A single molecule carrier for ocular posterior segment diseases.

Eye drops are envisaged as the most promising non-invasive formulation for the treatment of the ocular posterior segment diseases, while it is hindered by a series of complex ocular barriers, both static and dynamic in nature. In this context, we propose a single molecule nanomedicine based on host-guest chemistry to achieve highly efficient drug delivery targeted to ocular posterior segment. Sulfonated azocalix[4]arene (SAC4A) serves as the single molecule carrier, owing the multiple features of small size (24.0 Šin length, 21.2 Šin width, 14.8 Šin height with a Van der Waals volume of 930 Å3), negative charge, hydrophilicity, loading universality and hypoxia-triggered release. As a proof-of-concept, an eye drop formed by the complexation of SAC4A with sunitinib (SUN) is prepared to treat wet age-related macular degeneration (wAMD). SAC4A successfully transports SUN to the ocular posterior segment (the amount of SUN reaching the retinal-choroid tissue in the SUN@SAC4A group was 2.47 times larger than that in the SUN group at 30 min), significantly enhancing its anti-choroidal neoangiogenesis effect of SUN to wAMD, which played a key role in the treatment. We believe that the single molecule nanomedicine paradigm is highly amenable for treating various ocular posterior segment diseases in the future.

Optimizing the combination of chemotherapeutic drugs along with radiotherapy for extranodal NK/T-cell lymphoma.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

Light-Operated Diverse Logic Gates Enabled by Modulating Time-Dependent Fluorescence of Dissipative Self-Assemblies.

Light-fueled dissipative self-assembly possesses enormous potential in the field of optical information due to controllable time-dependent optical signals, but remains a great challenge for constructing intelligent light-operated logic circuits due to the limited availability of optical signal inputs and outputs. Herein, a series of light-fueled dissipative self-assembly systems with variable optical signals are reported to realize diverse logic gates by modulating time-dependent fluorescence variations of the loaded fluorophores. Three kinds of alkyl trimethylammonium homologs are employed to co-assemble with a merocyanine-based photoinduced amphiphile separately to construct a series of dissipative self-assemblies, showing unexpectedly different fluorescence control behaviors of loaded fluorophores during light irradiation and thermal relaxation processes. The opposite monotonicity of time-dependent emission intensity is achieved just by changing the excitation wavelength. Furthermore, by varying the types of trimethylammoniums and excitation wavelengths, a robust logic system is accomplished, integrating AND, XNOR, and XOR functions, which provides an effective pathway for advancing information transmission applications.

Nesfatin-1 enhances vascular smooth muscle calcification through facilitating BMP-2 osteogenic signaling.

Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.

Using nonlinear dynamics analysis to evaluate time response of cupping therapy with different intervention timings on reducing muscle fatigue.

Background: Cupping therapy has been indicated effective in reducing muscle fatigue after 24 h based on the spectral analyses of surface electromyography (sEMG). However, there is no sufficient evidence showing changes of sEMG nonlinear indexes at more time points after cupping therapy. Furthermore, it is unclear whether the intervention timings of cupping therapy affect the recovery from muscle fatigue. The purpose of this study was to use the sEMG nonlinear analysis to assess the difference of time response of cupping therapy between different intervention timings after muscle fatigue. Materials and methods: This randomized controlled trial recruited 26 healthy volunteers. Cupping therapy (-300 mmHg pressure for 5 min by the 45 mm-diameter cup) was applied before (i.e., pre-condition) or after (i.e., post-condition) muscle fatigue induced by performing repeated biceps curls at 75% of the 10 repetitions of maximum (RM) on the non-dominant upper extremity. Subjects were randomly allocated to the pre-condition group or the post-condition group. The sEMG signals during the maximal voluntary isometric contractions (MVC) of the biceps were recorded at four time points (i.e., baseline; post 1: immediate after cupping-fatigue/fatigue-cupping interventions; post 2: 3 h after cupping-fatigue/fatigue-cupping interventions; post 3: 6 h after cupping-fatigue/fatigue-cupping interventions). Two nonlinear sEMG indexes (sample entropy, SampEn; and percent determinism based on recurrence quantification analysis, %DET) were used to evaluate the recovery from exercise-introduced muscle fatigue. The Friedman test followed by the Nemenyi test and the Mann-Whitney U test were applied in statistics. Results: The SampEn and %DET change rate did not show any significant differences at four time points in the pre-condition group. However, there were significant delayed effects instead of immediate effects on improving muscle fatigue in the post-condition group (SampEn change rate: baseline 0.0000 ± 0.0000 vs. post 2 0.1105 ± 0.2253, p < 0.05; baseline 0.0000 ± 0.0000 vs. post 3 0.0627 ± 0.4665, p < 0.05; post 1-0.0321 ± 0.2668 vs. post 3 0.0627 ± 0.4665, p < 0.05; and %DET change rate: baseline 0.0000 ± 0.0000 vs. post 2-0.1240 ± 0.1357, p < 0.01; baseline 0.0000 ± 0.0000 vs. post 3 0.0704 ± 0.6495, p < 0.05; post 1 0.0700 ± 0.3819 vs. post 3 0.0704 ± 0.6495, p < 0.05). Moreover, the SampEn change rate of the post-condition group (0.1105 ± 0.2253) was significantly higher than that of the pre-condition group (0.0006 ± 0.0634, p < 0.05) at the post 2 time point. No more significant between-groups difference was found in this study. Conclusion: This is the first study demonstrating that both the pre-condition and post-condition of cupping therapy are useful for reducing muscle fatigue. The post-condition cupping therapy can e ffectively alleviate exercise-induced muscle fatigue and there is a significant delayed effect, especially 3 h after the interventions. Although the pre-condition cupping therapy can not significantly enhance muscle manifestations, it can recover muscles into a non-fatigued state.

