The microbiota-gut-brain axis plays a pivotal role in numerous neurological disorders, including traumatic brain injury (TBI). TBI induces neuroinflammation accompanied by alterations in the gut microbiota. However, the contribution of gut microbiota dysbiosis to post-TBI neuroinflammation and its underlying mechanisms remain poorly understood. Here, we found that TBI mice treated with Akkermansia(Akk) exhibited increased Akkermansia abundance at 28 days post-TBI, whereas those receiving fecal microbiota transplantation (FMT) showed elevated levels of Bifidobacteriaceae and Bifidobacterium. Both Akk and FMT alleviated persistent microglial activation in the hippocampus of TBI mice at 28 days. FMT prevented the reduction of 5-hydroxyindole in TBI mice, and prolonged FMT suppressed the sphingolipid signaling pathway in these animals. Furthermore, two macrophage activation-associated genes, ACx3cr1 and Cd68, were upregulated after TBI, but their expression was inhibited by FMT at 28 days. Sphingolipid metabolism was elevated in TBI mice at 7 and 28 days post-injury, and Akk treatment (p = 0.027) effectively blocked this increase at 28 days. This study suggests that prolonged Akkermansia supplementation may mitigate post-TBI microglial activation by modulating the sphingolipid metabolic pathway. Both FMT and Akk represent potential therapeutic targets for developing novel strategies to address persistent microglial activation and chronic neuroinflammation following TBI, though their precise mechanisms require further validation.

The technological revolution and industrial transformation led by digital technologies are driving the shift from global value chains (GVCs) to digital global value chains (DGVCs). To address the challenge of global climate change while achieving economic growth, many countries are prioritizing practical energy-saving and emission reduction measures, while simultaneously seeking greater trade gains through participation in digital GVCs and the international division of labor. This study examines whether participation in DGVCs reduces carbon emissions. Using balanced panel data covering 62 countries from 2007 to 2021, we employ a Panel Smooth Transition Regression (PSTR) model to investigate the nonlinear relationship between DGVC participation and CO2 emissions embodied in digital exports (EEDE). The empirical results reveal an inverted U-shaped relationship, indicating that DGVC participation increases emissions below a digitalization threshold but reduces emissions beyond this threshold. These findings provide new evidence for the dual role of digitalization in shaping trade-related emissions and highlight the importance of stage-specific strategies. Policy implications emphasize that less-digitized economies must prioritize breaking free from carbon lock-in by pursuing green transformation alongside digital expansion. The study deepens the understanding of the trade-environment nexus in the digital era and provides actionable insights for aligning digital economic development with global climate goals.

Animals learn and adapt to environmental changes. However, neural plasticity can also become maladaptive, leading to neurological and psychiatric disorders. How do we use known molecular mechanisms to harness the power of neural plasticity to prevent and treat diseases? Consolidating learning is known to require new protein synthesis. We found that mRNA m6A modifications and the RNA-binding protein YTHDF1 are required for molecular, cellular, and behavioral adaptations in response to environmental changes. Deletion of Ythdf1 in dopamine D1- or D2 receptor-expressing neurons selectively impaired D1- or D2-dependent learning, respectively, including both adaptive and maladaptive learning. This highlights YTHDF1 as a potential therapeutic target for preventing pathological plasticity. YTHDF1 recognizes m6A modifications on transcripts and regulates their translation. Elevated cAMP triggered increased protein synthesis in control striatal neurons but not in Ythdf1-deficient neurons. Behaviorally, cell-type-specific Ythdf1 deletion resembled learning phenotypes caused by deletion of the m6A methyltransferase gene Mettl14, suggesting YTHDF1 as the main mediator of m6A-dependent regulation in the striatum.

Additive manufactured high-temperature titanium alloys typically exhibit poor plasticity and crack sensitivity. In this work, a novel strategy incorporating high-melting-point, low-diffusivity tungsten (W) as a microstructural modifier was designed for Ti-6.5Al-3.5Mo-1.5Zr-0.3Si alloy, with subsequent processing by laser powder bed fusion. At the mesoscale, the columnar prior (3-grains of the alloys transformed to fine equiaxed-elongated morphology and formed a bimodal structure. Microscale characterization revealed that the alpha' phases were refined while the brittle alpha'/(3 interfaces were replaced with more ductile boundaries. Notably, the modified alloys achieved an outstanding tensile strength of 1717.6 MPa along with an improved elongation of 4.4%, which is attributed to the synergistic effects of grain structure and interface optimization. The present work proposes a promising approach for regulating the microstructure and mechanical properties of high-temperature titanium alloys by refractory elements.

