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Pulmonary endothelial barrier dysfunction is a hallmark of sepsis-induced acute lung injury (ALI). Ophiopogonin D (OP-D), isolated from the roots of Ophiopogon japonicus, is involved in regulating inflammation, apoptosis and intestinal permeability. However, the role of OP-D in ALI has not been reported and the related mechanisms remain unclear. In this study, cecal ligation and puncture (CLP) was used to establish a septic ALI model in mice. We found that OP-D effectively alleviated lung pathological damage. Moreover, OP-D decreased pulmonary microvascular permeability, restrained the inflammatory response and apoptosis in murine lung tissues and LPS-exposed PMVECs. Specifically, OP-D exerted the beneficial effects via mediating the inactivation of HIF-1α-VEGF pathway, which was partly abrogated by the overexpression of HIF-1α. Collectively, our findings showed that OP-D protected against sepsis-induced ALI through improving pulmonary microvascular endothelial barrier dysfunction via suppressing HIF-1α-VEGF pathway., Competing Interests: Compliance with Ethical Standards. Conflict of Interest: The authors declare no competing interests. Ethical Approval: All animal procedures were conducted in accordance with the Guide for the Institutional Animal Care and Use and approved by the Institutional Animal Care and Use Committee of Affiliated Changsha Central Hospital to Nanhua University., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Depressive disorders are a global mental health challenge that is closely linked to inflammation, especially in the post-COVID-19 era. The JAK-STAT pathway, which is primarily associated with inflammatory responses, is not fully characterized in the context of depressive disorders. Recently, a phase 3 retrospective cohort analysis heightened that the marketed JAK inhibitor tofacitinib is beyond immune diseases and has potential for preventing mood disorders. Inspired by these clinical facts, we investigated the role of the JAK-STAT signaling pathway in depression and comprehensively assessed the antidepressant effect of tofacitinib. We found that aberrant activation of the JAK-STAT pathway is highly conserved in the hippocampus of classical depressive mouse models: LPS-induced and chronic social defeat stress (CSDS)-induced depressive mice. Mechanistically, the JAK-STAT pathway mediates proinflammatory cytokine production and microgliosis, leading to synaptic defects in the hippocampus of both depressive models. Remarkably, the JAK inhibitor tofacitinib effectively reverses these phenomena, contributing to its antidepressant effect. These findings indicate that the JAK/STAT pathway could be implicated in depressive disorders, and suggest that the JAK inhibitor tofacitinib has a potential translational implication for preventing mood disorders far beyond its current indications., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objective: To elucidate how spinal manipulative therapy (SMT) exerts its analgesic effects through regulating brain function in lumbar disc herniation (LDH) patients by utilizing resting-state functional magnetic resonance imaging (rs-fMRI)., Methods: From September 2021 to September 2023, we enrolled LDH patients (LDH group, n=31) and age- and sex-matched healthy controls (HCs, n=28). LDH group underwent rs-fMRI at 2 distinct time points (TPs): prior to the initiation of SMT (TP1) and subsequent to the completion of the SMT sessions (TP2). SMT was administered once every other day for 30 min per session, totally 14 treatment sessions over a span of 4 weeks. HCs did not receive SMT treatment and underwent only one fMRI scan. Additionally, participants in LDH group completed clinical questionnaires on pain using the Visual Analog Scale (VAS) and the Japanese Orthopedic Association (JOA) score, whereas HCs did not undergo clinical scale assessments. The effects on the brain were jointly characterized using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo). Correlation analyses were conducted between specific brain regions and clinical scales., Results: Following SMT treatment, pain symptoms in LDH patients were notably alleviated and accompanied by evident activation of effects in the brain. In comparison to TP1, TP2 exhibited the most significant increase in ALFF values for Temporal&#95;Sup&#95;R and the most notable decrease in ALFF values for Paracentral&#95;Lobule&#95;L (voxelwise P<0.005; clusters >30; FDR correction). Additionally, the most substantial