Mango fruits undergo various biochemical changes and ripen rapidly after harvest. This study evaluated the effects of salicylic acid (SA) and hot water treatment (HWT) on the maintenance of postharvest quality of mango cv. Dashehari under ambient storage conditions. Physiologically mature fruits were subjected to different treatments, including SA 1 mM, SA 2 mM, HWT, HWT + SA 1 mM, HWT + SA 2 mM, and distilled water (control). Compared with untreated fruits, the combined treatments HWT + SA 1 mM and HWT + SA 2 mM significantly reduced weight loss, decay incidence, electrolyte leakage, reactive oxygen species accumulation, and activities of fruit softening enzymes, while better maintaining fruit firmness, soluble solids content, titratable acidity, and ascorbic acid during storage. The responses of these two combined treatments were statistically comparable for most quality attributes; however, fruits treated with HWT + SA 1 mM exhibited significantly lower malondialdehyde content after storage. These findings suggest that the integration of SA with HWT is an effective strategy for delaying ripening and preserving the postharvest biochemical quality of mango fruits under ambient conditions.
Tumor hypoxia provides a unique biochemical cue for the development of microenvironment-responsive drug delivery systems with enhanced selectivity and therapeutic efficacy. Herein, we report a hypoxia-responsive supramolecular albumin conjugate (MAC) constructed by covalently grafting an azo-functionalized calixarene derivative (SAC4A) onto bovine serum albumin (BSA). In this design, SAC4A serves as both a supramolecular host for drug encapsulation and a reductive "molecular switch" that enables hypoxia-triggered activation, while albumin provides a biocompatible and tumor-affinitive transport scaffold. MAC preserves the strong host-guest recognition capability of SAC4A toward a wide range of chemotherapeutic agents and fluorescent probes, with binding constants in the 104-106 M-1 range. Rigorous global fitting and residual analysis confirm the reliability of the binding models. Under reductive conditions, the azo bonds in SAC4A are efficiently cleaved, leading to pronounced structural transformation, surface charge reversal, and controllable dissociation of guest molecules. Both chemical (sodium dithionite, SDT) and enzymatic (DT-diaphorase (NQO1)/NADPH) reduction experiments demonstrate that MAC exhibits high sensitivity and selectivity toward hypoxic environments. Using mitomycin C (MMC) as a model drug, we show that MAC enables precise hypoxia-triggered intracellular drug release, efficient lysosomal escape, and enhanced mitochondrial dysfunction. In vitro cytotoxicity assays reveal that MMC-MAC displays markedly amplified antitumor activity under hypoxic conditions, whereas free MMC shows no oxygen dependence, indicating that hypoxia selectivity is introduced by the carrier rather than the drug itself. In vivo studies further demonstrate that MMC-MAC achieves rapid and sustained tumor accumulation, significantly suppresses tumor growth, induces robust apoptosis, alleviates tumor hypoxia, and exhibits improved systemic biosafety compared with free MMC. This work establishes a supramolecular-biological hybrid strategy that integrates host-guest chemistry, albumin-based delivery, and hypoxia-responsive activation into a single platform, providing a modular and generalizable paradigm for constructing tumor microenvironment-selective nanomedicines with enhanced therapeutic index.
Chronic stress is a major risk factor for depression and disrupts myelin integrity in brain regions involved in emotional regulation. Although intermittent fasting (IF) improves metabolic and inflammatory states, its effects on stress-induced depression and demyelination remain unclear. Here, we investigated whether IF alleviates depression-like behaviors and myelin deficits in mice exposed to chronic restraint stress (CRS) and whether these effects involve modulation of the gut microbiota. Adult male C57BL/6 J mice underwent 14 days of CRS while maintained on either an ad libitum (AL) diet or an IF regimen. CRS induced robust depression-like phenotypes-characterized by increased immobility in the forced swimming test and reduced sucrose preference-without affecting locomotor activity, whereas IF significantly attenuated these behavioral abnormalities. Black-Gold II staining and myelin basic protein (MBP) immunofluorescence revealed marked demyelination in the corpus callosum, medial prefrontal cortex, and hippocampus of CRS mice, which was substantially reversed by IF. 16S rRNA sequencing demonstrated that IF reshaped gut microbial diversity and community composition under stress. Species-level analyses identified Prevotellamassilia timonensis and Muricoprocola aceti as positively associated with myelin integrity and behavioral improvement, whereas Anaeroplasma abactoclasticum showed negative associations. Functional pathway prediction further indicated that IF partially normalized stress-induced alterations in microbial metabolic functions. Collectively, these findings demonstrate that IF mitigates depression-like behaviors and preserves myelin integrity in CRS-exposed mice, potentially through gut microbiota-mediated mechanisms. IF may therefore represent a promising non-pharmacological strategy for alleviating stress-related neurobiological dysfunction.
Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration and chronic neuroinflammation. Increasing evidence suggests that microglial ferroptosis plays a critical role in the pathogenesis of PD. Troxerutin (TRX), a natural flavonoid derivative with potent antioxidant and anti-inflammatory activities, has shown neuroprotective potential; however, its effects on microglial ferroptosis and the underlying mechanisms in PD remain unclear. Here, we investigated the effects of TRX in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and MPP+-stimulated BV2 cells. TRX improves motor performance, preserves nigrostriatal dopaminergic neurons, and attenuates microglial activation and pro-inflammatory cytokine expression in vivo. In BV2 cells, TRX attenuated ferroptosis-related changes, reduced lipid reactive oxygen species accumulation, and restored GPX4 and SLC7A11 expression. Furthermore, treatment with erastin, a classical ferroptosis inducer, reactivates ferroptosis-related responses and reverses the anti-inflammatory effects of TRX, linking ferroptotic stress to microglial inflammatory activation. Mechanistically, the cellular thermal shift assay supported target engagement between TRX and NOX4. TRX enhances K48-linked polyubiquitination of NOX4 and promotes its proteasomal degradation, which restores Nrf2 nuclear accumulation and activates downstream antioxidant responses. These results reveal that TRX alleviates ferroptosis-related neuroinflammation by modulating the microglial NOX4/Nrf2 axis in PD.
Ammonium (NH4+) and nitrite (NO2-) are key indicators of surface water quality, as their concentrations can change rapidly and even minor increases may threaten ecosystems and public health at trace levels. Although laboratory UV-vis spectrophotometry offers high accuracy, it is not suitable for on-site monitoring. Existing hand-held devices enable field testing but rarely integrate digitalization, online data storage, or geospatial mapping. In addition, portable colorimetric sensors often suffer from limited trace-level sensitivity and reduced accuracy over wide concentration ranges when single-regime calibration is used. In this study, we developed a simple, portable RGB colorimetric sensing device prototype combining indophenol-salicylate (NH4+) and Griess (NO2-) chemistries with smartphone-based readout using a compact TCS34725 sensor module. To address conventional calibration limitations, a machine learning-assisted dual-regime calibration (ML-assisted DRC) model based on segmented linear regression with a dummy-variable strategy was introduced. This approach preserves high low-level sensitivity while activating multivariate RGB corrections at higher concentrations, resolving the sensitivity-accuracy trade-off. Reliable quantification was achieved over an extended range, with LODs of 0.0221 mg·L-1 (NH4+) and 0.0096 mg·L-1 (NO2-), comparable to UV-vis results. The models showed excellent linearity (R2 ≥ 0.998), AOAC-consistent recoveries, good repeatability, and strong agreement with UV-vis measurements in real surface waters. Thus, the framework bridges low-cost portable sensing and laboratory-grade quantitative analysis for high-frequency field monitoring of inorganic nitrogen.
We systematically investigate PM6:Y12 bulk-heterojunction solar cells with donor fractions ranging from 1% to 45%, linking morphology, charge transport, and recombination to device performance. Complementary structural and spectroscopic methods reveal that a percolating PM6 network forms even at below 5% donor content, with lamellar stacking and vertical composition gradients that do not hinder the charge extraction. The reduction of the effective active layer conductivity toward low donor fractions obeys a three-dimensional percolation model, indicating that charge transport is governed by network topology rather without a pronounced percolation threshold. A transition from nongeminate Langevin recombination to a dispersive Smoluchowski-type loss occurs below 5% donor fraction. The latter regime is also nongeminate, i.e., pertains to recombination of the total charge carrier density. Correspondingly, we observe that the Langevin reduction in the higher donor fractions - mostly dominated by redissociation of electron-hole pairs after encounter - changes toward low donor fractions: in these cases, the nongeminate loss rate exceeds the prediction of the Langevin model. This regime coincides with increasing transport resistance due to topology-limited hole conduction, leading to reduced fill factors despite a high retained charge-generation efficiency. Our results demonstrate that strong donor dilution preserves photogeneration if a continuous donor network is maintained, and unveil how topology-controlled transport and non-Langevin recombination jointly define the performance limits of donor-diluted organic solar blends.