Dairy farm waste: A potential reservoir of diverse antibiotic resistance and virulence genes in aminoglycoside- and beta-lactam-resistant Escherichia coli in Gansu Province, China.

Aminoglycosides (AGs) and beta-lactams are the most commonly used antimicrobials in animal settings, particularly on dairy farms. Dairy farm waste is an important reservoir of antibiotic resistance genes (ARGs) and virulence genes (VGs) in environmental Escherichia coli, which is an important indicator of environmental contamination and foodborne pathogen that potentially threaten human and animal health. In the present study, we aimed to characterize the ARGs and VGs in AG- and beta-lactam-resistant E. coli from dairy farm waste in Gansu Province, China. The dairy farm waste consisted of fecal (n = 265) and sewage (n = 54) samples processed using standard microbiological techniques and the Clinical & Laboratory Standards Institute guidelines. The total DNA of AG- and beta-lactam-resistant E. coli was extracted, and whole-genome sequencing (WGS) was performed using the Illumina NovaSeq platform and analyzed using various bioinformatics tools. In this study, among 84.3% (269/319) of the E. coli strains, 23.8% (64/269) were identified as AG- and beta-lactam-resistant E. coli. WGS analysis revealed a large pool of ARGs belonging to multiple classes such as AGs, beta-lactams, aminocoumarins, fluoroquinolones, macrolides, phenicol, tetracyclines, phosphonic acid, disinfecting and antiseptic agents, elfamycin, rifamycin, and multidrug resistance genes. Furthermore, virulome analysis of 64 E. coli strains revealed clinically important virulence factors associated with adherence, biofilm, invasion, auto-transportation, siderophores, secretion systems, toxins, anti-phagocytosis, quorum sensing, regulation, metabolism, and motility. We identified dairy farm feces and sewage waste as important reservoirs of antimicrobial resistance and virulence determinants in E. coli in Gansu, China, which can threaten human and animal health through ecological exposure and contamination of food and water. We recommend continuous large-scale surveillance in dairy farm settings to formulate protective guidelines for public health safety.

Association of elevated exosomal miR-21 levels with nonunion in clavicular fractures post-ORIF: A prospective analysis.

BACKGROUND: This study investigates the relationship between plasma exosomal miRNAs and nonunion risk following open reduction and internal fixation (ORIF) of clavicle fractures, aiming to identify predictive molecule to enhance patient management and personalized orthopedic care. METHODS: Conducted as a prospective cohort study at Taian City Central Hospital, participants included individuals with unilateral, closed clavicle fractures who underwent ORIF (n = 763, 546 males and 217 females). Plasma samples were collected preoperatively for exosome isolation and miRNA extraction, specifically analyzing miR-100, miR-124, miR-125b, and miR-21 using quantitative polymerase chain reaction (qPCR). Patients were classified into union and nonunion groups based on follow-up outcomes at a minimum of three months post-surgery. RESULTS: Out of 763 patients, 720 achieved union while 43 developed nonunion. Notably, the nonunion group exhibited significantly elevated exosomal miR-21 expression levels. Univariate analysis demonstrated a significant association between high miR-21 expression and nonunion occurrence (Relative Risk [RR] = 1.82, P = 0.0004). Multivariate logistic regression analysis corroborated this association (RR > 1.8, P < 0.05), adjusting for covariates. High miR-21 levels (3.12 to 7.89) were robustly associated with nonunion outcomes (RR > 4), independent of other factors. Receiver operating characteristic (ROC) curve analysis indicated certain clinical diagnostic value of miR-21 for predicting nonunion (Area Under the Curve [AUC] = 0.7885). CONCLUSIONS: The elevated preoperative levels of exosomal miR-21 were significantly associated with an increased risk of bone nonunion at three months ORIF in patients with clavicle fractures, indicating that miR-21 holds potential as a non-specific predictive molecule.