DNA methylation is a stable epigenetic modification with essential roles in plant drought response. It is known that methyltransferase mutant is necessary for the regulation of methylation variations, but this epigenetic molecular mechanism based on methyltransferase mutant in responding to drought stress was still unclear in cotton. In this study, we aim to decipher the epigenetic code of drought response regulated by methyltransferase gene GhDMT9 in cotton, providing valuable information for the molecular research of drought resistance in cotton. We successfully created the first cotton methyltransferase mutant ghdmt9 using CRISPR/Cas9 method and performed methylation variations analysis with whole-genome bisulfite sequencing (WGBS) and transcriptome analysis based on ghdmt9 mutant. In addition, specific antibody of methyltransferase GhDMT9 was prepared and used for Chromatin Immunoprecipitation (ChIP-seq) analysis. The results indicated that ghdmt9 mutant interpreted approximately 2.06% methylation variations under drought stress. Demethylation variations, mainly derived from the CHG and CHH contexts, were closely correlated with drought response. Whether at normal growth stage or under drought stress, the number of up-regulated genes induced by demethylation variations was apparently higher than the number of down-regulated genes, especially genes regulating lipids and lipid-like molecules and hormone-related genes. In addition, fiber quality of ghdmt9 mutant was obviously better than that of wild type (WT). Interestingly, a transcription factor lsh (lysine-specific histone) was found to interact with methyltransferase gene GhDMT9 to activate its hyper-methylation function of target genomic regions by ChIP-seq analysis. Overall, our results extend our understanding of the epigenetic regulation of methyltransferase GhDMT9 in drought response and contribute to further investigations of the epigenetic mechanisms underlying abiotic stresses in cotton.

The abnormal accumulation of hyperphosphorylated tau in neurofibrillary tangles is a hallmark of neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia. In AD, tangle pathology characteristically develops in brain regions with heightened vulnerability, such as the entorhinal cortex and hippocampus. Emerging evidence implicates mitochondrial dysfunction and metabolic disturbances in AD progression, yet the relationship between regional vulnerability and pretangle tau-driven transcriptomic changes remains unclear. Here, to address this critical gap, we utilized the tau P301S transgenic mouse model (PS19 line), which develops tau inclusions. Using spatial transcriptomic profiling across the hippocampal and cortical regions at selected disease stages, we captured spatiotemporal transcriptional responses to tauopathy. Our findings reveal that disease-associated microglia and astrocyte phenotypes emerge concurrently with phosphorylated tau accumulation across multiple brain regions. Intriguingly, the expression of Pgk1, a hub gene of the glycolytic pathway, was upregulated along with other metabolic pathway genes in the CA3 region at 2 months of age, preceding the onset of detectable tau tangle pathology, and correlated with tangle severity, suggesting early metabolic dysregulation in vulnerable regions. Further analysis of differentially expressed genes uncovered region-specific and temporally dynamic transcriptional patterns in the cortex and hippocampus. Early saturable alterations in ATP metabolic processes, glycolysis and oxidative phosphorylation appeared in the hippocampus at 2 months of age, with delayed engagement in the cortical regions. These results underscore the contributions of metabolic stress and glial activation to tauopathy and regional vulnerability, highlighting spatial transcriptomics as a powerful tool for uncovering region-specific molecular insights into disease mechanisms.

INTRODUCTION:Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown. METHODS:We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq). RESULTS:PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation. DISCUSSION:Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.