Spatial transcriptomics technologies profile gene expression within its native spatial context, offering new insights into tissue organization and disease. However, accurate spatial domain identification remains challenging due to local oversmoothing, impaired topological fidelity, and insufficient modeling of global semantic structures. To address these challenges, we propose SpaVGMC, a unified representation learning framework that jointly models structural dependencies and transcriptional semantics. The framework integrates structured variational representation learning, structural information alignment, and semantic alignment, allowing the capture of probabilistic uncertainty, multiscale spatial dependencies, and global transcriptional organization. Specifically, SpaVGMC formulates representation learning as a structured variational inference process with context-aware message-passing. A structural information alignment mechanism preserves topological fidelity by aligning latent embeddings with the spatial graph via mutual information at both the edge and neighborhood levels. In addition, a semantic alignment mechanism organizes representations according to transcriptional similarity through distribution-aware contrastive learning without requiring data augmentation. By jointly modeling representations, structures, and semantics, SpaVGMC learns robust, discriminative, and biologically interpretable embeddings. Extensive experiments across diverse spatial transcriptomics data sets demonstrate that SpaVGMC consistently outperforms state-of-the-art methods in spatial domain identification, showing improved agreement with tissue structures and enhanced detection of fine-grained subdomains. Collectively, these results establish SpaVGMC as a robust and scalable framework for spatial omics analysis.
Liquid-liquid phase separation (LLPS) generates dynamic coacervate compartments whose fusion and dissolution behaviors are difficult to control without perturbing bulk conditions. Here, we introduce an interfacial polydopamine (pDA) coating strategy that programs the stability and morphological evolution of poly-L-lysine/ATP (pLys/ATP) coacervates. Dopamine oxidation with potassium permanganate (KMnO4) at the droplet interface yields a thin pDA shell that initially promotes droplet-droplet adhesion and rapid coalescence but subsequently suppresses further coarsening and preserves the size distribution over extended incubation. Microscopic analysis reveals that this coating primarily restructures the interface while retaining a fluid interior, enabling long-lived yet internally dynamic protocell-like assemblies. We further show that the pDA shell can be mechanically actuated by a small bifunctional diamine, which triggers fast centripetal contraction and expulsion of encapsulated contents, whereas a longer PEG-based crosslinker does not elicit such behavior. This chemically simple, two-input scheme establishes a generalizable route to arrest and reactivate LLPS-derived compartments, offering a versatile design element for systems chemistry, protocell models, and LLPS-guided delivery platforms.
The blood-brain barrier (BBB) is a highly specialized interface that preserves neural homeostasis but severely limits the entry of therapeutic agents, posing a major challenge for central nervous system (CNS) drug development. While invasive approaches such as intracerebral injection and focused ultrasound can transiently bypass the barrier, their complexity and safety concerns restrict clinical applicability, particularly in chronic conditions. Non-invasive strategies that exploit endogenous transport mechanisms-carrier-mediated uptake, adsorptive-mediated transcytosis (AMT), and receptor-mediated transcytosis (RMT)-may offer a safer solution. Within this framework, brain shuttles have emerged as molecular vectors designed to cooperate with endothelial biology rather than disrupt it. These include antibodies, proteins, small molecules, and peptides, each with distinct advantages and limitations. Among them, peptides stand out for their versatility, manufacturability, and chemical tunability. Advances in solid-phase synthesis, non-natural modifications, and rational design have enabled peptides to achieve a balance between uptake efficiency and release beyond the endothelium. Their modular nature supports conjugation to diverse payloads, including small molecules, proteins, nucleic acids, and nanoparticles, while maintaining functional integrity. Peptide shuttles also offer broader receptor targeting and compatibility with multiple administration routes, positioning them as a cornerstone of future CNS delivery platforms. This chapter provides a mechanistic overview of the BBB, reviews invasive and non-invasive delivery strategies, and introduces the concept and evolution of brain shuttle peptides. It sets the stage for subsequent discussions on discovery methodologies, chemical optimization, validation models, and translational pathways, highlighting the promise of peptide-enabled systems to transform therapeutic access to the brain.