α-Synuclein disrupts microglial autophagy through STAT1-dependent suppression of Ulk1 transcription.

BACKGROUND: Autophagy dysfunction in glial cells is implicated in the pathogenesis of Parkinson's disease (PD). The previous study reported that α-synuclein (α-Syn) disrupted autophagy in cultured microglia. However, the mechanism of microglial autophagy dysregulation is poorly understood. METHODS: Two α-Syn-based PD models were generated via AAV-mediated α-Syn delivery into the mouse substantia nigra and striatal α-Syn preformed fibril (PFF) injection. The levels of microglial UNC-51-like kinase 1 (Ulk1) and other autophagy-related genes in vitro and in PD mice, as well as in the peripheral blood mononuclear cells of PD patients and healthy controls, were determined via quantitative PCR, western blotting and immunostaining. The regulatory effect of signal transducer and activator of transcription 1 (STAT1) on Ulk1 transcription was determined via a luciferase reporter assay and other biochemical studies and was verified through Stat1 knockdown or overexpression. The effect of α-Syn on glial STAT1 activation was assessed by immunohistochemistry and western blotting. Changes in microglial status, proinflammatory molecule expression and dopaminergic neuron loss in the nigrostriatum of PD and control mice following microglial Stat1 conditional knockout (cKO) or treatment with the ULK1 activator BL-918 were evaluated by immunostaining and western blotting. Motor behaviors were determined via open field tests, rotarod tests and balance beam crossing. RESULTS: The transcription of microglial ULK1, a kinase that controls autophagy initiation, decreased in both in vitro and in vivo PD mouse models. STAT1 plays a critical role in suppressing Ulk1 transcription. Specifically, Stat1 overexpression downregulated Ulk1 transcription, while Stat1 knockdown increased ULK1 expression, along with an increase in LC3II and a decrease in the SQSTM1/p62 protein. α-Syn PFF caused toll-like receptor 4-dependent activation of STAT1 in microglia. Ablation of Stat1 alleviated the decrease in microglial ULK1 expression and disruption of autophagy caused by α-Syn PFF. Importantly, the ULK1 activator BL-918 and microglial Stat1 cKO attenuated neuroinflammation, dopaminergic neuronal damage and motor defects in PD models. CONCLUSIONS: These findings reveal a novel mechanism by which α-Syn impairs microglial autophagy and indicate that targeting STAT1 or ULK1 may be a therapeutic strategy for PD.

Gut microbiome and metabolites mediate the benefits of caloric restriction in mice after acute kidney injury.

The role of gut microbiome in acute kidney injury (AKI) is increasing recognized. Caloric restriction (CR) has been shown to enhance the resistance to ischemia/reperfusion injury to the kidneys in rodents. Nonetheless, it is unknown whether intestinal microbiota mediated CR protection against ischemic/reperfusion-induced injury (IRI) in the kidneys. Herein, we showed that CR ameliorated IRI-elicited renal dysfunction, oxidative stress, apoptosis, and inflammation, along with enhanced intestinal barrier function. In addition, gut microbiota depletion blocked the favorable effects of CR in AKI mice. 16S rRNA and metabolomics analysis showed that CR enriched the gut commensal Parabacteroides goldsteinii (P. goldsteinii) and upregulated the level of serum metabolite dodecafluorpentan. Intestinal colonization of P. goldsteinii and oral administration of dodecafluorpentan showed the similar beneficial effects as CR in AKI mice. RNA sequencing and experimental data revealed that dodecafluorpentan protected against AKI-induced renal injury by antagonizing oxidative burst and NFκB-induced NLRP3 inflammasome activation. In addition, we screened and found that Hamaudol improved renal insufficiency by boosting the growth of P. goldsteinii. Our results shed light on the role of intestinal microbiota P. goldsteinii and serum metabolites dodecafluorpentan in CR benefits to AKI.

