Search Results (1,203)

Background: Lower phylogenetic species are known to rebuild cut-off caudal parts with regeneration of the central nervous system (CNS). In contrast, CNS regeneration in higher vertebrates is often attributed to immaturity, although this has never been conclusively demonstrated. The emergence of stem cells and their effective medical applications has intensified research into spinal cord regeneration. However, despite these advances, the impact of clinical trials involving spinal cord-injured (SCI) patients remains disappointingly low. Long-distance regeneration has yet to be proven. Methods: Our study involved a microsurgical dorsal myelotomy in fetal rats. The development of pioneering long primary afferent axons during early gestation was examined long after birth. Results: A single cut triggered the intrinsic ability of the dorsal root ganglion (DRG) neurons to reprogram. Susceptibility to hypoxia caused the axons to stop developing. However, the residual axonal outgrowth sheds light on the intriguing temporal and spatial events that reveal long-distance CNS regeneration. The altered phenotypes displayed axons of varying lengths and different features, which remained visible throughout life. The previously designed developmental blueprint was crucial for interpreting these enigmatic features. Conclusions: This research into immaturity enabled the exploration of the previously impenetrable domain of early life and the identification of a potential missing link in CNS regeneration research. Central axon regeneration appeared to occur much faster than is generally believed. The paradigm provides a challenging approach for exhaustive intrauterine reprogramming. When the results demonstrate pre-clinical effectiveness in CNS regeneration research, the transformational impact may ultimately lead to improved outcomes for patients with spinal cord injuries. Full article

This story began half a century ago with the discovery of an unusually high presence of tryptophan (Trp, W) in transthyretin (TTR), one of the three carrier proteins of thyroid hormones. With the Trp-rich retinol-binding protein (RBP), TTR forms a plasma complex implicated in the delivery of retinoid compounds to body tissues. W has the lowest concentration among all AAs involved in the sequencing of human body proteins. The present review proposes molecular maps focusing on the ratio of W/AA residues found in the sequence of proteins involved in immune events, allowing us to ascribe the guidance of inflammatory processes as fully under the influence of W. Under the control of cytokine stimulation, plasma biomarkers of protein nutritional status work in concert with major acute-phase reactants (APRs) and with carrier proteins to release, in a free and active form, their W and hormonal ligands, interacting to generate hot spots affecting the course of acute stress disorders. The prognostic inflammatory and nutritional index (PINI) scoring formula contributes to identifying the respective roles played by each of the components prevailing during the progression of the disease. Glucagon demonstrates ambivalent properties, remaining passive under steady-state conditions while displaying stronger effects after cytokine activation. In developing countries, inappropriate weaning periods lead to toddlers eating W-deficient cereals as a staple, causing a dramatic reduction in the levels of W-rich biomarkers in plasma, constituting a novel nutritional deficiency at the global scale. Appropriate counseling should be set up using W implementations to cover the weaning period and extended until school age. In adult and elderly subjects, the helpful immune protections provided by W may be hindered by the surge in harmful catabolites with the occurrence of chronic complications, which can have a significant public health impact but lack the uncontrolled surges in PINI observed in young infants and teenagers. Biomarkers of neurodegenerative and neoplastic disorders measured in elderly patients indicate the slow-moving elevation of APRs due to rampant degradation processes. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I–II clinical trials, events of QT prolongation or proarrhythmia were not observed. Here, we utilized cardiac NAMs to evaluate the functional consequences of vanoxerine treatment on human cardiac excitation–contraction coupling. The cardiac MPS used in this study was a microfabricated fluidic culture platform with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) capable of evaluating voltage, intracellular calcium handling, and contractility. Likewise, the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) was employed based on multielectrode array (MEA). Vanoxerine treatment delayed repolarization in a concentration-dependent manner and induced proarrhythmic events in both NAM platforms. The complex cardiac MPS displayed a frequency-dependent vanoxerine response such that EADs were eliminated at a faster pacing rate (1.5 Hz). Moreover, exposure analysis revealed a 99% vanoxerine loss in the cardiac MPS. TdP risk analysis demonstrated high to intermediate TdP risk at clinically relevant concentrations of vanoxerine and frequency-independent EAD events in the hiPSC-CM CiPA model. These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies. Full article