Salinized soil is a potential resource for agricultural development, and cotton can improve and rehabilitate saline-alkali soil. Therefore, identifying, analyzing, and validating salt tolerance genes in cotton are of great significance for remediating saline-alkali land. Flavonol synthase (FLS) plays a key role in flavonol biosynthesis in plant, and it is also important in plant growth, development, and abiotic stress tolerance. However, the function of the FLS gene in cotton under salt stress remains unclear. In this study, the function of GhFLS1 under salt stress was analyzed through combined transcriptomic and metabolomic, exogenous quercetin, 3-3’diaminobenzadine (DAB) and 2-aminoethyl diphyenylborate (DPBA) staining in cotton, and the generation and characterization of GhFLS1-overexpressing lines in Arabidopsis and cotton. Differentially expressed genes and differentially accumulated metabolites were significantly enriched in the flavonoid metabolic pathway. DAB and DPBA staining revealed significant reactive oxygen species (ROS) and flavonol accumulation in cotton leaves under salt stress. Exogenous quercetin application enhanced the salt stress tolerance of cotton. GhFLS1 expression was significantly upregulated in response to salt stress. GhFLS1-overexpressing Arabidopsis exhibited enhanced salt stress tolerance, and ROS accumulation was significantly reduced in GhFLS1-overexpressing cotton under salt stress. This study presents the first functional characterization of a cotton FLS gene in response to salt stress by overexpression in Arabidopsis and cotton. We integrated transcriptomic and metabolomic, identifying quercetin as the key downstream metabolite, and validated its protective role through exogenous application. These results establish a functional link from GhFLS to quercetin-mediated ROS homeostasis, providing a candidate gene and a metabolic marker for breeding salt-tolerant cotton.

Cancer differentiation therapy aims to induce the maturation of neoplastic cells, but the mechanisms regulating cell fate decisions in oncogenic contexts remain unclear. In this study, we integrated single-cell chromatin accessibility and single-cell transcriptome analyses to explore the regulatory trajectories of a classical PML/RARα+ acute promyeloid leukemia (APL) cell line (NB4) post treatment by all-trans-retinoid acid (ATRA). Our findings indicated that ATRA activated specific PML/RARα-target enhancers to trigger a regulatory circuit composed of a positive feedforward gene regulatory circuit involving two transcription factors, SPI1 and CEBPE. This regulatory circuit was both necessary and sufficient to drive NB4 cells through an intermediate cell fate decision point to initiate terminal granulopoiesis. Moreover, ectopic expression of SPI1 and CEBPE promoted granulocytic differentiation in non-APL leukemia cell lines HL60 and K562. Our study sheds mechanistic insights into the differentiation trajectories induced by ATRA and illustrates a gene regulatory circuit that could be widely applied to promote differentiation of leukemia cells.

Altruistic punishment is crucial in promoting cooperation and maintaining social fairness. The third-party punishment (TPP) game, a typical paradigm testing altruistic punishment behavior, involves individuals incurring personal costs to punish norm violations others commit. This altruistic (costly) punishment has been suggested as an adaptive trait in human evolution, influencing behaviors such as mate selection. Additionally, testosterone levels and facial attractiveness are key factors affecting altruistic behavior and mating preferences, influencing how altruism is displayed and perceived in mating contexts. However, the causal effect of mate choice motives on altruistic punishment behavior is obscure. In this study, we combined exogenous testosterone administration and a TPP game to explore the effect of exogenous testosterone on men's altruistic punishment behavior toward female recipients of varying attractiveness. In a double-blind, placebo-controlled withinsubjects crossover design, 85 heterosexual men came to the lab twice, once receiving testosterone gel and the other time receiving a placebo gel. Our results showed that participants in the testosterone condition (compared to the placebo condition) exhibited a higher frequency of altruistic punishment behavior toward others in the presence of female recipients. The effects varied across different coin allocation conditions and female recipient facial attractiveness, with participants balancing the signaling of altruistic traits and protecting their resources. Our findings highlight the complex interaction between hormonal factors and mating-related cues, which appears to be associated with altruistic punishment behavior.

The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylation in Alzheimer's disease. The cross-seeding between amylin and tau exacerbates tau pathology spread and synaptic loss, leading to neurodegeneration and cognitive deficits. Given the link between lysosomal dysfunction and tauopathy in the brain and amylin aggregation in the pancreas, we hypothesized that amylin could potentially worsen tau pathology in diabetic mice. We administered streptozotocin and/or amylin peripherally to the PS19 model of tauopathy at 3 months and characterized them at 6 months of age. We found that streptozotocin diminished body weight gain, increased blood glucose levels, worsened motor performance, and improved fear-conditioned memory in PS19 mice. Both amylin and streptozotocin administration prompted the emergence of tau pathology in the pancreas, which coincided with a decrease in the number of lysosomes in pancreatic islets. Mice treated with amylin and streptozotocin also developed robust tau pathology concomitant with lowering lysosomal cathepsin D levels in the visual cortex. These findings suggest that in diabetic mice, amylin administration diminished pancreatic lysosomes, possibly increasing the number of amylin aggregates that reached the brain and contributing to the worsening of tau pathology due to lysosomal impairment in the visual cortex. The outcome of our research enhances the understanding of the cellular pathways by which amylin may serve as a link between the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.