Synergistic Effects of Time-Restricted Feeding and Resistance Training on Body Composition and Metabolic Health: A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis examined the synergistic impact of time-restricted feeding (TRF) combined with resistance training (RT) (TRF + RT) on body composition and metabolic health in adults, contrasting it with habitual eating patterns (CON) and RT (CON + RT). METHODS: Adhering to PRISMA guidelines, five databases were searched up to 28 April 2024. Randomized controlled trials or crossover trials assessing the effects of TRF + RT for at least 4 weeks in adults were selected. Data were pooled as standardized mean differences (SMDs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). The risk of bias was evaluated using the revised Cochrane risk-of-bias tool. RESULTS: Seven studies with 164 participants were included in the final analysis. TRF + RT significantly reduced body mass (WMD -2.90, 95% CI: -5.30 to -0.51), fat mass (WMD -1.52, 95% CI: -2.30 to -0.75), insulin (SMD -0.72, 95% CI: -1.24 to -0.21), total cholesterol (WMD -9.44, 95% CI: -13.62 to -5.27), low-density lipoprotein cholesterol (LDL-C) (WMD -9.94, 95% CI: -13.47 to -6.41), and energy intake (WMD -174.88, 95% CI: -283.79 to -65.97) compared to CON + RT. No significant changes were observed in muscle mass, strength, or other metabolic markers. CONCLUSIONS: TRF + RT, in contrast to CON + RT, significantly improved body composition, insulin, and cholesterol levels without affecting muscle mass or strength.

CCDC181 is required for sperm flagellum biogenesis and male fertility in mice.

The structural integrity of the sperm flagellum is essential for proper sperm function. Flagellar defects can result in male infertility, yet the precise mechanisms underlying this relationship are not fully understood. CCDC181, a coiled-coil domain-containing protein, is known to localize on sperm flagella and at the basal regions of motile cilia. Despite this knowledge, the specific functions of CCDC181 in flagellum biogenesis remain unclear. In this study, Ccdc181 knockout mice were generated. The absence of CCDC181 led to defective sperm head shaping and flagellum formation. Furthermore, the Ccdc181 knockout mice exhibited extremely low sperm counts, grossly aberrant sperm morphologies, markedly diminished sperm motility, and typical multiple morphological abnormalities of the flagella (MMAF). Additionally, an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified, with CCDC181 regulating the localization of LRRC46 within sperm flagella. These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.

Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes.

Bioenergy decline occurs with reperfusion following acute ischemic stroke. However, the molecular mechanisms that limit energy metabolism and their impact on post-stroke cognitive and emotional complications are still unclear. In the present study, we demonstrate that the p53 transcriptional response is responsible for neuronal adenosine triphosphate (ATP) deficiency and progressively neuropsychiatric disturbances, involving the downregulation of mitochondrial voltage-dependent anion channels (VDACs). Neuronal p53 transactivated the promoter of microRNA-183 (miR-183) cluster, thereby upregulating biogenesis of miR-183-5p (miR-183), miR-96-5p (miR-96), and miR-182-5p. Both miR-183 and miR-96 directly targeted and post-transcriptionally suppressed VDACs. Neuronal ablation of p53 protected against ATP deficiency and neurological deficits, whereas post-stroke rescue of miR-183/VDAC signaling reversed these benefits. Interestingly, cyclin-dependent kinase 9 (CDK9) was found to be enriched in cortical neurons and upregulated the p53-induced transcription of the miR-183 cluster in neurons after ischemia. Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.

The role of 5-HTergic neuron activation in the rapid antidepressant-like effects of hypidone hydrochloride (YL-0919) in mice.

Introduction: Major depressive disorder (MDD) is a common and disabling mental health condition; the currently available treatments for MDD are insufficient to meet clinical needs due to their limited efficacy and slow onset of action. Hypidone hydrochloride (YL-0919) is a sigma-1 receptor agonist and a novel fast-acting antidepressant that is currently under clinical development. Methods: To further understand the fast-acting antidepressant activity of YL-0919, this study focused on the role of 5-HTergic neurons in the dorsal raphe nucleus (DRN) in mice. Using fiber photometry to assess neural activity in vivo and two behavioral assays (tail suspension test and forced swimming test) to evaluate antidepressant-like activity. Results: It was found that 3 or 7 days of YL-0919 treatment significantly activated serotonin (5-HT) neurons in the DRN and had significant antidepressant-like effects on mouse behaviors. Chemogenetic inhibition of 5-HTergic neurons in the DRN significantly blocked the antidepressant-like effect of YL-0919. In addition, YL-0919 treatment significantly increased the 5-HT levels in the prefrontal cortex (PFC). These changes were drastically different from those of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, which suggested that the antidepressant-like effects of the two compounds were mechanistically different. Conclusion: Together, these results reveal a novel role of 5-HTergic neurons in the DRN in mediating the fast-acting antidepressant-like effects of YL-0919, revealing that these neurons are potential novel targets for the development of fast-acting antidepressants for the clinical management of MDD.