Peanut (Arachis hypogaea L.) is a globally important oilseed cash crop, yet its limited genetic diversity and unique reproductive biology present persistent challenges for conventional crossbreeding. Traditional breeding approaches are often time-consuming and inadequate, mitigating the pace of cultivar development. Essential for double fertilization and programmed cell death (PCD), DUF679 membrane proteins (DMPs) represent a membrane protein family unique to plants. In the present study, a comprehensive analysis of the DMP gene family in peanuts was conducted, which included the identification of 21 family members. Based on phylogenetic analysis, these genes were segregated into five distinct clades (I–V), with AhDMP8A, AhDMP8B, AhDMP9A, and AhDMP9B in clade IV exhibiting high homology with known haploid induction genes. These four candidates also displayed significantly elevated expression in floral tissues compared to other organs, supporting their candidacy for haploid induction in peanuts. Subcellular localization prediction, confirmed through co-localization assays, demonstrated that AhDMPs primarily localize to the plasma membrane, consistent with their proposed roles in the reproductive signaling process. Furthermore, chromosomal mapping and synteny analyses revealed that the expansion of the AhDMP gene family is largely driven by whole-genome duplication (WGD) and segmental duplication events, reflecting the evolutionary dynamics of the tetraploid peanut genome. Collectively, these findings establish a foundational understanding of the AhDMP gene family and highlight promising targets for future applications in haploid induction-based breeding strategies in peanuts. Full article

In recent years, China has experienced growing impacts from extreme weather events, emphasizing the importance of understanding regional atmospheric moisture dynamics, particularly Precipitable Water Vapor (PWV), to support sustainable environmental and urban planning. This study utilizes ten years (2013–2022) of Global Navigation Satellite System (GNSS) observations in typical cities in eastern China and proposes a comprehensive multiscale frequency-domain analysis framework that integrates the Fourier transform, Bayesian spectral estimation, and wavelet decomposition to extract the dominant PWV periodicities. Time-series analysis reveals an overall increasing trend in PWV across most regions, with notably declining trends in Beijing, Wuhan, and southern Taiwan, primarily attributed to groundwater depletion, rapid urban expansion, and ENSO-related anomalies, respectively. Frequency-domain results indicate distinct latitudinal and coastal–inland differences in the PWV periodicities. Inland stations (Beijing, Changchun, and Wuhan) display annual signals alongside weaker semi-annual components, while coastal stations (Shanghai, Kinmen County, Hong Kong, and Taiwan) mainly exhibit annual cycles. High-latitude stations show stronger seasonal and monthly fluctuations, mid-latitude stations present moderate-scale changes, and low-latitude regions display more diverse medium- and short-term fluctuations. In the short-term frequency domain, GNSS stations in most regions demonstrate significant PWV periodic variations over 0.5 days, 1 day, or both timescales, except for Changchun, where weak diurnal patterns are attributed to local topography and reduced solar radiation. Furthermore, ERA5-derived vertical temperature profiles are incorporated to reveal the thermodynamic mechanisms driving these variations, underscoring region-specific controls on surface evaporation and atmospheric moisture capacity. These findings offer novel insights into how human-induced environmental changes modulate the behavior of atmospheric water vapor. Full article