The gene BIN1 is the second-largest genetic risk factor for late-onset Alzheimer's disease (LOAD). It is expressed in neurons and glia in the brain as cell-type-specific and ubiquitous isoforms. BIN1 is an adaptor protein that regulates membrane dynamics in many cell types. Previously, we reported that BIN1 predominantly localizes to presynaptic terminals in neurons and regulates presynaptic vesicular release. However, the function of neuronal BIN1 in relation to LOAD is not yet fully understood. A significant gap in the field is the unbiased characterization of neuronal BIN1-interacting proteins and proximal neighbors. To address this gap and help define the functions of neuronal BIN1 in the brain, we employed TurboID-based proximity labeling to identify proteins biotinylated by the neuronal BIN1 isoform 1-TurboID fusion protein (BIN1iso1-TID) in cultured mouse neuroblastoma (N2a) cells in vitro and in adult mouse brain neurons in vivo. Label-free quantification-based proteomic analysis of the BIN1iso1-TID biotinylated proteins led to the discovery of 360 proteins in N2a cells and 897 proteins in mouse brain neurons, identified as BIN1iso1-associated (proximal) or interacting proteins. A total of 92 proteins were common in both datasets, indicating that these are high-confidence BIN1-interacting or proximity proteins. SynapticGO analysis of the mouse brain dataset revealed that BIN1iso1-TurboID labeled 159 synaptic proteins, with 60 corresponding to the synaptic vesicle cycle. Based on phosphorylation site analysis of the neuronal BIN1iso1-TID interactome and related kinase prediction, we selected and validated AAK1, CDK16, SYNJ1, PP2BA, and RANG through immunostaining and proximity ligation assays as members of the BIN1 interactome in the mouse brain. This study establishes a foundation for further investigations into the function of neuronal BIN1 by identifying several previously unknown proximal and potential interacting proteins of BIN1.

Phenylalanine (Phe), an aromatic amino acid, is a key precursor of flavonoids, which are crucial for plant growth and development. Arogenate dehydratase (ADT) catalyzes the final step in Phe biosynthesis. This study identified eleven ADT genes in G. hirsutum, twelve in G. barbadense, six in G. arboreum, and six in G. raimondii. Among them, GhADT5 exhibited the highest upregulation under alkali stress. Silencing GhADT5 using virus-induced gene silencing (VIGS) reduced cotton tolerance to alkali stress. GhADT5 silencing also led to decreased plant phenylalanine content, total flavonoid content, and activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). These reductions caused intracellular accumulation of Malondialdehyde (MDA) and reactive oxygen species (ROS). This oxidative damage ultimately reduced tolerance to alkali stress. In addition, silenced plants displayed reduced stomatal aperture, cellular deformation, and irregular intercellular breaks in the leaf epidermis. In summary, these findings suggest that GhADT5 may enhance resistance to alkali stress by regulating enzymatic and non-enzymatic antioxidant systems. This study highlights the role of GhADT5 under alkali stress and provides novel insights for breeding cotton varieties with improved stress tolerance.

Cadmium (Cd2+) contamination threatens plant viability and human health by disrupting cellular homeostasis and metabolic processes. Investigating the molecular mechanism underlying Cd2+ tolerance in plants is necessary to remediate Cd2+-contaminated soil. This study presents an integrated physiological, metabolomic, and transcriptomic analysis of the roots, stems, and leaves in response to Cd2+ stress. The study found that Cd2+ accumulation was significantly lower in Cd2+-tolerant cotton. Under 4 mM Cd2+ stress, the Cd2+ content in cotton increased significantly, accompanied by elevated levels of malondialdehyde (MDA), proline (Pro), and hydrogen peroxide (H2O2), as well as noticeable damage to the cellular ultrastructure. Metabolomic profiling analysis revealed that Cd2+ stress significantly affected the distribution of lipids, amino acids, and organic acids in different tissues. The metabolic pathways of alanine, aspartate, and glutamate are closely associated with Cd2+ stress, and the induced elevation of GABA levels plays a crucial role in cotton’s adaptation to Cd2+ stress. Exogenous GABA application significantly enhances Cd2+ tolerance in cotton by reducing Cd2+ accumulation and decreasing the content of Pro, MDA, and H2O2. Silencing of the γ-aminobutyric acid (GABA) biosynthetic gene glutamate decarboxylase (GhGAD6) resulted in increased Cd2+ sensitivity, demonstrating that GABA alleviates Cd2+ toxicity in cotton through reducing Cd2+ accumulation and scavenging ROS. These findings elucidate the molecular basis of Cd2+ stress tolerance in plants and provide a key for the effective strategy of enhancing Cd2+ tolerance in cotton.

