SLC6A8 encodes the creatine transporter (CRT), which mediates creatine transport across the plasma membrane in the brain, including the blood-brain barrier and neurons. Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, leads to cerebral creatine depletion and cognitive impairment. Here, we investigated the developmental molecular mechanisms underlying CTD using the pathogenic c.1681G>C (G561R) variant of Slc6a8, which corresponds to a variant identified in SLC6A8 in a patient with CTD. In vitro analyses using HEK293 cells expressing mutant mouse CRT carrying the G561R variant demonstrated impaired N-glycan maturation and plasma membrane localization of the transporter, resulting in markedly reduced creatine uptake, consistent with previous reports on the corresponding human CRT variant. To investigate the in vivo effects of this pathogenic variant, we generated CRT-G561R knock-in mice by introducing the c.1681G>C point mutation into the mouse Slc6a8 gene using the CRISPR/Cas9 system. These male mice exhibited severe reductions in brain creatine levels, postnatal growth retardation, and impaired spatial memory, despite preserved gross brain morphology. Quantitative proteomic analyses of the hippocampus and cerebral cortex during postnatal development revealed region-dependent protein alterations in CTD. The hippocampus showed pronounced early postnatal remodeling involving proteins related to actin cytoskeleton organization and vesicle-mediated membrane trafficking, whereas the cerebral cortex exhibited a more gradual response involving creatine biosynthesis-related enzymes and later-emerging mitochondrial pathways, including the mitochondrial translation machinery. These findings demonstrate stage- and region-dependent proteomic remodeling during postnatal brain development in CTD.Significance Statement Creatine transporter deficiency (CTD) causes cerebral creatine depletion and intellectual disability; however, the developmental mechanisms linking creatine loss to brain dysfunction remain unclear. We performed developmental proteomic profiling of the hippocampus and cerebral cortex using a mouse model carrying a pathogenic Slc6a8 variant identified in patients with CTD. Creatine transporter dysfunction induces distinct region- and stage-dependent molecular responses during postnatal brain maturation. The hippocampus shows early alterations in cytoskeleton-dependent membrane trafficking pathways, consistent with impaired synaptic and circuit maturation, whereas the cerebral cortex exhibits progressive metabolic and mitochondrial adaptations. These findings suggest that impaired creatine-dependent energy buffering disrupts distinct developmental programs across brain regions, potentially contributing to cognitive dysfunction by hindering early hippocampal circuit maturation.
The organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are hepatic transporters that mediate the uptake of numerous therapeutics like antibiotics and statins. Various post-translational modifications, eg, phosphorylation and glycosylation, have been shown to impact OATP1B1 and OATP1B3 function and localization. S-palmitoylation (also known as S-acylation or palmitoylation) is a reversible post-translational modification that adds palmitic acid (C16:0) to cysteine residues and can influence a protein's function, localization, and protein-protein interactions. In this study, we investigated and characterized palmitoylation in OATP1B1 and OATP1B3. Using site-directed mutagenesis and acyl-resin-assisted capture assays, residue Cys24 was identified as the palmitoylation site for both these proteins. Uptake function and surface biotinylation experiments demonstrated that palmitoylation does not affect the individual function and surface expression of OATP1B1 and OATP1B3. Coexpression studies revealed a decrease in OATP1B1-OATP1B3 interactions when nonpalmitoylated OATP1B1 or nonpalmitoylated OATP1B3 are coexpressed with their wild-type counterparts, suggesting that S-palmitoylation regulates protein-protein interactions between OATP1B1 and OATP1B3. SIGNIFICANCE STATEMENT: This study identified and characterized palmitoylation of the organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Both OATP1B1 and OATP1B3 can be palmitoylated on the conserved Cys24 residue. Palmitoylation of these 2 transporters does not impact their individual function or surface expression. However, the interaction between these 2 proteins is affected when their palmitoylation state is altered.