The glycine N-methyltransferase (GNMT) reaction was examined using an integrated workflow combining molecular dynamics (MD), quantum mechanical (QM) cluster calculations, and machine learning (ML) analysis. Instead of relying on a single crystal-like conformation, multiple MD simulations were used to sample diverse reactant (SAM + glycine bound to GNMT) and product (SAH + sarcosine bound to GNMT) state geometries for QM cluster modeling. Across more than 150 QM-cluster models constructed by the Residue Interaction Network ResidUe Selector (RINRUS) from selected MD frames with and without explicit waters, the computed activation and reaction free energies span broad ranges (7 to 25 kcal mol-1 and -36 to +3 kcal mol-1), demonstrating a strong dependence on the initial MD conformation. Product-state consistently yields lower reaction barriers, while explicit water introduces only small shifts in energetics and preserves the relative ordering among frames. The two-coordinate potential energy surface (PES) offers only limited insight and cannot fully account for the observed energetic variability. These QM-cluster models were further analyzed using machine-learning methods to identify structural descriptors that correlate with the observed energy variations and provide insight into their structural origin. ML models trained on multiple feature representations show that the donor-methyl-acceptor distances are the most informative and yield the strongest predictive accuracy, while higher dimensional solvent- or residue-based features contribute comparatively little. Overall, the results highlight the importance of conformational sampling for reliable QM-cluster energetics and point toward more expressive structure-to-property representations for analyzing enzymatic reactions.
Testing patients with non-small cell lung cancer for actionable variants is essential for guiding treatment decisions in accordance with established cancer care guidelines, though limited quantity and quality of tumor tissue often leaves insufficient material for comprehensive testing. Cytopathology specimens obtained through minimally invasive techniques are a potential source of diagnostic material for genomic profiling, though typically challenging to analyze. A total of 85 DNA or total nucleic acid non-small cell lung cancer samples derived from 45 fine-needle aspirate rinse or pleural fluid samples from the Hospital of the University of Pennsylvania archive were tested using the Aspyre Clinical Test for Lung (Tissue) in Biofidelity's CAP/CLIA laboratory. All samples were previously characterized by the Oncomine Precision Assay Genexus assay (the orthogonal reference method). Eighty-four of 85 passed Aspyre Lung quality control, one failed. Twenty-six samples were positive for variants in the Aspyre Lung panel: 17 for single nucleotide variants (KRAS, EGFR), three for EGFR insertions/deletions, two for MET exon 14 skipping, and five for gene fusions. Eighty-two of 85 samples were run at standard input levels; three of 85 were run at low input but passed Aspyre Lung controls and include one EGFR exon 20 insertion variant-positive. All results were concordant between methods. Positive Percent Agreement and Negative Percent Agreement were 100%. Aspyre Clinical Test for Lung performs effectively on samples derived from fine needle aspirate rinses and pleural fluid. Using these cytology-based specimens for biomarker testing enables pathologists to perform simplified genomic profiling while preserving valuable tissue specimens, potentially reducing the need for additional invasive procedures.
l-Cysteine is a high-value sulfur-containing amino acid indispensable for industrial and medical applications. However, the production of l-cysteine is limited by the low sulfur assimilation efficiency and complex regulatory networks of native pathways. Here, we report the design and construction of a non-native biosynthetic pathway for l-cysteine in Escherichia coli, utilizing 3-mercaptopropionic acid as a starting substrate. Inspired by the 2-methylcitrate cycle, this pathway introduces sulfur via a thiol-functionalized carbon backbone, bypassing the energy-intensive sulfur assimilation pathway and establishing a self-sustaining C4 cycle to preserve central carbon flux. We systematically screened enzymes for the pathway, identifying a Salmonella typhimurium 2-methylcitrate synthase (StPrpC) capable of condensing the thiol-functionalized substrate (3-mercaptopropionyl-CoA), and we enhanced its specificity toward the thio-substrate through structure-guided engineering. The resulting variant, StPrpCD325 K, exhibited a 17.7% reduction in Km (from 23.7 to 19.5 mM) and a 33.1% increase in kcat (from 0.052 to 0.069 s-1), which significantly improved catalytic efficiency toward thio-substrate. Whole-cell biocatalysis using the engineered strain produced 0.63 g/L of l-cysteine with a yield of 0.59 g/g after metabolic optimization, including the deletion of degradation pathways and overexpression of transporters. This work demonstrates an atom-economical strategy for amino acid production and offers a promising synthetic route to alleviate the constraints of traditional fermentation processes.