enhancement in ReHo values was observed for the Cuneus&#95;R, while the most prominent reduction was noted for the Olfactory&#95;R (voxelwise P<0.005; clusters >30; FDR correction). Moreover, a comparative analysis revealed that, in contrast to HCs, LDH patients at TP1 exhibited the most significant increase in ALFF values for Temporal&#95;Pole&#95;Sup&#95;L and the most notable decrease in ALFF values for Frontal&#95;Mid&#95;L (voxelwise P<0.005; clusters >30; FDR correction). Furthermore, the most significant enhancement in ReHo values was observed for Postcentral&#95;L, while the most prominent reduction was identified for ParaHippocampal&#95;L (voxelwise P<0.005; clusters >30; FDR correction). Notably, correlation analysis with clinical scales revealed a robust positive correlation between the Cuneus&#95;R score and the rate of change in the VAS score (r=0.9333, P<0.0001)., Conclusions: Long-term chronic lower back pain in patients with LDH manifests significant activation of the "AUN-DMN-S1-SAN" neural circuitry. The visual network, represented by the Cuneus&#95;R, is highly likely to be a key brain network in which the analgesic efficacy of SMT becomes effective in treating LDH patients. (Trial registration No. NCT06277739)., Competing Interests: Conflict of Interest. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Fluorescent metal-organic frameworks (MOFs) are promising sensing materials that have received much attention in recent years, in which the organic ligand conformation changes usually lead to variations of their sensing behavior. Based on this, in the present work, perylene diimide (PDI) derivatives with excellent photochemical properties closely related to their conformation and molecule packing fashion were selected as organic linkers to detect sarin simulant diethyl chlorophosphate (DCP). By the coordination interactions with large lanthanide cations through terminal carboxylate groups from the PDI derivative, a series of one-dimensional coordination polymers, named [Ln(PDICl 4 -2COO)(μ 2 -O) 0.5 (DMF) 1.5 ] (SNNU-112, Ln = Yb/Tb/Sm/Nd/Pr/Gd/Eu/Er/Ce, PDICl 4 -2COOH = N , N '-bis(4-benzoic acid)-1,2,6,7-tetrachlorohydrazone-3,4,9,10-tetracarboxylic acid diimide) were synthesized. Regulated by the coordination process, the ligand undergoes a certain degree of conformational turnover and thus leads to an electron distribution change compared to free PDICl 4 -2COOH. Notably, the contact with the DCP molecule triggered a further ligand conformational conversion of PDI ligands in SNNU-112 and thus caused a fluorescence turn-on phenomenon realizing a well-defined fluorescence detection performance for DCP on the basis of a photoinduced electron transfer process. Among nine lanthanide MOFs, Yb-MOF sensor exhibited the lowest detection limit (4.36 ppb), fast response, high selectivity, and good recyclability. Such molecular conformation regulation of PDI derivatives by metal coordination may provide a new way for the exploration of fluorescent sensors.

The hydrolysis of structural extracellular polymeric substances (St-EPS) is considered a major limiting step in the anaerobic fermentation of waste activated sludge (WAS). However, the degradation of heteropolysaccharides, characterized by complex monomers of uronic acids and neutral saccharides in St-EPS, has rarely been reported. In this study, microbial-produced xanthan-like heteropolysaccharides, characterized by a blue filamentary film, were identified. The xanthan-producing bacteria comprised ∼7.2% of total genera present in WAS. An xanthan-degrading consortium (XDC) was enriched in an anaerobic batch reactor. This consortium could degrade Xanthan for over 90% and disrupt the gel structure of xanthan while promoting methane production from WAS by 29%. The xanthan degradation network consisting of extracellular enzymes and bacteria was elucidated by combining high-throughput sequencing, metagenomic, and metaproteomic analyses. Five enzymes were identified as responsible for hydrolyzing xanthan to monomers, including xanthan lyase, β-d-glucosidase, β-d-glucanase, α-d-mannosidase, and unsaturated glucuronyl hydrolase. Seven genera, including Paenibacillus (0.2%) and Clostridium (3.1%), were identified as key bacteria excreting one to five of the aforementioned enzymes. This study thus provides insights into the complex conversions in anaerobic digestion of WAS and gives a foundation for future optimization of this process., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 Published by Elsevier Ltd.)