The potassium-chloride cotransporter 2 (KCC2) is a neuron-specific transporter essential for maintaining low intracellular chloride levels. By extruding chloride ions, KCC2 ensures that activation of GABAA receptors produces hyperpolarizing inhibitory responses rather than depolarizing responses. Disruption of KCC2 function can therefore impair GABAergic signaling and neuronal maturation, contributing to a range of neurodevelopmental and neurological disorders. Pathogenic biallelic variants in SLC12A5, the gene encoding KCC2, are a rare cause of severe early-onset developmental and epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS). Here, we describe a novel homozygous SLC12A5 variant identified in a patient with severe, drug-resistant epilepsy, neonatal encephalopathy, and rapid neurological deterioration. Combined Western blot, thallium (Tl+) flux, and gramicidin-perforated patch-clamp assays revealed significantly reduced ion-transport function of the KCC2 construct encoding the variant, with no change in protein expression abundance or profile. Live-cell surface immunolabeling demonstrated markedly reduced plasma membrane expression and decreased internalization of the variant, suggesting that the functional deficit primarily results from defective trafficking or reduced membrane stability. These findings expand the spectrum of KCC2-related disorders and highlight the critical role of KCC2 in early brain development. By linking a specific SLC12A5 variant to impaired chloride homeostasis and neuronal hyperexcitability, this study provides mechanistic insight into disease pathogenesis and lays the groundwork for therapeutic strategies aimed at restoring or stabilizing KCC2 function.
Ion-track-etched membranes (ITEMs) have emerged as a distinct class of nanostructured materials and represent a versatile platform that offers precise control over pore shape, size, and areal density. These membranes offer considerable mechanical and chemical stability, making them valuable for a variety of applications, including nanoionic rectifiers, sensors, nanoiontronics devices, and energy harvesting systems. The chemical etching process of ITEMs introduces carboxylic acid groups on the surface, which serve as the sites for functionalization. Functionalization is crucial for using the ITEMs in sensor applications. ITEM-based sensors provide considerable sensitivity and selectivity. Moreover, the sensors have a low limit of detection compared to other traditional sensors. ITEMs also exhibit memristive behavior (hysteresis loop) and can perform logic gate functions. These attributes are crucial for nanoionic fluidic-based neuromorphic computing. Moreover, ITEMs can serve as efficient platforms for osmotic energy harvesting (OEH) as well as membrane-assisted cooling and dehumidification applications. This review article articulates the fundamentals of ITEMs, fabrication strategies, the origins of surface-charge-dominated ion-transport mechanisms under nanoconfinement, and chemical functionalization approaches. In addition to that, concepts of ionic rectification, hysteresis, and nonlinear functionalities related to the memristor and neuromorphic computing are also discussed. Moreover, special attention was paid to OEH systems, and power densities obtained with different membranes were also discussed and compared. The review article also provides insights into next-generation nanoionic systems by combining the concepts of nanofluidics and electrochemistry. In addition, a comprehensive analysis of the current challenges and future opportunities in developing multifunctional, scalable, and sustainable ITEM technologies is also presented.
The retina is considered one of the most metabolically active tissues in the mammalian central nervous system. Prior studies have defined the extent of metabolic diversity among all seven adult retinal cell types. However, the specific metabolic changes in retinal progenitor cells (RPCs) during development remain unknown. In this study, we characterized the histochemical patterns of oxidative phosphorylation (OXPHOS) and glycolysis indicators in the differentiating and maturing mouse retina. Also, by performing RPC-specific conditional knockout (CKO) of the mitochondrial transcription factor A (Tfam), we generated retinas in which RPC OXPHOS activity was lost throughout retinogenesis. We found that early-stage (embryonic) Tfam CKO RPCs were completely OXPHOS-deficient yet underwent normal proliferation, cell cycle exit, and differentiation into retinal neurons. In contrast, late-stage (postnatal) RPCs remained in a proliferative state well past the normal developmental period, leading to a later reduction in the generation of bipolar cells and Müller glia. Ultimately, as the CKO retina fully matures, it becomes severely hypoplastic due to cell death that we attribute to the previous loss of bipolar cells and Müller glia. In total, our data establishes that, over time, RPCs exhibit heterogeneity in their metabolic requirements, with the second wave of RPCs being more reliant on OXPHOS activity to undergo proper neurogenesis.
