Search Results (54)

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder, are genetically and phenotypically heterogeneous conditions affecting millions worldwide. High-throughput omics technologies—transcriptomics, proteomics, metabolomics, and epigenomics—offer a unique opportunity to link genetic variation to molecular and cellular mechanisms underlying these disorders. However, the high dimensionality, sparsity, batch effects, and complex covariance structures of omics data present significant statistical challenges, requiring robust normalization, batch correction, imputation, dimensionality reduction, and multivariate modeling approaches. This review provides a comprehensive overview of statistical frameworks for analyzing high-dimensional omics datasets in NDDs, including univariate and multivariate models, penalized regression, sparse canonical correlation analysis, partial least squares, and integrative multi-omics methods such as DIABLO, similarity network fusion, and MOFA. We illustrate how these approaches have revealed convergent molecular signatures—synaptic, mitochondrial, and immune dysregulation—across transcriptomic, proteomic, and metabolomic layers in human cohorts and experimental models. Finally, we discuss emerging strategies, including single-cell and spatially resolved omics, machine learning-driven integration, and longitudinal multi-modal analyses, highlighting their potential to translate complex molecular patterns into mechanistic insights, biomarkers, and therapeutic targets. Integrative multi-omics analyses, grounded in rigorous statistical methodology, are poised to advance mechanistic understanding and precision medicine in NDDs. Full article

Background: Type 2 diabetes (T2D) is a global health epidemic with rising prevalence within Asian populations, particularly amongst individuals with high visceral adiposity and ectopic organ fat, the so-called Thin-Outside, Fat-Inside phenotype. Metabolomic and microbiome shifts may herald T2D onset, presenting potential biomarkers and mechanistic insight into metabolic dysregulation. However, multi-omics datasets across ethnicities remain limited. Methods: We performed cross-sectional multi-omics analyses on 171 adults (99 Asian Chinese, 72 European Caucasian) from the New Zealand-based TOFI_Asia cohort at 4-years follow-up. Paired plasma and faecal samples were analysed using untargeted metabolomic profiling (polar/lipid fractions) and shotgun metagenomic sequencing, respectively. Sparse multi-block partial least squares regression and discriminant analysis (DIABLO) unveiled signatures associated with ethnicity, glycaemic status, and sex. Results: Ethnicity-based DIABLO modelling achieved a balanced error rate of 0.22, correctly classifying 76.54% of test samples. Polar metabolites had the highest discriminatory power (AUC = 0.96), with trigonelline enriched in European Caucasians and carnitine in Asian Chinese. Lipid profiles highlighted ethnicity-specific signatures: Asian Chinese showed enrichment of polyunsaturated triglycerides (TG.16:0_18:2_22:6, TG.18:1_18:2_22:6) and ether-linked phospholipids, while European Caucasians exhibited higher levels of saturated species (TG.16:0_16:0_14:1, TG.15:0_15:0_17:1). The bacteria Bifidobacterium pseudocatenulatum, Erysipelatoclostridium ramosum, and Enterocloster bolteae characterised Asian Chinese participants, while Oscillibacter sp. and Clostridium innocuum characterised European Caucasians. Cross-omic correlations highlighted negative correlations of Phocaeicola vulgatus with amino acids (r = −0.84 to −0.76), while E. ramosum and C. innocuum positively correlated with long-chain triglycerides (r = 0.55–0.62). Conclusions: Ethnicity drove robust multi-omic differentiation, revealing distinctive metabolic and microbial profiles potentially underlying the differential T2D risk between Asian Chinese and European Caucasians. Full article

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, comprises embryonal (ERMS) and alveolar (ARMS) subtypes with distinct histopathological features, clinical outcomes, and therapeutic responses. To better characterize their molecular distinctions, we performed untargeted plasma proteomics and metabolomics profiling in children with ERMS (n = 18), ARMS (n = 17), and matched healthy controls (n = 18). Differential expression, functional enrichment (GO, KEGG, RaMP-DB), co-expression network analysis (WGCNA/WMCNA), and multi-omics integration (DIABLO, MOFA) revealed distinct molecular signatures for each subtype. ARMS displayed elevated oncogenic and stemness-associated proteins (e.g., cyclin E1, FAP, myotrophin) and metabolites involved in lipid transport, fatty acid metabolism, and polyamine biosynthesis. In contrast, ERMS was enriched in immune-related and myogenic proteins (e.g., myosin-9, SAA2, S100A11) and metabolites linked to glutamate/glycine metabolism and redox homeostasis. Pathway analyses highlighted subtype-specific activation of PI3K-Akt and Hippo signaling in ARMS and immune and coagulation pathways in ERMS. Additionally, the proteomics and metabolomics datasets showed association with clinical parameters, including disease stage, lymph node involvement, and age, demonstrating clear molecular discrimination consistent with clinical observation. Co-expression networks and integrative analyses further reinforced these distinctions, uncovering coordinated protein–metabolite modules. Our findings reveal novel, subtype-specific molecular programs in RMS and propose candidate biomarkers and pathways that may guide precision diagnostics and therapeutic targeting in pediatric sarcomas. Full article