BIN1 , the second strongest GWAS risk factor for late-onset Alzheimer’s disease (AD), encodes a nucleocytoplasmic adaptor protein that plays many roles in multiple tissue and cell types. It is known that BIN1 can directly bind to tau in vitro , and neuronal BIN1 expression decreases in patients with AD. Accumulation of intracellular hyperphosphorylated tau is a hallmark pathogenic feature of AD and related tauopathies. Neuronal BIN1 localizes to presynaptic terminals and influences excitatory synaptic transmission, however, the molecular events underpinning neuronal BIN1 function in disease progression i n vivo has remained unclear. To mimic the decrease in neuronal BIN1 expression in Alzheimer’s patients, we recently generated and characterized tau pathology in novel conditional Bin1 knock-out (tau P301S transgenic mice lacking BIN1 expression in the forebrain excitatory neurons; PS19: Bin1 -cKO) and examined tau pathogenesis. In order to establish a direct connection between neuronal BIN1 and the degree of neurofibrillary tangle pathology, we injected tau seeds into the brains of PS19: Bin1 -cKO mice and investigated tau propagation and spreading. We observed that the loss of excitatory neuronal BIN1 expression attenuates tau accumulation and neurodegeneration selectively in the hippocampus, entorhinal/piriform cortex, and amygdala. Furthermore, the knock-out mice had significantly reduced neuroinflammation, preservation of hippocampal synapses, and complex transcriptomic changes in the neurons and glial cells. In addition, we observed reduced brain-derived tau seed propagation from the site of injection in the hippocampus into connected cortical regions. Instead, there is an accumulation of Ser202/Thr205 phosphorylated tau and MC1 + tau in hippocampal CA1 pyramidal neurons. Thus, our findings reveal an interesting region-specificity in neuronal BIN1 regulation of tau pathogenesis and propagation. Overall, our findings reveal that excitatory neuronal BIN1 promotes region-specific tau pathogenesis and tau propagation through neuroanatomically connected brain regions. These findings add to our understanding of in vivo BIN1 function in the context of tau pathogenesis, revealing cell-autonomous and non-cell-autonomous mechanisms involved in BIN1 modulation of tau burden in AD.

Microglia play significant roles in Alzheimer’s disease (AD) pathophysiology. Current evidence suggests microglia may function in both protective and degenerative capacities, which has received little clarity from transcriptionally-characterised phenotypes uncovered from transgenic pathologies alone. BIN1 - the second-most significant risk gene for the development of late-onset AD (LOAD) - is expressed at high levels in neurons, oligodendrocytes and microglia. We examined microglial BIN1 expression and function and previously demonstrated that BIN1 regulates proinflammatory and disease-associated activation responses in microglia in vitro and in vivo (PMID 35526014). However it’s role in AD-specific pathologies is as yet unknown. We used a reverse-genetic approach to conditionally delete Bin1 in microglia of the PS19 mouse model of tauopathy. We used histology, biochemistry and RNAseq analyses to determine the effects of Bin1 -cKO on tau pathology and microglial responses. Our data demonstrate that microglial BIN1 facilitates levels of pathologically phosphorylated tau (p-tau), specifically in female PS19 mice. RNAseq analysis identified cell -autonomous and non-autonomous effects for microglial BIN1 during tau pathogenesis in the PS19 model. Weighted gene co-expression analyses revealed complex networks of genes regulated by microglial gene expression during tau pathogenesis. We also identified gene networks correlated with levels of formic acid-soluble p-tau, irrespective of microglial Bin1 gene manipulation. These gene networks offer novel insight into microglial genes involved in responses to tau pathology, and the potential impact of BIN1 as a LOAD risk gene.

Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) are a class of highly conserved serine/threonine-protein kinases in eukaryotes. They participate in the typical MAPK cascade system and various signal transduction pathways regulating biological processes in plants, during stressful conditions. To date, genome-wide identification of MAP4Ks in cotton has not been reported. In this study, 77 MAP4K genes were identified in four Gossypium species. Protein characteristics, gene structures, conserved motifs and gene expression analysis were carried out. Genome-wide or fragment duplication has played an important role in the expansion of the GhMAP4K. Promoter cis-acting elements and expression patterns indicated that GhMAP4Ks are related to plant hormones (ABA, MeJA, GA, IAA, SA) and various stresses (drought, hypothermia and wound). Overexpressing GhMAP4K13 in Arabidopsis showed higher stem length in response to drought and salt stress. The wilting degree in virus-induced GhMAP4K13 gene silenced plants was substantially greater than wild type plants under drought and salt stress. Transcriptomic analysis showed that most differentially expressed genes were involved in the MAPK signaling pathway, carbon metabolism and porphyrin metabolism. Additionally, transgenic Arabidopsis and VIGS cotton showed that GhMAP4K13 was positively responsive to drought and salt stresses. This study will play an important role in understanding the function of the MAP4K gene family in response to abiotic stress in cotton.

Silicon plays a dual role in plant growth. However, excessive application of sodium silicate (Na2SiO3), commonly utilised Si-based fertiliser, can adversely affect plant development. In the present study, a pretreatment concentration of 20 mM Na2SiO3 was used to investigate its effect on the growth and development of cotton during the germination and three-leaf stages. The radicle necrosis rates of 84 upland cotton genotypes were assessed. RNA-seq analysis revealed 9098 differentially expressed genes (DEGs). Gene Ontology (GO) analysis revealed the enrichment of DEGs associated with various stimuli and stress responses. Concurrently, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis identified the regulation of DEGs linked to the plant MAPK signalling pathway, lipid metabolism-related pathways, carotenoid biosynthesis pathway, plant hormone signal transduction, and secondary metabolite biosynthesis under Na2SiO3 stress. Notably, key genes within the carotenoid biosynthesis pathway were upregulated, suggesting that this pathway plays a significant role in mitigating oxidative damage. This study demonstrates that under saline-alkali stress conditions, excessive exogenous application of Na2SiO3 exacerbates toxicity in cotton plants. These findings provide a theoretical foundation for understanding the mechanisms underlying the response of cotton to Na2SiO3 stress and inform the judicious use of Si fertilisers.

Abnormal accumulation of hyperphosphorylated tau in neurofibrillary tangles is a hallmark of neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia. In AD, tangle pathology characteristically develops in brain regions with heightened vulnerability, such as the entorhinal cortex and hippocampus. Emerging evidence implicates mitochondrial dysfunction and metabolic disturbances in AD progression, yet the relationship between regional vulnerability and pretangle tau-driven transcriptomic changes remains unclear. To address this critical gap, we utilized the tau P301S transgenic mouse model (PS19 line), which develops tau inclusions. Using spatial transcriptomic profiling across the hippocampal and cortical regions at selected disease stages, we captured spatiotemporal transcriptional responses to tauopathy. Our findings reveal that disease-associated microglia and astrocyte phenotypes emerge concurrently with phosphorylated tau accumulation across multiple brain regions. Intriguingly, the expression of Pgk1, a hub gene of the glycolytic pathway, was upregulated along with other metabolic pathway genes in the CA3 region at 2 months of age, preceding the onset of detectable tau tangle pathology, and correlated with tangle severity, suggesting early metabolic dysregulation in vulnerable regions. Further analysis of differentially expressed genes uncovered region-specific and temporally dynamic transcriptional patterns in the cortex and hippocampus. Early saturable alterations in ATP metabolic processes, glycolysis, and oxidative phosphorylation appeared in the hippocampus at two months of age, with delayed engagement in the cortical regions. These results underscore the contributions of metabolic stress and glial activation to tauopathy and regional vulnerability, highlighting spatial transcriptomics as a powerful tool for uncovering region-specific molecular insights into disease mechanisms.