The developmental origins of health and disease (DOHaD) is based on the observation that environmental conditions during sensitive windows of development shape lifelong physiology and disease susceptibility. While fetal organs are often viewed as direct programming targets, the placenta is a crucial mechanistic hub because it senses maternal conditions and actively constructs the fetal environment through nutrient transport, endocrine signaling, and immune regulation. Placental plasticity spans morphology and how exchanges are favored by tissue topology, vascular development and perfusion, transporter density/localization, mitochondrial metabolism, inflammatory status tone, and endocrine outputs. These adaptive responses can mitigate short-term threats to fetal survival, but also readjust developmental signals (including exposure to nutrients, oxygen, and glucocorticoids) with enduring consequences, particularly when prenatal and postnatal environments are mismatched. This review synthesizes data showing that adverse maternal environments in domestic species induce conserved functional responses-vascular remodeling, altered nutrient transport capacity, endocrine regulation and inflammatory signaling-while species-specific placental architecture constrains adaptative capacity. In ruminants, cotyledonary placentomes exhibit compensatory changes in placentome type, vascularization and transport systems in cases of undernutrition, while heat stress induces placental remodeling associated with changes in placental inflammation, oxygen regulation, and epigenomic/transcriptomic remodeling with measurable neonatal phenotypes. In horses, diffuse microcotyledonary placentation links fetal growth to allantochorion size and microcotyledon density, uterine capacity, parity/age and maternal metabolic status modulate placental vascular structure and gene expression, with postnatal growth and metabolic effects. In pigs, diffuse folded placentation and litter-bearing competition reveal strong within-litter variability. Intrauterine crowding and maternal heat stress lead to fold- and efficiency-related (in terms of transporter expression) remodeling and alter placental nutrient transport and metabolic gene networks. Finally, we highlight the importance of studying placental epigenetic marks as molecular "memory" of in utero exposures and propose future directions for the search for in vivo biomarkers-especially circulating placental extracellular vesicles and microRNAs-associated with in-depth placental phenotyping that could allow for risk assessment during pregnancy and then targeted interventions in veterinary and production settings.
Arsenic (As) contamination poses a significant threat to crop production and food safety. In plants, arsenate [As(V)] is taken up into cells through phosphate transporters due to their chemical similarity, where it disrupts metabolic processes and causes oxidative stress. However, the precise role of phosphate transporters in As accumulation and tolerance remains unclear. Here, we investigated the function of BnPHT5;1b, a vacuolar phosphate influx transporter in Brassica napus. Double mutants of two BnPHT5;1b genes, BnA09.PHT5;1b and BnCn.PHT5;1b (hereafter referred to as BnPHT5;1b DM) exhibited enhanced tolerance to As(V) at the seedling stage, showing increased biomass, longer roots, and higher chlorophyll content under As stress. Transcriptome analysis revealed that both wild-type and mutant plants activated oxidative stress responses, but the BnPHT5;1b DM displayed stronger enrichment of antioxidant and detoxification pathways. Importantly, disruption of BnPHT5;1bs promoted root-to-shoot As translocation, with xylem sap As(III) and As(V) increased by 51.0% and 75.0%, respectively, and As concentrations in cotyledons, old leaves, and new leaves increased by 61.3%, 153.7%, and 129.7%, respectively. This was accompanied by 6.8-fold higher As accumulation in shoot cell walls, while seed As levels remained similar to or slightly lower than those of wild-type. These findings establish BnPHT5;1b as a key regulator of As transport and detoxification in B. napus. This study reveals a previously unrecognized strategy for enhancing arsenate tolerance while promoting root-to-shoot As translocation and shoot cell wall retention without increasing seed As accumulation, providing a potential genetic resource for phytoremediation of As-contaminated soils.
Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is transported into hepatocytes via OATP1B1, which is encoded by the SLCO1B1 gene. Although interindividual variability in vadadustat pharmacokinetics (PK) has been reported, the influence of SLCO1B1 polymorphisms and the clinical relevance of coproporphyrin-I (CP-I) as a biomarker of OATP1B1 activity on vadadustat exposure remain unclear in Japanese patients with chronic kidney disease-related anemia. This study evaluated the effects of SLCO1B1 polymorphisms on vadadustat plasma concentration in this population. A prospective observational study was conducted in 11 patients who received vadadustat. Plasma concentrations at 12 h post administration (C12) were measured using high-performance liquid chromatography with ultraviolet detection, and dose-adjusted concentrations (C12/D) were calculated. CP-I, an endogenous biomarker of OATP1B1 activity, was quantified simultaneously. SLCO1B1 c.388A>G and c.521T>C were genotyped, and haplotypes were assigned. Associations between SLCO1B1*15, vadadustat C12/D, and CP-I were analyzed. A total of 71 samples were analyzed. C12/D was significantly higher in SLCO1B1*15 carriers than in noncarriers (median: 60.3 versus 37.6 µg/mL/g, P = 0.009). CP-I concentrations were also higher in SLCO1B1*15 carriers (median: 0.72 versus 0.36 ng/mL, P = 0.030). A significant correlation was observed between C12/D and CP-I (ρ = 0.627, P = 0.039). SLCO1B1*15 significantly influenced vadadustat concentration, and CP-I was associated with vadadustat C12/D, suggesting an association with OATP1B1-related transporter function. These findings provide insights into variability in vadadustat PK and support the larger studies to clarify the clinical utility of therapeutic drug monitoring strategies that incorporate pharmacogenomic and biomarker information. Video abstract available in online supplementary file. Supplementary file2 (MP4 35720 KB).
