. Thus, the influence of WDR on the hygrothermal performance of exterior wall assemblies necessitates systematic investigation. This study aims to explore variations in moisture resistance among different wall assemblies under WDR exposure and differences in hygrothermal performance of identical assemblies across designated thermal zones. To this end, the hygrothermal behavior of five typical insulated wall assembly types was evaluated across 21 representative cities spanning four major thermal zones in China. Results indicate significant disparities in the hygrothermal performance of wall assemblies under WDR across thermal zones: dryness rates decreased by an average of 100%, 93.33%, 44%, and 30% in Severe Cold, Cold, Hot Summer and Cold Winter, and Hot Summer and Warm Winter Zones, respectively. Furthermore, although certain wall assemblies eventually dried over time, the risk of mold growth persisted. Notably, wall assemblies with external EPS insulation exhibited high sensitivity to WDR, while self-insulated and internal insulation systems were also vulnerable to WDR in the Hot Summer and Warm Winter Zone. In conclusion, annual WDR exposure and U-value are key factors in designing wall assemblies for optimal hygrothermal performance. Full article

Background/Objectives: Lower-grade gliomas (LGGs) are a biologically and clinically heterogeneous group of brain tumors, for which molecular stratification plays essential role in diagnosis, prognosis, and therapeutic decision-making. Conventional unimodal classifiers do not necessarily describe cross-layer regulatory dynamics which entail the heterogeneity of glioma. Methods: This paper presents a protein–protein interaction (PPI)-informed hybrid model that combines multi-omics profiles, including RNA expression, DNA methylation, and microRNA expression, with a Graph Attention Network (GAT), Random Forest (RF), and logistic stacking ensemble learning. The proposed model utilizes ElasticNet-based feature selection to obtain the most informative biomarkers across omics layers, and the GAT module learns the biologically significant topological representations in the PPI network. The Synthetic Minority Over-Sampling Technique (SMOTE) was used to mitigate the class imbalance, and the model performance was assessed using a repeated five-fold stratified cross-validation approach using the following performance metrics: accuracy, precision, recall, F1-score, ROC-AUC, and AUPRC. Results: The findings illustrate that a combination of multi-omics data increases subtype classification rates (up to 0.984 ± 0.012) more than single-omics methods, and DNA methylation proves to be the most discriminative modality. In addition, analysis of interpretability using attention revealed the major subtype-specific biomarkers, including UBA2, LRRC41, ANKRD53, and WDR77, that show great biological relevance and could be used as diagnostic and therapeutic tools. Conclusions: The proposed multi-omics based on a biological and explainable framework provides a solid computational approach to molecular stratification and biomarker identification in lower-grade glioma, bridging between predictive power, biological clarification, and clinical benefits. Full article

Proanthocyanidins (PAs) are a significant class of polyphenolic compounds found in grapes, playing important roles in human health and plant stress resistance. Previous studies have shown that the VvMYBPA1/PA2-VvWDR1-VvMYC2 (MBW) complex can regulate the biosynthesis of proanthocyanidins, and some studies have shown that the homologous genes of VvWRKY26 are involved in the biosynthesis of proanthocyanins and anthocyanins in Arabidopsis thaliana and petunias, but the molecular mechanism of VvWRKY26 in regulating the biosynthesis of proanthocyanins in grapes is still unclear. In this study, we found that the content of proanthocyanidins and the expression of related structural genes were significantly increased by salicylic acid (SA) incubation in grapes during the color transition period. Overexpression of VvWRKY26 in grapevine healing tissues revealed that overexpression of VvWRKY26 significantly promoted the accumulation of proanthocyanidins and up-regulation of related structural genes when compared with the empty vector. Further investigation into the interaction mechanisms through yeast two-hybrid and bimolecular fluorescence complementation assays revealed that VvWRKY26 can interact with VvMYBPA1/PA2, VvMYC2, and VvWDR1 to form VvMYBPA1/PA2-VvWDR1-VvMYC2-VvWRKY26 (W-MBW) complex. Through yeast one-hybrid assays and dual-luciferase reporter analysis, it was confirmed that VvWRKY26 could bind to the promoters of VvANR and VvLAR2 and activate their activity. Finally, through the co-overexpression of VvWRKY26 and MBW complex, it was discovered that the promoting activity of VvANR and VvLAR2, as well as the biosynthesis of PAs, were significantly enhanced, which was much higher than the effect of the MBW complex alone, while the opposite occurred after co-interference. In conclusion, this study explored the role of VvWRKY26 in the biosynthesis of proanthocyanidins in grapes after the interaction with the MBW complex to form W-MBW under SA incubation, providing a new regulatory mechanism for the biosynthesis of proanthocyanidins in grapes. Full article