Network pharmacology combined with molecular docking revealed the potential targets of Coridius chinensis in prostate cancer treatment.

BACKGROUND: Prostate cancer (PCa) has high morbidity and mortality rates in elderly men. With a history of thousands of years, traditional Chinese medicine derived from insects could be an important source for developing cancer-targeted drugs to prevent tumorigenesis, enhance therapeutic effects, and reduce the risk of recurrence and metastasis. Multiple studies have shown that Coridius chinensis (Cc) has anticancer effects. AIM: To elucidate the mechanism of action of Cc against PCa via network pharmacology and molecular docking. METHODS: Potential targets for Cc and PCa were predicted using ChemDraw 19.0 software, the PharmMapper database and the GeneCards database. Then, the STRING database was used to construct the protein-protein interaction network. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and molecular docking analyses were subsequently conducted to identify the key targets, active ingredients and pathways involved. RESULTS: GO and KEGG analyses indicated that the PI3K-Akt signalling pathway was the critical pathway (P value < 1.0 × 10-8). Multiple targeting ingredients that can affect multiple pathways in PCa have been identified in Cc. Seven active compounds (asponguanosines A, asponguanine B, asponguanine C, aspongpyrazine A, N-acetyldopamine, aspongadenine B and aspongpyrazine B) were selected for molecular docking with 9 potential targets, and the results revealed that aspongpyrazine A and asponguanosine A are the main components by which Cc affects PCa (affinity<-5 kcal/mol, hydrogen bonding), but more studies are needed. CONCLUSION: We used network pharmacology to predict the bioactive components and important targets of Cc for the treatment of PCa, supporting the development of Cc as a natural anticancer agent.

Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke.

Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY-cAMP-PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY-PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.

Alternative splicing variants of IiSEP3 in Isatis indigotica are involved in floral transition and flower development.

The SEPALLATA3 genes regulate several aspects of plant development. This study identified four distinct splicing isoforms of the SEPALLATA3 gene in Isatis indigotica (I. indigotica). IiSEP3-1 and IiSEP3-2 have eight exons and were named as IiSEP3-2/1. However, IiSEP3-3 and IiSEP3-4 with the missing sixth exon were labeled IiSEP3ΔK3. Furthermore, the IiSEP3-1 and IiSEP3-4 amino acids sequences lack the V90. IiSEP3 splicing variants were primarily expressed in floral organs, with petals showing the highest expression. Ectopic expression of IiSEP3-2 or IiSEP3-3 may cause early flowering and reduce the number of sepals, petals, and stamens. The ectopic expression of IiSEP3-2 resulted in cauline leaves and sepals converting to carpelloid structures. In contrast, the four floral whorls prematurely wilted, and the entire flower displayed an abortive state when IiSEP3-3 was expressed ectopically. Silencing the IiSEP3 gene of I. indigotica employing VIGS (tobacco rattle virus-mediated virus-induced gene silencing) technology using the TRV-IiSEP3-2/1 vector delayed flowering time and reduced the number of petals and stamens. Plants silenced with TRV-IiSEP3ΔK3 also exhibited similar phenotypes, including fewer sepals. The transcriptome analysis of silenced plants (TRV-IiSEP3-2/1 treatment group) indicated significant alterations in 1861 genes, with 1035 upregulated and 826 downregulated. TRV-IiSEP3ΔK3 treatment altered the expression of 2063 genes in plants, with 1289 genes upregulated and 774 genes transcription inhibited. Y2H and BIFC experiments revealed that IiSEP3-2 and IiSEP3-3 had distinct interacting proteins. Thus, we can conclude that IiSEP3-2 and IiSEP3-3 interact with different proteins, affecting floral transition and organ development in I. indigotica.

Bioinspired Functional Composites for Enhanced Thermally Conductivity via Fractal-Growth CuNP Fillers.