Harmful algal blooms (HABs), denoted by the excessive growth or 'bloom' of cyanobacteria, have increased in frequency, duration, and intensity worldwide over the past decades, primarily due to the rise in global temperature and nutrient enrichment. The blooms of cyanobacteria release various HAB toxins, with the cyclic heptapeptide microcystin-LR (MC-LR) as the most prevalent and well-characterized. Evidence suggests that exposure to HAB toxins poses significant risks to female reproductive health. Herein, we summarized current knowledge on the female reproductive impacts of MC-LR and other HAB toxins with a focus on the ovary, oocyte, and early pregnancy events. Following ingestion, inhalation, or dermal contact, MC-LR can accumulate in the ovaries via organic anion transporting polypeptide (OATP)-mediated transport. Across mammalian, fish, and amphibian models, MC-LR has been shown to interfere with ovarian folliculogenesis, steroidogenesis, oocyte maturation, ovulation, and luteinization. Mechanistically, MC-LR inhibits protein phosphatase (PP) 1 and PP2A, triggering widespread phosphorylation dysregulation, oxidative stress, endoplasmic reticulum (ER) stress, autophagy, cytoskeletal disruption, and apoptosis in follicular cells. Beyond the ovary, exposure to MC-LR may impair fertilization, embryogenesis, decidualization, and placental health, and maternal exposure to MC-LR likely causes multi-generational toxicities. Despite increasing experimental evidence, human data remain scarce, and there are currently limited studies investigating the reproductive effects of other MC congeners and HAB toxin mixtures. Addressing these knowledge gaps is essential for assessing the female reproductive risks of exposure to HAB toxins as well as informing the development of environmental and public health policy and regulatory guidelines.
With the dual advantages of environmental friendliness and high efficiency, interfacial solar steam generation (ISSG) holds significant promise for sustainably alleviating global water shortages. However, how to achieve efficient evaporation and salt resistance simultaneously still face challenge. Herein, inspired by the mangrove, a TPU/PAN/CNTs double-layer (TPCD) evaporator was constructed using a combination of directional freezing and salt templating. The prepared evaporator features vertically ordered channels in the upper layer and a honeycomb-like pore structure in the bottom layer. The upper vertical channels enhance surface light absorption, salt ion diffusion, and water transport rate, while the honeycomb structure facilitates water absorption and minimizes heat loss, and thus enables coordination between thermal management and water transport. The advantages of this structure in evaporation and salt resistance were demonstrated by numerical simulations. The TPCD evaporator with optimized structure achieves an evaporation rate of 2.66 and 2.61 kg m-2 h-1 for pure water and seawater under one sun illumination. Moreover, salt crystallization predominantly occurs at the evaporator's edge and detaches spontaneously. Thus, the TPCD evaporator demonstrated efficient and stable desalination performance in the long term even when used to treat high-concentration brine. These findings highlight its promising applicability in the fields of desalination and water purification.
Humanity will eventually inhabit extraterrestrial environments, yet crucial questions remain regarding the feasibility of reproduction and long-term survival away from the Earth. Exposure to space radiation might induce DNA damage, potentially resulting in harmful mutations in future generations. Altered gravity on other planets or within space colonies could also interfere with embryonic and fetal development. For sustainable colonization beyond Earth, humans and essential animal species, e.g., livestock and companion animals, must be transported. To prevent inbreeding and genetic deterioration, hundreds of individuals per strain would need to be transferred between planets; however, moving live animals, particularly large species, might be impossible. To address this challenge, technological innovations are required for long-term preservation and secure transport of genetic resources. In addition, maintaining genetic diversity will depend on collecting genetic resources from as many individuals as possible, including those who are infertile or elderly. Although interplanetary migration is not yet practical, the technologies discussed herein are highly relevant to current challenges on Earth, including infertility treatment. This review summarizes our ongoing research on mammalian reproduction under space conditions.
