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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.
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.
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.
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.
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.
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.
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.
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.
To evaluate the level of insight into illness in patients with schizophrenia and its associations with demographic factors, clinical symptoms, executive functions, and selected metabolic parameters. This cross-sectional study included 60 outpatients diagnosed with schizophrenia according to DSMIV criteria. Participants were divided into two groups based on the median score of the Self-Appraisal of Illness Questionnaire (SAIQ): preserved insight (n=30) and impaired insight (n=30). Positive symptoms were assessed with the Positive Symptoms Rating Scale (PSRS), negative symptoms with the Brief Negative Symptom Assessment (BNSA), executive functions with the Wisconsin Card Sorting Test (WCST) and Wechsler-Bellevue Intelligence Scale-II (WB-II) subscales. Metabolic parameters included body mass index (BMI), systolic and diastolic blood pressure, and waist circumference. Statistical analysis was performed using t-tests, ANOVA, Pearson correlation, and multiple linear regression (p<0.05). Patients with impaired insight exhibited significantly higher positive (PSRS: 28.5±4.2 vs 18.3±3.1; p<0.001) and negative symptoms (BNSA: 35.2±5.6 vs 22.1±4.0; p<0.001), poorer executive performance (WCST total score: 45.6±8.9 vs 68.4±7.2; p<0.001), higher BMI (28.7±3.4 vs 24.5±2.8; p<0.01), and elevated blood pressure values. SAIQ total score negatively correlated with positive (r=-0.62; p<0.001) and negative symptoms (r=-0.58; p<0.001), illness duration (r=-0.45; p<0.01), and positively with years of education (r=0.48; p<0.01) and WCST score (r=0.52; p<0.001). Regression analysis showed that negative symptoms (β=-0.41; p<0.001) and executive dysfunction (β=-0.35; p<0.01) were the strongest independent predictors of poor insight (R²=0.62). Impaired insight in schizophrenia is strongly associated with greater psychopathological burden, neurocognitive deficits (especially executive dysfunction), and metabolic disturbances. These findings support the implementation of integrated therapeutic strategies targeting insight, cognition, and cardiometabolic health to improve long-term outcomes.
Molybdenum carbide (Mo2C) is recognized as a promising electrocatalyst for water splitting owing to its platinum-like electronic structure. However, its practical application is severely impeded by the agglomeration of active sites, excessively strong MoH bonding, and poor resistance to oxidation and corrosion. To address these limitations, we propose a "template size control-multimetal coordination" strategy to fabricate nitrogen-doped carbon-supported CoNi-modified Mo2C hollow microspheres (CoNi@Mo2C/C). By rationally tuning the template architecture, an optimal balance between graphitic carbon and carbon defects is achieved, enabling rapid electron transport while preserving a high density of active sites. The CoNi bimetallic components were introduced to downshift the Mo d-band center, which weakened the MoH bond strength and boosted the electrocatalytic activity. Moreover, Co and Ni spontaneously form an active oxyhydroxide phase through self-oxidation, which effectively protects Mo2C from oxidative corrosion and leaching, thereby substantially improving operational stability. Among the series, the CoNi@Mo2C/C catalyst synthesized with a 500 nm polystyrene (PS) template exhibits exceptional bifunctional activity and durability in 1.0 M KOH. At a current density of 10 mA·cm-2, the catalyst delivers an overpotential of 73.2 ± 2.2 mV for the hydrogen evolution reaction (HER), 212.8 ± 2.8 mV for the oxygen evolution reaction (OER), and a full-cell voltage of 1.515 V for overall water splitting. This work not only offers critical experimental insights but also establishes a theoretical foundation for the rational design of high-performance non-precious-metal electrocatalysts.