Obesity is a major risk factor for Type 2 diabetes mellitus (T2DM), with substantial genetic determinants. The fat mass and obesity-associated (FTO) gene rs9939609 polymorphism has been consistently associated with obesity risk across diverse populations. This case-control study is aimed at investigating FTO rs9939609 and its associations with obesity risk and glycemic parameters in a Syrian population for the first time. A total of 97 participants (50 obese cases and 47 nonobese controls) were recruited from two university hospitals in Damascus, Syria. Among obese participants, 25 had T2DM, including 11 newly diagnosed, treatment-naïve patients. Genotyping was performed using PCR-RFLP, and associations were assessed using logistic and linear regression analyses. The minor allele frequency was significantly higher in obese cases compared to controls (36.0% vs. 20.21%, p = 0.015). Under the dominant genetic model, risk allele carriers exhibited a 3.76-fold increased obesity risk (95% CI: 1.62-8.74, p = 0.002). This association was preserved when the analysis was restricted to nondiabetic obese participants. No significant associations were observed between genotypes and anthropometric parameters within the obese group. Among obese nondiabetic individuals, A-allele carriers showed significantly elevated fasting blood glucose (p = 0.004) and HbA1c levels (p = 0.034) compared to TT homozygotes; these associations remained significant after adjusting for BMI, WC, and WHR in separate models. A pooled analysis of all obese T2DM patients (n = 25) revealed significantly higher HbA1c in A-allele carriers (p = 0.027), with exploratory subgroup analyses suggesting a stronger association in treatment-naïve patients, though these findings require confirmation in larger studies. Our study provides the first evidence that FTO rs9939609 is significantly associated with obesity risk in the Syrian population and may contribute to early glycemic dysregulation in genetically susceptible obese individuals. Subgroup findings warrant validation in larger cohorts.
Disseminating the details and processes involved in a participatory-based selection, adaptation, and implementation of evidence-based interventions (EBI) in support of refugee families in resettlement is paramount for an equitable, trauma-informed, public health approach to promoting family health and resilience. We describe the participatory cultural adaptation of EBIs to establish a multigenerational mindfulness-based and resilience enhancing family program for war-affected families with adolescent youth. The study team integrated conceptual and pragmatic approaches to the adaptation and implementation of an intervention program composed of two well-supported interventions to target intergenerational trauma in war-affected refugee families. The integration and adaptation of the program described in this report was conducted in partnership with members of the Karen refugee community (originating from Burma in Southeast Asia and resettled in the United States). Based on three adaptation models and a FRAME-IS reporting structure, the process produced a focused set of contextual, content, and implementation adaptations. Most modifications were contextual, such as considering culturally responsive familial dynamics and selecting community-preferred delivery settings and facilitation. Content changes were limited and involved a careful examination of word choice and phrasing, and emphasized emotion-regulation and parenting strategies aligned with existing community practices. Implementation adaptations refined facilitator guidance and strengthened Community Health Worker Interventionist training. Iterative input from community experts enhanced relevance and feasibility while preserving the core intervention elements. Engaging members of a Community Leadership Board and Community Health Worker Interventionists in training, practice and feedback sessions informed the adaptation of evidence-supported interventions into a mindfulness-based family intervention to disrupt intergenerational trauma transmission in war-affected Karen families. We provide transparent intervention and program development documentation and guidance for other teams considering adaptations of health and resilience oriented EBIs for refugee families. The adapted program has the potential to be translated to other refugee populations.
This paper examines the use of praise in the care of people living with dementia (PLWD) in the acute hospital. Perceptions of praise vary. 'Excessive' praise is typically classified as elderspeak, with attendant debates over whether this is patronising and/or infantilising. However, some sources suggest praise may serve useful structural functions in conversation, or should be used for encouragement of PLWD, reflecting the pervasive person-centred care ideology of supporting PLWD's existing abilities. Conversation analysis was used to examine 85 video and audio recordings of interactions involving PLWD and healthcare professionals in acute UK hospital wards. Findings suggest that although context sensitive, praise: 1) works as a supportive action to aid orientation to tasks and activities; and 2) has implications for the preservation of agency and face. Findings demonstrate the importance of sensitivity to individual interactional circumstances and have implications for healthcare practice, training and wider care of PLWD.