Thermal conduction for electronic devices has attracted extensive attention in light of the development of 5G communication. Thermally conductive materials with high thermal conductivity and extensive mechanical flexibility are extremely desirable in practical applications. However, the construction of efficient interconnected conductive pathways and continuous conductive networks is inadequate for either processing or actual usage in existing technologies. In this work, spherical copper nanoparticles (S-CuNPs) and urchin-inspired fractal-growth CuNPs (U-CuNPs), thermally conductive metal fillers induced by ionic liquids, were fabricated successfully through the electrochemical deposition method. Compared to S-CuNPs, the U-CuNPs shows larger specific surface contact area, thus making it easier to build a continuous conductive pathway network in the corresponding U-CuNPs/liquid silicone rubber (LSR) thermally conductive composites. The optimal loading of CuNP fillers was determined by evaluating the rheological performance of the prepolymer and the mechanical properties and thermal conductivity performances of the composites. When the filler loading is 150 phr, the U-CuNPs/LSR produces optimal mechanical properties (e.g., tensile strength and modulus), thermal conductivity (above 1000% improvement compared to pure LSR), and heating/cooling efficiency. The enhanced thermal conductivity of U-CuNPs/LSR was also confirmed through the finite element analysis (FEA) overall temperature distribution, indicating that U-CuNPs with larger specific surface contact areas exhibit more advantages in forming a continuous network in composites than S-CuNPs, making U-CuNPs/LSR a promising and competitive alternative to traditional flexible thermally interface materials.

Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium.

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

Association Between Statin Use and Dementia, and Related Mechanisms: A Bibliometric Analysis from 2007 to 2023.

Background: Emerging evidence suggests the potential of hydroxymethylglutaryl-coenzyme A (HMG-CoA, statins) as a therapeutic option for dementia. Objective: The primary objective of this study is to assess the current state of research on statins use in dementia, with a focus on identifying pivotal questions within the field. Methods: A systemic search for publications on statin use in dementia between 2007 and 2023 was conducted, utilizing the Web of Science Core Collection. The scientific output was analyzed from various perspectives through VOSviewer, CiteSpace, and the bibliometrics website (https://bibliometric.com/). Results: 560 articles authored by 2,977 individuals and 999 institutions across 58 countries were included, which were published in 295 periodicals and cited 21,176 references from 16,424 authors. The annual publication output remained steady, while the number of citations increased consistently. The U.S. and Mayo Clinic emerged as the most significant country and institution, respectively. B. McGuinness and D.L. Sparks were the most eminent authors. Journal of Alzheimer's Disease was the most influential journal. Three sets of keywords and the top 10 references were identified, suggesting pivotal questions within the field. Conclusions: While statins show promising potential as a treatment option for dementia, their use remains uncertain due to the reported short-term cognitive impairment events and questionable long-term protective effects against dementia. The pivotal question is to ascertain the association between statins and cognition. The mechanisms underlying the effects of statins on cognition are multifaceted. This study provides insights into the current status within the field of statin use in dementia.

Dual-Function Nanoscale Coordination Polymer Nanoparticles for Targeted Diagnosis and Therapeutic Delivery in Atherosclerosis.

Atherosclerosis is the primary cause of cardiovascular events such as heart attacks and strokes. However, current medical practice lacks non-invasive, reliable approaches for both imaging atherosclerotic plaques and delivering therapeutic agents directly therein. Here, a biocompatible and biodegradable pH-responsive nanoscale coordination polymers (NCPs) based theranostic system is reported for managing atherosclerosis. NCPs are synthesized with a pH-responsive benzoic-imine (BI) linker and Gd3+. Simvastatin (ST), a statin not used for lowering blood cholesterol but known for its anti-inflammatory and antioxidant effects in mice, is chosen as the model drug. By incorporating ST into the hydrophobic domain of a lipid bilayer shell on NCPs surfaces, ST/NCP-PEG nanoparticles are created that are designed for dual purposes: they diagnose and treat atherosclerosis. When administered intravenously, they target atherosclerotic plaques, breaking down in the mild acidic microenvironment of the plaque to release ST, which reduces inflammation and oxidative stress, and Gd-complexes for MR imaging of the plaques. ST/NCP-PEG nanoparticles show efficacy in slowing the progression of atherosclerosis in live models and allow for simultaneous in vivo monitoring without observed toxicity in major organs. This positions ST/NCP-PEG nanoparticles as a promising strategy for the spontaneous diagnosis and treatment of atherosclerosis.