Periarterial divestment has emerged as an artery-preserving alternative to formal arterial resection for borderline resectable and locally advanced pancreatic cancer. However, the available evidence remains limited. This study aimed to evaluate the perioperative and oncologic outcomes of periarterial divestment in pancreatic cancer. A systematic review was conducted using PubMed, Scopus, Web of Science, and the Cochrane Central Register to identify studies' data published up to March 2026. Continuous outcomes were pooled as means with 95% confidence intervals (CIs), and binary outcomes were pooled as proportions using random-effects models. Heterogeneity was assessed using the I2 statistic and the Cochrane Q test. Sensitivity analyses were performed using leave-one-out methods. All analyses were conducted in R version 4.4.2. Five retrospective observational studies comprising 474 patients were included, of whom 92.8% had locally advanced pancreatic cancer and 64.8% received neoadjuvant therapy. The pooled operative time was 333.0 minutes (95% CI: 232.6-433.4; I2 = 99%), estimated blood loss was 620.6 mL (95% CI: 292.4-948.7; I2 = 97%), and length of hospital stay was 12.4 days (95% CI: 9.1-15.6; I2 = 99%). The pooled incidence of intraabdominal infection, postoperative pancreatic fistula, postpancreatectomy hemorrhage, delayed gastric emptying, reoperation, major complications (Clavien-Dindo grade ≥ III), and 90-day mortality was 10.57%, 8.72%, 8.56%, 14.13%, 3.36%, 11.27%, and 4.18%, respectively. The pooled rates of venous resection, arterial resection, and R0 resection were 36.18%, 3.56%, and 43.33%, respectively. The pooled 1-year and 3-year disease-free survival rates were 50.42% and 17.77%, respectively, while the corresponding overall survival rates were 75.99% and 29.11%. Periarterial divestment has been applied in selected patients, with reported perioperative and oncologic outcomes across studies. However, the current evidence remains descriptive and does not allow comparative inference.
Autophagy plays a critical role in regulating inflammation, and its modulation is essential for managing inflammatory disorders such as inflammatory bowel disease (IBD). Postbiotics, derived from probiotic bacteria, have recently attracted attention for their health-promoting properties. This study evaluated the protective effects of postbiotics produced by native Limosilactobacillus spp. and Bifidobacterium spp. on inflammation through autophagy regulation. Fifteen male C57BL/6 mice were randomly assigned to three groups: control (PBS), DSS-induced colitis, and DSS plus postbiotics. Colitis was induced with 2% DSS, and postbiotics (1 × 109 CFU/mL) were administered daily for 14 days. Disease activity index, colon length, histopathology, and autophagy-related gene expression (Atg5, Atg7, Atg12, Atg13, and Beclin 1) were assessed. DSS treatment resulted in significant body weight loss, shortened colon length, increased disease activity, and higher pathological scores (p value < 0.05). In contrast, postbiotics administration mitigated these colonic damages and preserved body weight. Furthermore, postbiotics enhanced the expression of autophagy-related genes compared to the DSS group. Collectively, molecular and phenotypic findings highlight the regulatory role of native postbiotics in modulating inflammation via autophagy. These results suggest that native postbiotics may serve as a safe and effective therapeutic alternative for IBD management.
Salt-bridge conservation has traditionally been evaluated at the primary sequence level, leaving the persistence of three-dimensional interaction sites across homologous families largely unexplored. In this study, we developed a systematic family-level structural framework to redefine salt-bridge conservation based on spatial interaction sites rather than residue identity by mapping salt bridges onto unified SCOP2-aligned domain coordinates. We classified these interactions into three categories: classically conserved (CLA), nonclassically conserved (NOCLA; i.e., charge compensation), and nonconserved. This spatial definition enabled the identification of charge-swapped interactions that are invisible to standard sequence alignment. Through a comprehensive analysis of 5,679 protein families, we demonstrated that charge compensation is a recurrent and evolutionarily preserved mode of spatial salt-bridge conservation across homologous families. NOCLA was not uniformly distributed but instead showed marked structural-context dependence, being preferentially enriched in alpha and beta proteins (a/b) and concentrated in a limited subset of folds, particularly protein kinase-like, PLP-dependent transferase-like, TIM beta/alpha-barrel, and globin-like folds. To assess functional relevance, we integrated variant-effect predictors, including AlphaMissense and ESM-1v. Our results revealed that spatially conserved salt bridges exhibited significantly higher mutational sensitivity and functional constraint than nonconserved sites (CLA > NOCLA > nonconserved). Notably, highly sensitive NOCLA positions were also the most structurally concentrated, arising predominantly from a restricted set of folds, especially protein kinase-like folds, in contrast to the broader distribution of CLA and the highly dispersed pattern of nonconserved sites. Furthermore, molecular dynamics (MD) simulations coupled with MDPath-based mutual-information network analysis demonstrated that disruption of a representative NOCLA site significantly reorganizes long-range communication pathways within conserved catalytic regions of kinase domains. These findings suggest that spatially conserved salt bridges serve not only as local electrostatic stabilizers but also as critical dynamic coupling nodes within protein structures. Together, this study provides a three-dimensional family-level paradigm for analyzing electrostatic interactions in protein evolution and offers new mechanistic insights for interpreting variant effects and guiding structure-based drug design.