Acute central nervous system (CNS) injuries impose a significant global burden. Microsurgical decompression effectively stabilizes primary anatomy. However, it often fails to stop the complex biochemical cascades of secondary neurodegeneration. There is a critical need to bridge the gap between anatomical preservation and functional recovery. Strong preclinical evidence indicates that delayed bioenergetic failure within the injury microenvironment heavily dictates long-term outcomes. We synthesize the ARFE (autophagy-reactive oxygen species-ferroptosis-edema) axis as a mechanistic framework delineating the pathological continuum from subcellular failure to macroscopic tissue edema. In this irreversible cascade, adenosine triphosphate depletion blocks autophagic flux, forcing ferritinophagy-driven iron release and lipid peroxidation, while succinate accumulation locks microglia in metabolic collapse. A translational gap persists because mechanical hematoma evacuation does not inherently reverse the metabolic cascades driving secondary injury. Current single-target modalities fail because they do not account for the evolving metabolic microenvironment, leading to unchecked inflammation and cell death despite successful surgical intervention. We propose a paradigm shift from single-target modalities to "spatiotemporal metabolic engineering." This strategy synchronizes interventions with metabolic logic. Hyperacute treatments focus on redox containment to neutralize iron. Acute phases prioritize immune-metabolic reprogramming for inflammation. Finally, subacute stages aim for bioenergetic reconstruction to support axonal regrowth. Antioxid. Redox Signal. 00, 000-000.
Artificial intelligence (AI) is transforming cardiology across ECG interpretation, imaging, risk prediction, remote monitoring, and workflow automation. Cardiologists need governance models that preserve clinical judgment, reduce harm, and reflect Indian realities. This narrative reviews policy documents (2018-February 2026) spanning the EU AI Act, WHO, OECD, ICMR, FDA GMLP, FUTURE-AI, CHAI, Joint Commission, and MLOps frameworks, alongside medico-legal, automation-bias, fairness, and cardiology-AI implementation studies. We compared these instruments in human-in-the-loop (HITL) oversight and identify gaps in high-risk domains such as echocardiography AI, CT-FFR, cath-lab decision support, and wearable-based rhythm monitoring in India. We propose practical HITL governance priorities for cardiology: local validation, calibrated alerting, explicit override pathways, bias surveillance, medico-legal accountability, and governance structures embedded within everyday cardiac workflows. Realizing meaningful human-in-the-loop oversight requires investment in governance infrastructure, workforce development, transparent performance metrics, and learning systems treating AI-related incidents as opportunities for continuous improvement.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation in the colon. Maintaining intestinal mucosal barrier integrity is a fundamental therapeutic objective in managing UC. Swertiamarin (STM) exhibits diverse biological activities and holds promise for the treatment of UC. Autophagy is a critical mechanism that safeguards the integrity of the intestinal mucosal barrier, yet it remains uncertain whether STM ameliorates UC and modulates autophagy to preserve this barrier. An acute colitis mouse model was induced by administering dextran sulfate sodium (DSS) in drinking water. The protective effects of different concentrations of STM against colitis were evaluated by monitoring body weight changes, disease activity index (DAI), colon length, spleen index, histological score, and AB-PAS staining. Colonic inflammation severity was assessed using ELISA and qPCR, while intestinal permeability was evaluated through FITC-dextran permeability assays, Western blotting, and immunohistochemistry. Caco-2/HIEC-6 cell monolayers were treated with 2% DSS, and the effects of STM on cellular inflammation and barrier function were assessed using Western blotting, qPCR, and a FITC-dextran permeability assay. Potential mechanisms and targets of STM for alleviating UC through intestinal epithelial cells were predicted using online databases and network pharmacology analysis. These predictions were subsequently validated through Western blotting. To elucidate the roles of autophagy and the PI3K/AKT/mTOR pathway in STM's protective effects, functional rescue experiments were conducted. These experiments utilized the autophagy inhibitor 3-methyladenine (3-MA) and the PI3K-specific agonist 740YP. Autophagic structures were directly visualized by transmission electron microscopy (TEM). STM dose-dependently alleviated DSS-induced colitis in mice. It reversed body weight loss, improved the DAI score, and inhibited colon shortening. Treatment also reduced the spleen index, attenuated colonic pathological damage, increased goblet cell counts, suppressed cytokine production, and protected epithelial barrier function. In vitro experiments demonstrated that STM effectively protected the intestinal epithelial barrier and mitigated inflammatory responses. Network pharmacology analysis revealed that STM safeguards the intestinal barrier by promoting intestinal epithelial cell autophagy and mitigating UC through the PI3K/AKT/mTOR-signaling pathway. DSS treatment elevated p62 expression and suppressed LC3-II levels in colonic tissues, suggesting impaired autophagy. Conversely, STM induced autophagy and inhibited the PI3K/AKT/mTOR-signaling pathway in both in vivo and in vitro models. TEM revealed a significantly higher number of autophagosomes in the STM-treated group. Treatment with the autophagy inhibitor 3-MA significantly abrogated the protective effects of STM. Treatment with the PI3K agonist 740YP significantly increased phosphorylation levels of PI3K, AKT, and mTOR. This was accompanied by p62 accumulation, decreased LC3-II expression, and reduced tight junction protein (ZO-1 and Occludin) levels, indicating that PI3K activation counteracts the protective effects of STM on autophagy and barrier function. STM mitigates colonic inflammation in DSS-induced colitis mice by reducing pro-inflammatory cytokine levels. This effect is likely mediated through enhanced autophagy, achieved by inhibiting the PI3K/AKT/mTOR pathway, ultimately ameliorating intestinal barrier dysfunction.
The swelling of the Li metal anode and its adverse impacts have barred lithium metal batteries (LMBs) from practical applications. Owing to insufficient recognition of the energy density-stress trade-off, no viable solution has emerged to halt their expansion or diminish their internal stress accumulation (SA) while preserving their exceptional energy density. We proposed principle-based criteria to guide the development of high-energy and low-swelling LMBs by defining the boundary parameters of strain-buffering techniques. Taking a typical space-adaptive buffering (SAB) layer as an example, we have materialized this criterion and verified its scientific validity and forward-looking nature, effectively reducing SA and mitigating the local stress concentration (SC). As a result, the Ah-level NCM9 (LiNixCoyMn1-x-yO2, x ≥ 0.9)||SAB-Cu pouch cell prototype with the high bare-cell energy densities of 465 Wh/kg and 1330 Wh/L exhibits the uniform stress distribution and low SC (extreme difference in local pressure<2 MPa), avoiding the failure of Li dendrite puncture. Furthermore, the Ah-level NCM811(Li1.2Ni0.8Co0.1Mn0.1O2)||SAB-Cu pouch cell demonstrates a perfect trade-off among energy densities (418 Wh/kg and 1061 Wh/L), cycle life (164 cycles with 77% capacity retention), SA (<2 MPa), and swelling ratio (3.6%), underscoring the practical feasibility of the SAB-AF-LMB.
Darigabat is a selective γ-aminobutyric acid type A (GABA-A) receptor positive allosteric modulator targeting α2, α3, and α5 subunits, developed to preserve anxiolytic and anticonvulsant effects while reducing α1-mediated sedation and cognitive adverse events. Subtype-selective modulation represents a strategy to improve the safety of GABAergic therapies. A literature search in PubMed, Embase, CENTRAL, and ClinicalTrials.gov up to June 2025 identified 20 preclinical and clinical studies. Darigabat demonstrated dose-proportional pharmacokinetics, high brain penetration, and overall acceptable tolerability, with dose-dependent central nervous system adverse effects at higher exposures. Preclinical models showed anticonvulsant and anxiolytic activity. However, clinical trials reported heterogeneous and inconsistent efficacy across indications. Darigabat supports the feasibility of subtype-selective GABA-A modulation. Early-phase studies in healthy volunteers suggested improved acute tolerability compared with nonselective benzodiazepines. In contrast, repeated-dose studies in patients revealed dose-dependent central nervous system adverse effects, including somnolence, psychomotor slowing, and cognitive impairment, indicating that α1-sparing reduces but does not eliminate these effects. Current evidence does not support a clear therapeutic role in chronic central nervous system disorders. Future research should focus on exposure - response relationships, identification of responsive subgroups, and biomarker integration. The ability to retain efficacy with improved safety remains uncertain.