Background: The precise role of RNA modification in post-traumatic stress disorder (PTSD) remains incompletely understood. This study aims to elucidate the effects of five common RNA modifications in PTSD, specifically m⁶A, m⁵C, m¹A, m⁷G, and ψ. Methods: We extracted data from the GEO repository to conduct a series of bioinformatics analyses. These included differential analysis to identify key regulators of five common RNA modifications, model construction using random forest (RF), least absolute shrinkage and selection operator (LASSO), and nomogram techniques, as well as consensus clustering of RNA modification subtypes. Furthermore, GO enrichment analysis was performed on DEGs associated with various RNA modification patterns. Immune cell infiltration was assessed using PCA and ssGSEA. RT-qPCR was performed to validate RNA modification-related genes (RMGs). Results: Twenty-one differentially expressed RMGs were identified. LASSO and RF intersection yielded eight signature genes (YTHDC1, IGFBP1, IGF2BP1, ALKBH5, NSUN4, TET2, TET3, WDR4) that robustly diagnosed PTSD (AUC = 0.804). Furthermore, these feature genes were validated using RT-qPCR, which was basically consistent with the results of bioinformatics analysis. Consensus clustering analysis may reveal two distinguishable subtypes: clusterA marked by high immunoinflammation, and clusterB characterized by high-neuroendocrine dysregulation. Conclusions: RMGs may play a crucial role in the pathogenesis of PTSD. Analyzing RNA modification patterns could offer potential diagnostic markers and help to guide immunotherapeutic approaches or neurotransmitter system interventions for PTSD in the future. Full article

Myricetin (MYR), a naturally occurring flavonoid widely distributed in fruits and vegetables, was investigated for its potential to reduce inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc), which is associated with hyperalgesia. The study also compared MYR’s impact with that of celecoxib (CEL), a non-steroidal anti-inflammatory drug (NSAID). To induce inflammation, Complete Freund’s adjuvant was injected into the whisker pads of rats. Subsequently, we measured the mechanical escape threshold by applying mechanical stimuli to the orofacial region. We found that inflamed rats exhibited a significantly lower threshold compared to naive rats (each group, n = 4). This reduced threshold returned to the naive level two days after the administration of MYR (16 mg/kg, i.p.), CEL (10 mg/kg, i.p.), and a combination of MYR (8 mg/kg, i.p.) + CEL (5 mg/kg, i.p.). To investigate the nociceptive neural response to orofacial mechanical stimulation, we performed extracellular single-unit recordings to measure the activity of SpVc wide-dynamic range (WDR) neurons in anesthetized subjects. In inflamed rats, administration of MYR, CEL, or 1/2MYR + 1/2CEL (each group, n = 4) significantly reduced both the average spontaneous activity and the evoked firing rate of SpVc neurons in response to non-painful and painful mechanical stimuli. The increased average receptive field size in inflamed rats was normalized to the naive level following treatment with MYR, CEL, or 1/2MYR + 1/2CEL. These findings suggest that MYR administration can mitigate inflammatory hyperalgesia by reducing the heightened excitability of SpVc WDR neurons. This supports the notion that MYR could be a viable therapeutic option in complementary and alternative medicine for preventing trigeminal inflammatory mechanical hyperalgesia, potentially serving as an alternative to selective cyclooxygenase-2 blockers. Full article

This study investigated the potential of astaxanthin (AST), a natural carotenoid, to mitigate inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) and the associated hyperalgesia. The efficacy of systemic AST application was compared to that of celecoxib (CEL). Inflammation was induced by injecting Complete Freund’s adjuvant into the whisker pads of rats. The mechanical escape threshold was then assessed by delivering mechanical stimuli to the orofacial region. Although inflamed rats exhibited a significantly lower mechanical threshold compared to naïve rats, this threshold was restored to normal levels two days after treatment with AST, CEL, and the 1/2 CEL + 1/2 AST combination. The activity of SpVc wide-dynamic range (WDR) neurons was measured using extracellular single-unit recordings in response to mechanical stimulation of the orofacial area under anesthesia. In inflamed rats, AST, CEL, and 1/2 CEL + 1/2 AST administration significantly reduced the average firing rate of these neurons elicited by both non-noxious and noxious mechanical stimuli. In addition, all three treatments significantly decreased the heightened average spontaneous activity of SpVc neurons and normalized the increased average receptive field size in inflamed rats. This study provides evidence that systemic AST administration attenuates inflammatory mechanical hyperalgesia. This action is associated with the suppression of hyperexcitability in nociceptive SpVc WDR neurons, likely through the inhibition of the cyclooxygenase-2 signaling pathway. These findings support the potential of AST as a therapeutic agent for complementary and alternative medicine. It may provide a valuable alternative to non-steroidal anti-inflammatory drugs for the prevention of trigeminal inflammatory mechanical hyperalgesia. Full article