Despite several years passing since the COVID-19 pandemic was declared, challenges remain in understanding the factors that can predict the severity of COVID-19 disease and complications of SARS-CoV-2 infection. While many large-scale multi-omic datasets have been published, integration of these datasets has the potential to substantially increase the biological insight gained, allowing a more complex comprehension of the disease pathogenesis. Such insight may improve our ability to predict disease progression, detect severe cases more rapidly and develop effective therapeutics. In this study, we have applied an innovative machine learning algorithm to delineate COVID severity based on the integration of paired samples of proteomic and transcriptomic data from a small cohort of patients testing positive for SARS-CoV-2 infection with differential disease severity. Targeted plasma proteomics and an onco-immune targeted transcriptomic panel were performed on sequential samples from a cohort of 23 severe, 21 moderate and 10 mild COVID-19 patients. We applied DIABLO, a new integrative method, to identify multi-omics biomarker panels that can discriminate between multiple phenotypic groups, such as the varied severity of disease in COVID-19 patients. As COVID-19 severity is known among our sample group, we can train models using this as the outcome variable and calculate features that are important predictors of severe disease. In this study, we detect highly correlated key variables of severe COVID-19 using transcriptomic discriminant analysis and multi-omics integration methods. This approach highlights the power of data integration from a small cohort of patients, offering a better biological understanding of the molecular mechanisms driving COVID-19 severity and an opportunity to improve the prediction of disease trajectories and targeted therapeutics. Full article

The preservation of historic irrigation infrastructure is vital for sustainable water management, especially in regions grappling with rural depopulation, land degradation, and wildfire risk. This study presents a rehabilitation framework for the Acequia del Diablo (Teruel, Spain), a centuries-old gravity-fed canal that supported 60 hectares of agriculture and contributed to ecological connectivity. Its deterioration—following landslides in 1992 and water source loss in 2020—has led to land abandonment, biodiversity decline, and increased wildfire vulnerability. The proposed solution, centered on restoring the original intake at the Azud de Fonseca and stabilizing damaged sections, reestablishes water autonomy and integrates heritage conservation into water governance. A multi-criteria analysis identified this gravity-based alternative as the most technically, economically, and environmentally viable. Drawing from precedents in the literature, the conservation and rehabilitation of historical irrigation systems play a crucial role in sustainable water management in rural areas; this initiative offers a replicable model for other Mediterranean and semi-arid areas. However, challenges include engineering complexity in unstable terrain, administrative delays, and long-term maintenance. Despite these, this intervention enhances rural resilience, wildfire prevention, and biodiversity, while aligning with circular economy principles and European Green Deal objectives. Full article

A two-dimensional longitudinal profile model was used to evaluate groundwater flow along a 48 km flowline in the Southeastern Hueco Aquifer, extending from the Diablo Plateau in Texas to the Sierra de San Ignacio in Chihuahua, Mexico. The model, incorporating geologically distributed permeability values, closely matched the predevelopment potentiometric surface. Predicted recharge rates and travel times aligned with published estimates and environmental isotopes, suggesting potential transboundary groundwater movement. The model estimated recharge rates needed to reach flow capacity, or the maximum volume a system can transmit, typically saturating the water table. Current moisture levels are insufficient, but flow capacity may have been reached during late Pleistocene pluvial periods. Required recharge rates were 297% higher than initial calibration in the U.S. and 1080% higher in Mexico, with only U.S. estimates appearing plausible for the Pleistocene–Holocene transition. These findings are relevant to regional waste disposal considerations because water tables near land surface present a risk to groundwater resources. A transient simulation modeled hydraulic head decay due to recharge abatement linked to climate change over 14,000 years. It simulated a decrease from a “flow capacity” recharge rate of 10.4 mm/year to 3.5 mm/year today. The modeling simulations ended with the hydraulic head remaining only 20 m above current levels, suggesting a minimal-to-negligible fossil hydraulic gradient in the low-permeability flow system. Full article