The pathogenesis of perioperative neurocognitive disorders (PND) involves a complex interplay of genetic vulnerability and environmental insults, with epigenetic regulation acting as a dynamic mediator. However, the cell-specific epitranscriptomic responses to perioperative stressors like sevoflurane anesthesia, and their functional consequences for cognitive decline, are not well defined. Here, we report that the m6A demethylase FTO is significantly upregulated in the medial prefrontal cortex (mPFC) of male mice exposed to sevoflurane anesthesia. Astrocytic FTO, but not neuronal or endothelial FTO, is highly sensitive to sevoflurane exposure. Conditional knockout of FTO in astrocytes attenuated sevoflurane-induced cognitive deficits, while astrocyte-specific FTO overexpression exacerbated sevoflurane-induced cognitive deficits. Mechanistically, astrocytic FTO mediated m6A demethylation of glutamate transporter-1 (GLT-1) mRNA, leading to enhanced GLT-1 protein expression and aberrant glutamatergic transmission. Sevoflurane exposure disrupted synaptic transmission, neuronal morphology, and calcium activity in the mPFC, which were rescued by astrocytic FTO deletion. Supplementation with the methyl donor S-adenosylmethionine (SAMe) normalized m6A levels and improved cognitive performance. This study demonstrates that astrocytic FTO is a critical epitranscriptomic modulator of sevoflurane-induced PND and a potential therapeutic target for PND.Significance Statement PND are a major clinical concern for which effective mechanism-based interventions are lacking. This study identifies astrocytic FTO as a cell-type-selective epitranscriptomic driver of sevoflurane-induced PND and establishes that its m6A-demethylase activity disrupts glutamate homeostasis by post-transcriptionally regulating the astrocytic glutamate transporter GLT-1. Astrocyte-restricted deletion of FTO preserves synaptic transmission, neuronal structure, and calcium dynamics, thereby preventing cognitive decline, while astrocytic FTO overexpression exacerbates deficits. Therapeutic restoration of m6A methylation with the methyl donor SAMe normalizes the epitranscriptomic landscape and rescues cognitive function. These findings reveal astrocytic m6A regulation as a previously unrecognized pathogenic mechanism and a druggable target for PND.
Cannabis-impaired driving is an increasing public health concern. Effective communication strategies are essential for shaping risk perceptions, influencing normative beliefs, and encouraging safer behaviors. UC San Diego Transportation Research and Education for Driving Safety Center evaluated how cannabis consumers perceive and respond to cannabis-impaired driving messages, message sources, and strategies to promote safer driving behaviors. Eligible participants were adults who reported cannabis use within the past three months, perceived it as safe to drive on the same day of use, and resided in one of eight U.S. states selected for diversity in cannabis policy contexts. The study aimed to recruit 800 participants. Using a cross-sectional, mixed-methods design, participants reported cannabis use patterns and driving behaviors before reviewing a series of cannabis-impaired driving messages. Messages were developed through an iterative process informed by literature, expert review, and formative testing, and represented communication styles commonly used in safety campaigns. Participants rated each message on attention, appeal, relevance, believability, influence on behavioral intentions, and source credibility. 846 cannabis users participated. Messages emphasizing concrete effects and impairment (e.g., Feel Different, Drive Different) consistently received the highest ratings across attention, appeal, relevance, and believability. In contrast, more informational or evaluative messages (e.g., Studies Show) performed significantly less favorably. Factual messages yielded the highest proportion of participants reporting they were very likely to increase wait time before driving (59%), while self-reflective messages were most effective in encouraging alternative transportation (55%). All message types produced similar effects on intentions to remain in the same location (56-58%), and substantially fewer participants reported intentions to reduce cannabis use overall (23-29%). Message responsiveness varied by driving risk profile. Ultra-high-risk drivers reported lower likelihood of engaging in safer behaviors compared with medium- and high-risk drivers, although differences were not uniformly statistically significant. Qualitative findings indicated that exaggerated, fear-based, or stigmatizing messages were viewed negatively across groups, whereas messaging that was clear, evidence-based, and nonjudgmental was perceived as credible and effective. Source trust also varied, with healthcare providers and science-based organizations rated most credible and celebrities and social media influencers rated least trustworthy. This study offers new evidence on how cannabis users respond to messaging about cannabis-impaired driving. Messages emphasizing concrete effects and impairment, particularly those that are factual, direct, and evidence-based, were most consistently associated with higher ratings on outcome measures. However, differences in behavioral intentions across message types were modest, with limited impact on intentions to reduce cannabis use. Findings also indicate that individuals reporting higher-risk cannabis use and driving behaviors, particularly ultra-high-risk drivers, may be less responsive to messaging overall and may require more tailored approaches and complementary strategies to mitigate impaired driving. Across groups, messages perceived as exaggerated, stigmatizing, or fear-based were viewed as less credible and potentially counterproductive. These results can inform the development of user-centered, harm-reduction safety campaigns as cannabis legalization expands, while underscoring the need for continued evaluation and refinement of messaging strategies.