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Mountain lakes are highly sensitive to climatic change, yet the extent to which alpine aquatic communities respond to recent warming remains uncertain. We used a palaeolimnological approach based on analysing the remains of non-biting midge (chironomid) larvae preserved in surface sediments from 24 Swiss mountain lakes to assess species-environment relationships of chironomids and compare our results to previous, detailed survey data from similar campaigns in 1993/2002. This allowed us to determine changes in chironomid assemblages relative to lake physicochemistry and increasing temperatures over the past decades. We show that high-elevation oligo- to mesotrophic lakes generally experienced a shift towards warmer chironomid assemblages, expansion of taxa with larger thermal range, and a simultaneous reduction in cold-stenothermic taxa, consistent with rising air and water temperatures. However, 9 out of 24 lakes, mainly in the lower-elevational range, exhibited stable assemblages or, in some cases, shifts towards colder chironomid communities. This is likely related to local catchment and lake conditions such as shading, changing human activities such as pasturing or hydrological inputs from snow and ice, indicating highly individual, lake-specific responses. Environmental parameters accounting for the highest variability in the modern distribution of chironomid assemblages include variables representing lakewater organic matter content and elevation, as well as oxygen, total nitrogen, and total phosphorus concentrations, demonstrating the sensitivity of chironomid assemblages to temperature and associated limnological variables. Overall, our findings highlight that both large-scale climatic drivers and local environmental heterogeneity shape chironomid assemblages in alpine environments, and that the majority of Swiss mountain lakes are showing responses in aquatic insect communities due to increasing temperatures. We conclude that shifts in chironomid populations are expected to further increase in amplitude under continued warming in the Alps, as rising temperatures increasingly affect alpine ecosystems and progressively cross critical thermal thresholds and tipping points.
Renal ischemia-reperfusion (IR) injury increases the production of reactive oxygen species (ROS), alters tubular sodium transport, and activates tubuloglomerular feedback (TGF). Closantel is an allosteric inhibitor of the SPAK/OSR1 signaling pathway. This study investigated whether closantel mitigates IR-induced acute kidney injury (AKI) by modulating the SPAK/NKCC2 pathway, renal redox balance and hemodynamics. Male Wistar rats underwent 30 min of bilateral renal ischemia and 72 h of reperfusion. Closantel (2.5, 5, or 10 mg/kg) was administered 24 h before and after ischemia. Renal IR resulted in increased serum creatinine (~70%), albuminuria (~400%), tubulointerstitial injury score (8-fold), and fractional excretion of Na+, K+, and Cl- (by 200-450%). Cortical (Na++K+) ATPase activity decreased by 40%, while medullary activity increased by 133%. Oxidative stress markers (ROS, lipid peroxidation, NADPH oxidase) were elevated, and antioxidant defenses (SOD, catalase) were impaired. Closantel (10 mg/kg) significantly inhibited the SPAK/NKCC2 pathway, reducing protein levels of SPAK, total NKCC2, and phosphorylated NKCC2 (p-NKCC2) by ~70%. This was accompanied by normalized fractional excretion of Na+, K+, and Cl-, reflecting restored tubular reabsorptive efficiency. In the cortex, closantel induced a supraphysiological upregulation of (Na++K+)ATPase activity, whereas medullary activity was restored to Sham levels. Furthermore, closantel improved glomerular filtration rate and renal blood flow while reducing renal vascular resistance. In conclusion, closantel protects against AKI by inhibiting the SPAK/p-NKCC2 signaling axis, mitigating oxidative stress, and restoring renal reabsorptive efficiency and hemodynamics.
Chronic lung allograft dysfunction (CLAD) is characterized by fibrotic graft remodeling and limits long-term survival after pulmonary transplantation. Despite clinical evidence that myeloid cells drive conditions that increase the risk of CLAD development, contemporary immunosuppression primarily target lymphocytes. We evaluated an mTOR inhibiting nanobiologic (mTORi-NB) targeting myeloid cells and their progenitors in a semi-allogeneic mouse lung transplant model of CLAD. We found that the mTORi-NB preferentially targeted myeloid and endothelial cells (ECs) in the allografts. Brief perioperative therapy with the mTORi-NB reduced early macrophage graft infiltration and inhibited acute inflammation. In mTORi-NB-treated lung recipients, transcriptomic analysis revealed downregulation of fibrotic genes in macrophages and type I (AT1) and type II (AT2) alveolar epithelial cells, known drivers of pulmonary fibrogenesis. We also observed upregulation of anti-fibrotic genes in macrophages after treatment with mTORi-NB, as well as reduction of allograft fibrosis, associated with preservation of club and AT2 cells. Our findings suggest that myeloid-avid nanobiologics may be a promising immunosuppressive strategy for inhibiting CLAD.
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.