This study examined atmospheric mechanisms affecting the East Bay Hills Fire (1991) in Oakland, California, using the Advanced Weather Research and Forecasting (WRF) model and North American Regional Reanalysis (NARR) dataset. High-resolution WRF simulations, initially at 16 km, were downscaled to 4 km and 1 km for analyzing primary and secondary circulations at synoptic and meso-α/meso-β scales, respectively, before the fire. Additionally, the interaction between the synoptic-scale and mesoscale environments was examined using backward trajectories derived from NARR data. The findings reveal that a strong pressure gradient created by a ridge over the Great Basin and a trough off the Pacific coast generated favorable meso-α conditions for the hot, dry northeasterly winds, known as “Diablo winds”, which initiated the wildfire in northern California. Mountain waves, enhanced by jet stream dynamics, contributed to sinking air on the Sierra Nevada’s western slopes. The main conclusion is that jet circulation did not directly transport warm, dry air to the fire but established a vertical atmospheric structure conducive to wave amplification and breaking and downward dry air fluxes leading to the necessary warm and dry low-level air for the fire. The hot–dry–windy (HDW) fire weather index further confirmed the highly favorable fire weather conditions. Full article

Concomitant administration may improve vaccination rates. This analysis of a phase 1/2 randomized study included 1073 healthy ≥65-year-olds who previously received ≥3 mRNA COVID-19 vaccine doses. Participants received concomitantly administered RSVpreF and bivalent BA.4/BA.5-adapted BNT162b2 vaccine (concomitant administration) with or without quadrivalent influenza vaccine (QIV), admixed combined RSVpreF + BNT162b2 vaccine (combined vaccine) with or without QIV, RSVpreF, BNT162b2, or QIV. Immunogenicity objectives included demonstrating the noninferiority of neutralizing antibody titers elicited by concomitant administration and combined vaccine compared with RSVpreF or BNT162b2 administered alone, and by concomitant administration and combined vaccine given with QIV compared with RSVpreF, BNT162b2, and QIV alone. Reactogenicity (≤7 days) and safety ≤1 month (adverse events (AEs)) and ≤6 months (serious AEs (SAEs)) after vaccination were assessed. Noninferiority for all immunogenicity comparisons was demonstrated. All vaccine groups were well tolerated; no new safety concerns were identified. Reactogenicity was mostly mild/moderate with rates generally similar across groups, except injection site pain and fatigue, which were less frequent with RSVpreF + placebo vs. other groups. AEs were infrequent, mostly mild/moderate, occurring at similar frequencies across groups. No AEs leading to study withdrawal or vaccine-related SAEs were reported. Favorable safety and tolerability alongside similar immunogenicity provide support for concomitant or combined use of RSVpreF and BNT162b2, with or without QIV, to help protect older adults from these important respiratory pathogens (NCT05886777). Full article

Background: Percutaneous electrolysis is an invasive physical therapy technique that is receiving attention. The objective of this article is to evaluate the biological and cellular effects of percutaneous electrolysis and its influence on tissue healing processes. Methods. The search strategy performed in PubMed, Cochrane Library, and Web of Sciences databases resulted in a total of 25 studies. Once inclusion and exclusion criteria were applied, seven studies were finally included in this systematic review. The biological effects of percutaneous electrolysis were evaluated and grouped into pro-inflammatory and anti-inflammatory effects, cell death, and extracellular matrix and tissue remodeling effects. Results. Percutaneous electrolysis generates a significant pro-inflammatory increase in the chronic tendon condition of IL1β-6-18-1α-1rn, NLRP3, and M1 polymorphonuclear cells and increased expression of COX2, TNFα, Cxcl10, and TGFβ1 during the first 7 days. This inflammation is regulated as of day 13. A significant increase in cell death markers, such as LDH, Yo-Pro, cytochrome C, and Smac/Diablo markers, was observed during the first 7 days. Finally, a significant increase in markers Mmp9, VEGF, VEGFR, PPAR-γ/tubulin, and COL-I was observed in the extracellular matrix and tissue remodeling, and a decrease in COL-III was observed during the first 7 days. In the acute inflammatory injury condition, an increase in anti-inflammatory markers, such as IL-10-13, CCL1, and IkB, and a significant decrease in pro-inflammatory cytokines, such as IL-6-1β, CCL3-4-5, CCR5-8, NFkB, and TNFα, were observed during the first 7 days. Finally, a significant increase in VEGF, VEGFR, and PPAR-γ/tubulin markers in the extracellular matrix and tissue remodeling was observed for this condition during the first 7 days. Conclusions. Percutaneous electrolysis generates a controlled local pro-inflammatory effect in chronic conditions and regulates inflammation in inflammatory injuries (during the first 7 days). Electrolysis has short-term effects (0–7 days post) of cell death and controlled extracellular matrix destruction. Additionally, it facilitates subsequent healing by improving extracellular matrix synthesis starting from 7 days after application. Full article