In the present study, optoelectronic, thermoelectric (TE), and elastic characteristics of LiHfIrZ Heusler alloys (HAs) (Z = Ge and Si) are studied through first-principles calculations and semi-classical Boltzmann transport theory. The structural properties were studied using the generalized gradient approximation (GGA) with the Perdew-Burke-Ernzerhof (PBE) functional, while electronic and transport properties were analysed using the Tran-Blaha modified Becke-Johnson potential. The calculated elastic constants, thermodynamic parameters, and formation energy confirm the mechanical, thermodynamic, and structural stability of the HAs, as well as their anisotropic character. Moreover, the alloys exhibit semiconducting behaviour. The calculated band gaps (Eg) of LiHfIrSi and LiHfIrGe are 1.72 and 0.84 eV, respectively. The semiconducting nature of both HAs has been established by their band structure (BS) and density of states (DOS) calculations. The optical analysis reveals a high dielectric response in the low-energy region (~ 2 eV), which decreases with increasing photon energy. Our HAs exhibit strong reflectivity in the ultraviolet (UV) region, indicating significant interaction with high-energy electromagnetic radiation, while appreciable optical conductivity is observed in the visible energy range. Moreover, both HAs displayed an increasing power factor, highlighting their potential for high-temperature TE applications. Notably, LiHfIrSi achieves a maximum ZT of 0.72 at 1200 K. Given the limited studies on these HAs, this study provides a valuable basis for future theoretical and experimental investigations.
Alzheimer's disease (AD), a leading cause of dementia, remains incurable, necessitating novel insights into its pathogenesis and therapeutic strategies. Recent studies highlight cuproptosis-a copper (Cu)-dependent mitochondrial cell death pathway-as a critical player in AD progression. Cuproptosis is triggered by Cu overload, which disrupts mitochondrial tricarboxylic acid cycle enzymes, resulting in toxic aggregation of lipoylated proteins and iron-sulfur cluster destabilization. This process exacerbates mitochondrial dysfunction, oxidative stress, and neuronal loss, synergizing with hallmark AD pathologies like Aβ deposition and Tau hyperphosphorylation. Unlike ferroptosis or apoptosis, cuproptosis uniquely involves mitochondrial protein lipoylation and Cu homeostasis imbalance. Therapeutic strategies targeting cuproptosis include Cu chelators, inhibitors of Cu transporters, antioxidants, and gene editing approaches to restore Cu homeostasis or mitigate protein aggregation. Immunotherapy and neuroprotective agents further show promise in alleviating cuproptosis-driven neuroinflammation. Despite preclinical advancements, challenges remain in balancing Cu's essential roles with therapeutic interventions. This review underscores cuproptosis as a pivotal mechanism in AD and outlines emerging therapeutic avenues, emphasizing the ncessity for precision in targeting Cu dysregulation to halt neurodegeneration.