Ravine forests are key to conserving biodiversity and maintaining ecosystem processes in fragmented landscapes. Here, we evaluated the phenology of plant species in the Los Nogales Nature Sanctuary (Lo Barnechea, Chile) using Sentinel-2 images (2019–2024) and the Alos Palsar DEM (12.5 m). We calculated the Normalized Difference Vegetation Index (NDVI), the Topographic Position Index (TPI), and Diurnal Anisotropic Heat (DAH) to assess vegetation dynamics across different topographic and thermal gradients. Generalized Additive Models (GAM) revealed that tree species exhibited more stable, regular seasonal NDVI trajectories, while shrubs showed moderate fluctuations, and herbaceous species displayed high interannual variability, likely reflecting sensitivity to climatic events. Spatial analysis indicated that trees predominated on steep slopes and higher elevations, herbs were concentrated in low-lying, moisture-retaining areas, and shrubs were more common in areas with higher thermal load. These findings highlight the significant role of terrain and temperature in shaping plant phenology and distribution, underscoring the utility of remote sensing and topographic indices for monitoring ecological processes in complex mountainous environments. Full article

Background: Fish escape events from aquaculture facilities are increasing and pose significant ecological, economic, and traceability concerns. Accurate methods to differentiate between wild, cultured, and escaped fish are essential for fishery management and seafood authentication. Methods: This study analyzed muscle tissue from Sparus aurata, Dicentrarchus labrax, and Argyrosomus regius using a multiomics approach. Heavy metals were quantified by ICP-MS, fatty acid profiles were assessed via GC-MS, and metabolomic and lipidomic signatures were identified using 1H NMR spectroscopy. Multivariate statistical models (MDS and PLS-LDA) were applied to classify fish origins. Results: Wild seabream showed significantly higher levels of arsenic (9.5-fold), selenium (3.5-fold), and DHA and ARA fatty acids (3.2-fold), while cultured fish exhibited increased linoleic and linolenic acids (6.5-fold). TMAO concentrations were up to 5.3-fold higher in wild fish, serving as a robust metabolic biomarker. Escaped fish displayed intermediate biochemical profiles. Multivariate models achieved a 100% classification accuracy across species and analytical techniques. Conclusions: The integration of heavy metal analysis, fatty acid profiling, and NMR-based metabolomics enables the accurate differentiation of fish origin. While muscle tissue provides reliable biomarkers relevant to human exposure, future studies should explore additional tissues such as liver and gills to improve the resolution of traceability. These methods support seafood authentication, enhance aquaculture traceability, and aid in managing the ecological impacts of escape events. Full article

The floral transition in Chinese cabbage (Brassica rapa ssp. pekinensis) is governed by a complex interplay of gene expression and hormonal regulation. Temporal transcriptome profiling was conducted across three developmental stages: pre-bolting (PBS), bolting (BS), and flowering stages (FS), to investigate the underlying molecular mechanisms. A total of 7092 differentially expressed genes (DEGs) were identified, exhibiting distinct expression trajectories during the transition. Moreover, functional enrichment analyses revealed strong associations with plant hormone signaling, MAPK pathways, and developmental regulation processes. Key flowering-related genes, such as BrFLM, BrAP2, BrFD, BrFT, and BrSOC1s displayed antagonistic expression patterns. Hormonal pathways involving auxin, ABA, ET, BR, GA, JA, CK, and SA showed stage-dependent modulation. Further, orphan genes (OGs), especially EARLY FLOWERING 1 (EF1), showed significant upregulation during the transition, which exhibited 1.84-fold and 1.93-fold increases at BS and FS compared to PBS, respectively (p < 0.05). Functional validation through EF1 overexpression (EF1OE) in Arabidopsis consistently promoted early flowering. The expression levels of AtFT and AtSOC1 were significantly upregulated in EF1OE lines compared to wild-type (WT) plants. The findings contribute to understanding the coordinated genetic and hormonal events driving floral development in Chinese cabbage, suggesting EF1 as a candidate for bolting resistance breeding. This work also expands the existing regulatory framework through the successful integration of OGs into the complex floral induction system of Brassica crops. Full article