Numerous epidemiologic studies have used remote sensing to quantify the contribution of greenness, air pollution, and wildfire smoke to asthma and other respiration outcomes. This is the first review paper to evaluate the influence of remote sensing exposures on specific outcome severity and risk factors in different ecological settings. Literature searches utilizing PubMed and Google Scholar identified 61 unique studies published between 2009 and 2023, with 198 specific outcomes. Respiration-specific outcomes were lower in greenness and higher in air pollution and wildfire ecological settings. Aerosol optical depth (AOD)-PM_2.5 readings and specific outcomes were higher in economically developing than in economically developed countries. Prospective studies found prenatal and infant exposure to higher ambient AOD-PM_2.5 concentration level readings contributed to higher childhood asthma incidence. Lung function was higher in greenness and lower in the other two ecological settings. Age, environment, gender, other, and total risk factors showed significant differences between health outcomes and ecological settings. Published studies utilized physiologic mechanisms of immune, inflammation, and oxidative stress to describe obtained results. Individual and total physiologic mechanisms differed between ecological settings. Study results were used to develop a descriptive physiologic asthma model and propose updated population-based asthma intervention program guidelines. Full article

The aim of this study was to explain the mechanism underlying the liver injury of juvenile largemouth bass Micropterus salmoides in response to high-starch diet intake. Three diets were formulated with different starch levels, being abbreviated as treatment LS (low starch, 8.13% starch), MS (medium starch, 14.1% starch), and HS (high starch, 20.1% starch), respectively. Fish were fed with their respective diets to apparent satiation for 56 days. The results showed that growth retardation of the HS fish was associated with the reduction in feed intake rather than feed utilization. Histological evaluation of the livers showed that vacuolization was the most prevalent characteristic in the MS fish, while ballooning degeneration, apoptosis, fibrosis, and inflammation were observed in the HS fish. Transcriptome profiling suggested that liver inflammation was mediated by Tlr signal transduction, which activated the Pi3k/Akt/Nfκb signaling axis to promote the release of proinflammatory factors including Il-8 and Ip-10. Hepatocyte apoptosis was mediated by the extrinsic pathway through death receptors including Fas and Tnfr, which coordinately activated the Fadd/caspase-8 death signaling axis. An autonomous inhibition program was identified to counteract the apoptosis signal, and the PI3K/Akt signaling pathway might play an important role in this process through regulating the expression of iap and diablo. Liver fibrosis was mediated through the Tgf-β and Hh signaling pathways. Upon secretion, Tgf-β1/3 bound to TgfβrI/II complex on the liver cell membrane, which induced the phosphorylation of downstream Smad2/3. When Hh interacted with the membrane receptor Ptc, Smo was activated to initiate signaling, driving the activation of Gli. The activation of both Smad2/3 and Gli promoted their nuclear translocation thereby regulating the transcription of target genes, which resulted in the activation and proliferation of HSCs. The activated HSCs constantly expressed colla1 and ctgf, which facilitated substantial accumulation of ECM. It should be noted that the molecular mechanism of liver injury in this study was speculated from the transcriptome data thus further experimental verification is warranted for this speculation. Full article