Halide perovskite-based photovoltaics have urged a significant research community to investigate photovoltaic features due to their exceptional stability, optimal energy gap, and optical response. This study emphasizes the scrutiny of structural, mechanical, stability, and opto-electronic aspects of K2LiInI6 by using the DFT-oriented Wien2k code to utilize as an absorber material in solar cells. The structural aspects confirm cubic phase configuration and formation energy value (-2.35 eV/atom), and ab initio molecular dynamics (AIMD) simulation validates thermal robustness and stability of K2LiInI6. The mechanical attributes are illustrated thoroughly, which confirm the ductility, mechanical stability, and anisotropic response of K2LiInI6. The optoelectronic features validate direct Eg of 1.50 eV, high absorption (7.95 × 104/cm), lower reflectivity (0.12), and optical loss in the visible photo spectrum. Thermal transport features of K2LiInI6 are determined to evaluate the figure of merit, which is found to be 0.74 at ambient temperature, ensuring the thermal energy harvesting potential. The solar cell device simulation, ITO/ETL(CSTO/PEIE/ZnS)/K2LiInI6/HTL (SrCu2O2), is achieved by using SCAPS-1D simulation. The effect of optimization of device parameters, such as absorber thickness and operational temperature, on the photovoltaic (PV) performance is also investigated. Among the explored device structures, optimized configuration ITO/CSTO/K2LiInI6/SrCu2O2 reveals the conversion efficiency of 30%, which is the highest among the studied configurations. Hence, the findings on thermoelectric and photovoltaic performance discussed in the present investigation will be significantly beneficial in the enhancement of the effectiveness of thermoelectric devices and perovskite solar cells.
Microplastics (MPs) are a global threat but their transport and behavior vary between geographic regions. Arid zones cover 40% of the Earth's land area and are characterized by limited rainfall, intermittent streams, and hydrophobic soils; yet little is known about the behavior of MPs in these regions. We quantified spatial patterns of MPs in a large fluvial valley in northern Oman, (wadi Al Khoud), and tested how a rainfall event altered MP abundance, composition, and associated pollution indices. Surface sediments (top 4 cm) were collected at 11 sites spanning agricultural, natural, residential, flood retention, and coastal residential zones during dry-season baseflow (October 2023) and again following flooding associated with heavy rainfall (March 2024). MPs were extracted and characterized by shape, size, and color, and polymer type. Pollution and polymer toxicity indices were calculated. MP concentrations differed significantly among sites, between zones, and between sampling periods, with a significant site by rainfall interaction. Flooding increased MP abundance at most locations, notably a 1000% increase at a flood-retention dam, relative to pre-flood conditions. Land use influenced MP burdens: before flooding, agricultural and residential sites exceeded the natural zone; after flooding, the flood retention became a pronounced hotspot. Fragments dominated in both periods, while fibers declined markedly after flooding. The smallest size class (0.01-0.05 mm) was the most prevalent in both periods. Polypropylene and polyethylene were the most common polymers across sites and seasons. MP abundance correlated positively with total organic content, silt, and clay, and negatively with sand. Pollution indices increased following flooding, indicating heightened post-flood toxicological risk. These results identify flooding, particularly retention-dam trapping, as a control on MP distribution in arid-zone stream sediments. The findings provide insights on the movement of MPs in arid zones and can act as a guide to assessing risks and mitigation strategies in the future.
Tea diseases caused by Lasiodiplodia theobromae are prevalent in many tea-producing countries, substantially affecting both yield and quality of tea. In this study, fluoxastrobin, a strobilurin fungicide, exhibited a half-maximal effective concentration (EC50) of 143.44 μg/ml for inhibiting mycelial growth in vitro. At a dose of 800.0 μg/ml, it demonstrated 42.00% antifungal activity against leaf spot on detached tea twigs. Micromorphological observations revealed that fluoxastrobin induced hyphal abnormalities, including surface roughness, deformation, and swelling. Integrated transcriptomic, proteomic, metabolomic, and bioinformatic analyses indicated that fluoxastrobin significantly modulate the expression and abundance of genes, proteins, and metabolites associated with energy metabolism pathways. Fluoxastrobin notably reduced mitochondrial membrane potential, thereby inhibiting electron transport and impairing energy production. Molecular docking and molecular dynamics simulations suggested that fluoxastrobin binds to NAD(P)H quinone oxidoreductase (NQO), with a binding free energy of -10.1 kcal/mol. Microscale thermophoresis assay revealed a dissociation constant (Kd) of 0.121 μM for fluoxastrobin binding to NQO, which is significantly lower than that of azoxystrobin (0.319 μM). Surface plasmon resonance assay further confirmed the stronger binding affinity of fluoxastrobin to NQO, with a Kd value of 7.098 ×10-5 M. To enhance disease control efficacy, the combinations of fluoxastrobin with pyrrolnitrin or osthole at a ratio of 1:2 was screened, yielding EC50 values being 0.0036 and 15.25 μg/ml and synergistic ratio values being 1.29 and 4.00, respectively. Collectively, these findings suggest that fluoxastrobin targets quinone oxidoreductase to disrupt membrane redox balance and suppress L. theobromae, supporting its potential application in the management of tea diseases.