This study presents a comprehensive analysis of the microphysical structures of Meiyu heavy rainfall (near-surface rainfall intensity > 8 mm/h) across different life stages in the Yangtze-Huaihe River Valley (YHRV). We classified the heavy rainfall events into three life stages of developing, mature, and dissipating using ERA5 reanalysis and IMERG precipitation estimates, and examined vertical microphysical structures using Dual-frequency Precipitation Radar (DPR) data from the Global Precipitation Measurement (GPM) satellite during the Meiyu period from 2014 to 2023. The results showed that convective heavy rainfall during the mature stage exhibits peak radar reflectivity and surface rainfall rates, with the largest near-surface mass weighted diameter (D_m ≈ 1.8 mm) and the smallest droplet concentration (dBN_w ≈ 38). Downdrafts in the dissipating stage preferentially remove large ice particles, whereas sustained moisture influx stabilizes droplet concentrations. Stratiform heavy rainfall, characterized by weak updrafts, displays narrower particle size distributions. During dissipation, particle breakups dominate, reducing D_m while increasing dBN_w. The analysis of the relationship between microphysical parameters and rainfall rate revealed that convective heavy rainfall shows synchronized growth of D_m and dBN_w during the developing stage, with D_m peaking at about 2.1 mm near 70 mm/h before stabilizing in the mature stage, followed by small-particle dominance in the dissipating stage. In contrast, stratiform rainfall exhibits a “small size, high concentration” regime, where the rainfall rate correlates primarily with increasing dBN_w. Additionally, convective heavy rainfall demonstrates about 22% higher precipitation efficiency than stratiform systems, while stratiform rainfall shows a 25% efficiency surge during the dissipation stage compared to other stages. Full article

The circadian clock is a self-sustaining oscillator with a period of approximately 24 h, enabling organisms to anticipate daily recurring events, such as sunrise and sunset. Since the circadian period is not exactly 24 h and the environmental day length varies throughout the year, the clock must be periodically reset to align an organism’s physiology with the natural light/dark cycle. This synchronization, known as entrainment, is primarily regulated by nocturnal light, which can be replicated in laboratory settings using a 15 min light pulse (LP) and by assessing locomotor activity. An LP during the early part of the dark phase delays the onset of locomotor activity, resulting in a phase delay, whereas an LP in the late dark phase advances activity onset, causing a phase advance. The clock gene Period 2 (Per2) plays a key role in this process. To investigate its contributions, we examined the effects of Per2 deletion in neurons versus astrocytes using glia-specific GPer2 (Per2/GfapCre) knockout (KO) and neuronal-specific NPer2KO (Per2/NesCre) mice. All groups were subjected to Aschoff type II protocol, where an LP was applied at ZT14 or ZT22 and the animals were released into constant darkness. As control, no LP was applied. Phase shift, period, amplitude, total activity count, and rhythm instability were assessed. Our findings revealed that mice lacking Per2 in neurons (NPer2) exhibited smaller phase delays and larger phase advances compared to control animals. In contrast, mice with Per2 deletion specifically in glial cells including astrocytes (GPer2) displayed normal clock resetting. Interestingly, the absence of Per2 in either of the cell types resulted in a shorter circadian period compared to control animals. These results suggest that astrocytic Per2 is important for maintaining the circadian period but is not required for phase adaptation to light stimuli. Full article

Species have different strategies for implantation and placentation. Much can be learned about general molecular and cellular biology through the examination and comparison of these differences. To varying degrees, implantation in all species includes alterations in epithelial polarity, the transformation of the endometrial stroma, the differentiation of the trophoblast, cell-to-cell and tissue-to-tissue signaling through hormones, cytokines, and extracellular vesicles, and the alteration of the maternal immune system. This review focuses on implantation in pigs, sheep, and cows. These species share with mice/rats and humans/primates the key events of early embryonic development, pregnancy recognition, and the establishment of functional placentation. However, there are differences between the pregnancies of livestock and other species that make livestock unique biomedical models for the study of pregnancy and cell biology in general. Pig, sheep, and cow conceptuses (embryo/fetus and associated placental membranes) elongate prior to implantation, displaying central implantation, extended periods of conceptus attachment to the uterus, and epitheliochorial (pigs) and synepitheliochorial (sheep and cows) placentation. This review will discuss what is understood about how the trophoblast and extraembryonic endoderm of pig, sheep, and cow conceptuses elongate, and how a major goal of current in vitro models is to achieve conceptus elongation. It will then examine the adhesion cascade for conceptus implantation that initiates early placental development in pigs, sheep, and cows. Finally, it will conclude with a brief overview of early placental development in pigs, sheep, and cows, with a listing of some important “omics” studies that have been published. Full article