Despite significant advances in gene discovery, the molecular basis of many rare genetic disorders remains poorly understood. The concept of disease modules, clusters of functionally related genes whose disruption leads to overlapping phenotypes, offers a valuable framework for interpreting these conditions. However, identifying such relationships remains particularly challenging in ultra-rare syndromes due to the limited number of documented cases. We hypothesized that AI-based facial phenotyping could aid in identifying shared molecular mechanisms by detecting phenotypic convergence among clinically related syndromes. To test this, we used Schuurs–Hoeijmakers syndrome (SHMS; OMIM #615009), caused by a recurrent de novo variant in PACS1, as a model to explore potential phenotypic and functional associations with PACS2-related disorder (DEE66; OMIM #618067) and WDR37-related disorder (NOCGUS; OMIM #618652). Facial photographs of individuals with SHMS were analyzed using the DeepGestalt and GestaltMatcher algorithms. In addition to consistently recognizing SHMS as a distinct clinical entity, the algorithms frequently matched DEE66 and NOCGUS, suggesting a shared facial gestalt. Binary comparisons further confirmed overlapping craniofacial features among the three disorders. These findings were supported by literature review, indicating clinical overlapping and potential functional associations. Overall, our results confirm the presence of consistent facial similarities among PACS1-, PACS2-, and WDR37-related syndromes and highlight the utility of AI-driven facial phenotyping as a complementary tool for uncovering clinically relevant relationships in ultra-rare genetic disorders. Full article

Breeding programs often overlook the use of root traits. Therefore, we investigated the relevance of sorghum root traits in explaining its adaptation to combined drought and heat stress (CDHS). Six (i.e., three pre-release lines + three checks) sorghum genotypes were established at two low-altitude (i.e., <600 masl) locations with a long-term history of averagely very high temperatures in the beginning of the summer season, under two management (i.e., CDHS and well-watered (WW)) regimes. At each location, the genotypes were laid out in the field using a randomized complete block design (RCBD) replicated two times. Root trait data, namely root diameter (RD), number of roots (NR), number of root tips (NRT), total root length (TRL), root depth (RDP), root width (RW), width–depth ratio (WDR), root network area (RNA), root solidity (RS), lower root area (LRA), root perimeter (RP), root volume (RV), surface area (SA), root holes (RH) and root angle (RA) were gathered using the RhizoVision Explorer software during the pre- and post-flowering stage of growth. RSA traits differentially showed significant (p < 0.05) correlations with grain yield (GY) at pre- and post-flowering growth stages and under CDHS and WW conditions also revealing genotypic variation estimates exceeding 50% for all the traits. Regression models varied between pre-flowering (p = 0.013, R² = 47.15%, R² Predicted = 29.32%) and post-flowering (p = 0.000, R² = 85.64%, R² Predicted = 73.30%) growth stages, indicating post-flowering as the optimal stage to relate root traits to yield performance. RD contributed most to the regression model at post-flowering, explaining 51.79% of the 85.64% total variation. The Smith–Hazel index identified ICSV111IN and ASAREACA12-3-1 as superior pre-release lines, suitable for commercialization as new varieties. The study demonstrated that root traits (in particular, RD, RW, and RP) are linked to crop performance under CDHS conditions and should be incorporated in breeding programs. This approach may accelerate genetic gains not only in sorghum breeding programs, but for other crops, while offering a nature-based breeding strategy for stress adaptation in crops. Full article

The mismatch between the rapid expansion of breeding scale and outdated techniques has hindered the development of the sea cucumber (A. japonicus) industry. Our previous work revealed that ecological seedling breeding can produce red-colored A. japonicus, a phenotype not observed in traditional artificial breeding, where individuals are typically green. To investigate the molecular and genetic basis of this novel red coloration, we compared the growth conditions of red sea cucumbers and green sea cucumbers, as well as the differences in the pigment composition, gene expression and metabolites of their body walls. Red individuals showed higher body length and weight, and elevated levels of astaxanthin, lutein, canthaxanthin, and β-carotene in the body wall. Transcriptomic and metabolomic analyses identified differentially expressed genes and metabolites associated with pigmentation. In particular, FMO2 and WDR18, involved in the cytochrome P450 drug metabolism pathway, were significantly upregulated in red individuals and are known to play roles in pigment biosynthesis and light signal perception. Key metabolites such as astaxanthin and fucoxanthin were implicated in body color formation. Moreover, genes in the arachidonic acid metabolism pathway were highly expressed, suggesting that dietary factors may contribute to pigment synthesis and accumulation. These findings provide novel insights into the mechanisms underlying body color variation in A. japonicus and offer potential for improved breeding strategies. Full article