Adult-onset seizure reflects the burden of acquired brain insults, but established disease-modifying preventive strategies are limited. We evaluated whether semaglutide initiation is associated with a lower incidence of adult-onset seizure compared with sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other glucose-lowering drugs (GLDs) in adults with type 2 diabetes. Using the All of Us Research Program, we emulated a population-based target trial in new-user, active-comparator cohorts from January 2018 to October 2023. We compared semaglutide vs other GLDs and semaglutide vs SGLT2i. Incident epilepsy or seizure was identified from diagnostic codes. Effects were estimated using inverse probability of treatment weighting with weighted Cox models and targeted maximum likelihood estimation (TMLE). Subgroup and sensitivity analyses with multiple outcome definitions and analytic approaches were conducted to assess the robustness of findings. We evaluated mediation through hemoglobin A1c (HbA1c) and body mass index (BMI) using the longitudinal Vansteelandt framework. We analyzed 10,213 patients in the semaglutide (n = 2,586, mean age, 60.1 years; 56.8% female) vs other GLDs cohort (n = 7,627, mean age, 63.7 years; 54.2% female) and 8,605 patients in the semaglutide (n = 2,814, mean age, 60.5 years; 66.2% female) vs SGLT2i cohort (n = 5,791, mean age, 64.4 years; 47.3% female). Semaglutide was associated with a lower risk of adult-onset seizure compared with other GLDs (weighted HR 0.44 [95% CI 0.25-0.79]; 4-year risk difference -1.78% [95% CI -2.58 to -0.98]) and SGLT2i (weighted HR 0.48 [95% CI 0.27-0.85]; 4-year risk difference -1.46% [95% CI -2.41 to -0.51]). TMLE estimated risk differences per 1,000 persons of -14.20 (95% CI -18.33 to -10.07) vs other GLDs and -7.62 (95% CI -11.65 to -3.60) vs SGLT2i, corresponding to numbers needed to treat of 70 and 131, respectively. Mediation was minimal for HbA1c (2.4% vs other GLDs; 6.5% vs SGLT2i) and BMI (0% vs other GLDs; 0.7% vs SGLT2i). Semaglutide initiation was associated with a lower risk of adult-onset seizure compared with SGLT2i and other GLDs in patients with type 2 diabetes, independent of glycemic and weight effects. Residual confounding, low event counts, and shorter follow-up limit causal interpretation. This study provides Class II evidence that semaglutide use was associated with a lower risk of adult-onset seizures compared with other GLDs and SGLT2i.
Aqueous zinc-ion batteries (AZIBs) as promising candidates for grid-scale storage are constrained by the poor conductivity and structural instability of manganese dioxide (MnO2) cathodes during cycling. Herein, we report a rationally designed cathode comprising β-MnO2 nanorods intimately decorated with reduced graphene oxide (β-MnO2@rGO) through an in-situ hydrothermal and thermal activation process. The one-dimensional β-MnO2 nanorods provide shortened diffusion pathways for H+/Zn2+ions, while the conformal rGO network establishes a three-dimensional conductive skeleton that enhances electronic transport and buffers volumetric expansion during cycling. X-ray photoelectron spectroscopy (XPS) confirms the formation of robust Mn-O-C interfacial bonds, which facilitate charge transfer and mitigate manganese dissolution. The optimized β-MnO2@rGO-30 exhibits a high reversible specific capacity of 387 ± 3.0 mAh g-1 at 0.1 A g-1 and maintains 89 ± 1% capacity retention after 6000 cycles at 1.0 A g-1. A sequential insertion mechanism, beginning with H+ intercalation followed by Zn2+ storage, with excellent structural reversibility, is elucidated by ex-situ spectroelectrochemical analysis. This work provides a viable strategy for designing high-performance MnO2-based cathodes through synergistic nanoengineering and conductive hybridization for advanced AZIBs.