We describe enhancements to an operational forecast system based on the Weather Research and Forecasting (WRF) model for the prediction of high-impact weather events affecting power utilities, particularly conditions conducive to wildfires. The system was developed for Pacific Gas and Electric Corporation (PG&E) to forecast conditions in Northern and Central California for critical decision-making such as proactively de-energizing selected circuits within the power grid. WRF forecasts are routinely produced on a 2 km grid, and the results are used as input to wildfire fuel moisture, fire probability, wildfire spread, and outage probability models. This forecast system produces skillful real-time forecasts while achieving an optimal blend of model resolution and ensemble size appropriate for today’s computational resources afforded to utilities. Numerous experiments were performed with different model settings, grid spacing, and ensemble configuration to develop an operational forecast system optimized for skill and cost. Dry biases were reduced by leveraging a new irrigation scheme, while wind skill was improved through a novel approach involving the selection of Global Ensemble Forecast System (GEFS) members used to drive WRF. We hope that findings in this study can help other utilities (especially those with similar weather impacts) improve their own forecast system. Full article

Parkinson’s disease (PD), the second most common neurodegenerative disease in the elderly, is characterized by selective loss of dopaminergic neurons and accumulation of α-synuclein (α-syn), mitochondrial dysfunction, Ca²⁺ dyshomeostasis, and neuroinflammation. Since current treatments for PD merely address symptoms, there is an urgent need to identify the PD pathophysiological mechanisms to develop better therapies. Increasing evidence has identified K_V3.4, a ROS-sensitive K_V channel carrying fast-inactivating currents, as a potential therapeutic target against neurodegeneration. In fact, it has been hypothesized that K_V3.4 channels could play a role in PD etiopathogenesis, controlling astrocytic activation and detrimental pathways in A53T mice, a well-known model of familial PD. Here, we showed that the A53T midbrain, primarily involved in the initial phase of PD pathogenesis, displayed an early upregulation of the K_V3.4 channel at 4 months, followed by its reduction at 12 months, compared with age-matched WT. On the other hand, in the A53T striatum, the expression of K_V3.4 remained high at 12 months, decreasing thereafter, in 16-month-old mice. The proteomic profile highlighted a different detrimental phenotype in A53T brain areas. In fact, the A53T striatum and midbrain differently expressed neuroprotective/detrimental pathways, with the variation of astrocytic p27^kip1, XIAP, and Smac/DIABLO expression. Of note, a switch from protective to detrimental phenotype was characterized by the upregulation of Smac/DIABLO and downregulation of p27^kip1 and XIAP. This occurred earlier in the A53T midbrain, at 12 months, compared with the striatum proteomic profile. In accordance, an upregulation of Smac/DIABLO and a downregulation of p27^kip1 occurred in the A53T striatum only at 16 months, showing the slowest involvement of this brain area. Of interest, HIF-1α overexpression was associated with the detrimental profile in midbrain and its major vulnerability. At the cellular level, patch-clamp recordings revealed that primary A53T striatum astrocytes showed hyperpolarized resting membrane potentials and lower firing frequency associated with K_V3.4 ROS-dependent hyperactivity, whereas primary A53T midbrain astrocytes displayed a depolarized resting membrane potential accompanied by a slight increase of K_V3.4 currents. Accordingly, intracellular Ca²⁺ homeostasis was significantly altered in A53T midbrain astrocytes, in which the ER Ca²⁺ level was lower than in A53T striatum astrocytes and the respective littermate controls. Collectively, these results suggest that the early K_V3.4 overexpression and ROS-dependent hyperactivation in astrocytes could take part in the different vulnerabilities of midbrain and striatum, highlighting astrocytic K_V3.4 as a possible new therapeutic target in PD. Full article

Metabolomic analysis has been explored to search for disease biomarkers in humans for some time. The application to animal species, including fish, however, is still at the beginning. In the present study, we have used targeted and untargeted metabolomics to identify metabolites in the plasma of Atlantic salmon (Salmo salar) challenged with Piscine orthoreovirus (PRV-1), aiming to find metabolites associated with the progression of PRV-1 infection into heart and skeletal muscle inflammation (HSMI). The metabolomes of control and PRV-1-infected salmon were compared at three time points during disease development by employing different biostatistical approaches. Targeted metabolomics resulted in the determination of affected metabolites and metabolic pathways, revealing a substantial impact of PRV-1 infection on lipid homeostasis, especially on several (lyso)phosphatidylcholines, ceramides, and triglycerides. Untargeted metabolomics showed a clear separation of the treatment groups at later study time points, mainly due to effects on lipid metabolism pathways. In a subsequent multi-omics approach, we combined both metabolomics datasets with previously reported proteomics data generated from the same salmon plasma samples. Data processing with DIABLO software resulted in the identification of significant metabolites and proteins that were representative of the HSMI development in the salmon. Full article

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies. Full article