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K⁺] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K⁺]_o rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K⁺-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target. Full article

This study presents the living coccolithophore communities and the morphological variability of Emiliania huxleyi in the South Aegean Sea from three sampling regions during winter-early spring (March 2017, March 2019) and summer (August 2019). Emphasis is given to March 2017 to monitor the variations in coccolithophore assemblages after an exceptionally cold event in December 2016, which resulted in newly produced dense waters that ventilated the Aegean deep basins. The assemblages displayed distinct seasonality with the predominance of E. huxleyi and Syracosphaera molischii during winter-early spring, associated with the water column mixing. By contrast, summer assemblages were featured by holococcolithophores and typical taxa of warm, oligotrophic upper waters. It seems that the phytoplanktonic succession as well as the nutrient supply to the upper euphotic layers were affected by the water column perturbation during the extreme winter of 2016–2017, which led to strong convective mixing and dense water formation. The decreased coccosphere densities during March 2017, accompanied by the notable presence of diatoms, were most probably associated with a prolonged diatom bloom, causing delay in the development of the coccolithophore community and resulting in a nitrogen-limited setting. Emiliania huxleyi morphometry showed the characteristic seasonal calcification trend of the Aegean, with the dominance of smaller coccoliths in the summer and increased coccolith length and width during the cold season. The intense cold conditions and wind-induced mixing during the winter of 2016–2017 possibly increased the absorption of atmospheric CO₂ in surface waters, causing increased acidity and the subsequent presence of etched/undercalcified E. huxleyi coccoliths and other taxa, most probably implying in situ calcite dissolution. Full article

Background/Objectives: In the aftermath of the COVID-19 pandemic, individuals infected with SARS-CoV-2 have progressively displayed a range of symptoms linked to protracted COVID during the post-acute phase of illness. Concurrently, in several nations globally, the phenomenon of population aging has been intensifying. In this scenario, the aged population has become both vulnerable and high-risk during the acute phase of COVID-19, and faces significant dangers associated with long-COVID. This study seeks to analyze the incidence and spatial distribution of health complications in older people affected by COVID-19, in the first year of the pandemic (2020), in the State of Paraná, as well as to identify the factors associated with the development of cardiovascular, neurological, respiratory, and metabolic diseases. Method: An observational and retrospective study was carried out in the Brazilian state of Paraná. Participants were randomly selected from two databases. A total of 893 older people (≥60 years) participated in the study 12 months after acute COVID-19 infection. Telephone questionnaires were applied between March and December 2021. The Moran index test, logistic regression, and Poisson models were used to analyze the data. Results: In terms of age, most participants (66%) were between 60 and 69 years old, 25.8% were between 70 and 79 years old, and 8.2% were 80 years old or older. Most participants were female (51.2%), white (98.1%), had a partner (69.8%), and had been hospitalized due to COVID-19 (59.3%). Cardiovascular diseases were the most frequent in the population (39.5%), followed by metabolic diseases (27.3%). The long-term use of medication was associated with the development of metabolic diseases (aOR = 9.8), cardiovascular diseases (aOR = 6.6), and diseases in multiple organic systems (aOR = 3.2); living alone was associated with neurological diseases (aOR = 2.5), and the age group of 80 years or older (aOR = 2.4) was associated with cardiovascular events. The spatial distribution showed that complications in body groups are distributed randomly among the health regions of the state, with no influence from neighboring locations. Conclusions: Post-COVID-19 health complications are more frequent in older adults who have comorbidities and long-term medication use. Therefore, long-term monitoring of these individuals and investment in public policies for rehabilitation and prevention of complications are necessary. Full article