Background and Study Aims: Hirschsprung disease (HD) is a complex developmental disease that resulted from impaired proliferation and migration of neural crest cells. Despite the genetic causation of enteric nervous system have been found to be responsible for part of HD cases, the genetic aetiology of most HD patients still needs to be explored., Patients and Methods: Whole-genome sequencing and subsequent Sanger sequencing validation analysis were performed in 13 HD children and their unaffected parents. Autophagy assays were performed to validate the functions of the identified locus., Results: After the initial quality checking (SNP quality score ≥ 40, coverage ≥ 10X) of the raw data, we identified 3182 single nucleotide variants (SNVs). We subsequently compared these SNVs against the public databases and got a total of 15 suspicious genes shared among these patients. Subsequent Sanger sequencing and bioinformatics analyses revealed that amino acid-altering de novo mutation c.1648C > T(p.L550F) in ALK was responsible for HD. For validation, we sequenced all 29 exons ofALKin 76 additional sporadic HD cases and 200 healthy children and identified this variant in five of the HD cases. We further illustrated that ALK mutation c.1648C > T interrupted the interactions between ALK and its ligand midkine (Mdk), and induced autophagic cell death through AKT/mTORC1 axis., Conclusion: These finding implied that the abnormal variant of ALK c.1648C > T may account for the pathogenesis of HD., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Background: Subarachnoid hemorrhage (SAH) remains a serious public health problem worldwide, especially in economically developed regions/countries. This study intends to thoroughly analyze the incidence, mortality, and disability-adjusted life years (DALYs) rate of SAH at the global, regional, and national levels. This study focused on the differences in SAH incidence between China and Japan from 1990 to 2019, and projected global, Chinese, and Japanese SAH incidence rates until 2030., Methods: Data on the disease burden owing to SAH from 1990 to 2019 were obtained from the Global Burden of Disease (GBD) Study 2019. linear regression analysis was used to calculate the estimated annual percentage change (EAPC) and linear regression method was used to calculate the average annual percentage change (AAPC). Bayesian age-period-cohort (BAPC) model was used to predict the disease burden from 2020 to 2030., Results: Globally, age-standardised incidence, mortality, and DALYs rates was declined from 1990 to 2019. In 1990-2019, the incidence of SAH decreased in China, while it increased in Japan, especially among middle-aged and elderly women. Projections suggest that the global incidence of SAH will decrease by 2.06% in 2030, with an increase of 6.24% in China and 13.82% in Japan, with the highest increase among Japanese women being 16.19%., Conclusions: Global SAH incidence, mortality, and DALYs rates declined over the 1990-2019 period, with regional/national SAH mortality and DALYs rates negatively correlated with socio-demographic index (SDI), while SAH incidence was positively correlated with SDI. The incidence of SAH decreased in China and increased in Japan during this period. The predictions show that over the next 10 years, while the incidence of SAH continues to decline globally, the incidence of SAH in China and Japan has increased. Thus, SAH remains a serious disease burden that requires early intervention targeting risk factors and populations at risk that may have increased because of economic development., Competing Interests: Declarations. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study presents a comprehensive evaluation of the application of online multi-internal standard calibration (M.ISC) in determining iodine concentrations through inductively coupled plasma mass spectrometry (ICP-MS). Notably, M.ISC streamlines the calibration process by requiring only a single standard solution, thereby enhancing sample throughput and minimizing liquid waste. In addition, unlike conventional internal standard (IS) methods, M.ISC omits the need for time-consuming species identification by utilizing multiple IS species simultaneously to minimize signal biases. The effectiveness of M.ISC was validated through the analysis of six standard reference samples, with the results of LOD and LOQ also being calculated by the error propagation approach. The traditional chemical analytical methods (TCAM), external standard calibration (EC) and single IS methods were also evaluated as comparative purpose. Nonetheless, M.ISC emerges as a straightforward matrix-correction strategy, offering a simple and efficient alternative to traditional calibration methods for iodine detection by ICP-MS., (© 2025 John Wiley & Sons Ltd.)

Background: The invasion of viruses and fungi can cause pathological changes in the normal growth of plants and is an important factor in causing plant infectious diseases. These pathogenic microorganisms can also secrete toxic metabolites, affecting crop quality and posing a threat to human health. In this work, we selected the natural product rutaecarpine as the lead compound to achieve the total synthesis and structural derivation. The antiphytoviral activities of these compounds were systematically studied using tobacco mosaic virus (TMV) as the tested strain, and the structure-activity relationships were summarized., Result: The anti TMV activities of compounds 5a, 5n, 6b, and 7c are significantly higher than that of commercial antiviral agent ningnanmycin. We chose 5n for further antiviral mechanism research, and the results showed that it can directly act on viral particles. The molecular docking results further confirmed the interaction of compound 5n and coat protein (CP). These compounds also exhibited broad-spectrum fungicidal activities against eight plant pathogens. Especially compounds 5j and 5p have significant anti-fungal activities (EC 50 : 5j, 1.76 μg mL -1 ; 5p, 1.59 μg mL -1 ) and can be further studied as leads for plant-based anti-fungal agents., Conclusion: The natural product rutaecarpine and its derivatives were synthesized, and evaluated for their anti-TMV and fungicidal activities. Compounds 5n and 5p with good activities emerged as new antiviral and anti-fungal candidates, respectively. This study provides important information for the research and development of the novel antiviral and fungicidal agents based on rutaecarpine derivatives. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The consecutive growth of antimicrobial resistance and the spread of resistance genes worldwide, especially the emergence of superbugs, have made traditional antibiotic-based treatments inadequate to fight bacterial infections. Therefore, new therapeutic modalities for bacterial infections are urgently needed. Antibodies are considered to be an effective alternative to antibiotics. The emergence and advancement of technologies such as hybridoma, antibody purification, transgenic mice, phage display, and protein engineering have enabled the production of large quantities of humanized antibodies with high purity and affinity. Antibodies has achieved remarkable achievements in the field of medicine in the past decades. Antibody-based therapy is expected to be an effective way to treat drug-resistant bacterial infections in the post-antibiotic era due to its merits of high specificity, which leads to no selective pressure on non-target bacteria and could cooperate with antibiotics to enhance the antimicrobial effect. This review first introduces the mechanism of action of antibodies against bacterial infections, then summarizes the reported antimicrobial antibodies according to different targets, discusses the advantages and limitations of the antibody-based therapy for antimicrobial treatment, and finally, the perspectives of antimicrobial antibodies developing have been prospected, providing a reference for the development of new antimicrobial antibodies., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

To investigate differences in the clinical features of patients with sporotrichosis and cutaneous Mycobacterium marinum infection, and develop a prediction model for the initial identification. A total of 121 patients were selected based on the results from etiological culture. Logistic regression analyses were employed to identify the most valuable variables. In the multivariate logistic regression analysis, the following were finally considered independent predictors (OR = 3.650∼14.024, P<0.05) of cutaneous M. marinum infection: age<60 years (P = 0.031); female (P = 0.001); only the extremities involved (P = 0.031); clear triggers (P = 0.022); and presence of swelling (P = 0.024). A nomogram was developed based on these factors, and the area under the curve was 0.860. The model presented is based on clinical features and can help identify patients with sporotrichosis and cutaneous M. marinum infection. This may help increase the accuracy of doctors' initial examination and diagnostic outcomes., Competing Interests: Declaration of competing interest The authors declare no financial interests or personal relationships that could have appeared to influence the work reported in this paper. No conflict of interest was reported., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aimed to investigate the knowledge about, attitudes toward, and acceptance and predictors of receiving the mpox vaccine among Chinese cancer patients. Patients were selected using a convenience sampling method. A web-based self-report questionnaire was developed to assess cancer patients' knowledge, attitudes, and acceptance regarding the mpox vaccine. Multivariate logistic regression analysis was used to determine predictors of acceptance of the mpox vaccine. A total of 805 cancer patients were included in this study, with a vaccine hesitancy rate of 27.08%. Approximately 66% of the patients' information about mpox and the vaccine came from the mass media, and there was a significant bias in the hesitant group's knowledge about mpox and the vaccine. Multivariable logistic regression analysis suggested that retirement; chemotherapy; the belief that the mpox vaccine could prevent disease, that vaccination should be compulsory when appropriate and that the mpox vaccine prevents mpox and reduces complications; the willingness to pay for the mpox vaccine; the willingness to recommend that friends and family receive the mpox vaccine; and the belief that the mpox vaccine should be distributed fairly and equitably were factors that promoted vaccination. The belief that mpox worsens tumor prognosis was a driving factor for vaccine hesitancy. This study investigated the knowledge of cancer patients about mpox and the vaccine, evaluated the acceptance and hesitancy rates of the mpox vaccine and examined the predictors of vaccination intention. We suggest that the government scientifically promote the vaccine and develop policies such as free vaccination and personalized vaccination to increase the awareness and acceptance rate of the mpox vaccine.

Dysregulated IL-10 producing regulatory B cells (Bregs) are associated with the progression of systemic lupus erythematosus. An immunomodulatory role of heat shock proteins (HSPs) is implicated in autoimmune diseases. However, the molecular basis underlying the role of Hspa13 in regulating Bregs function and lupus pathogenesis remains unclear. In this study, Bregs display higher Hspa13 expression than IL-10 - B cells. Induction of IL-10 production is weakened in B cells with Hspa13 knockdown or knockout. Hspa13 binds to the IL-10 promoter via the TATA or CAAT box and activates IL-10 transcription in the nucleus. Furthermore, Hspa13 positive cells are enriched in marginal zone (MZ) B cells to regulate IL-10 production. Stimulated B220 + B or MZ B cells from CD19 cre Hspa13 fl/fl mice for Breg induction show an impaired capacity to promote CD4 + Foxp3 + regulatory T cells (Treg) differentiation. In lupus MRL/lpr mice, a decline in Treg differentiation is accompanied by decreased Hspa13 expression in both Bregs and MZ B cells. Moreover, adoptive transfusion of Bregs and MZ B cells from CD19 cre Hspa13 fl/fl mice fails to increase the frequency of Tregs, attenuate renal pathology, or decrease anti-dsDNA antibody levels. These results explain the unique role of Hspa13 in determining MZ regulatory function and affecting lupus pathogenesis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

To ascertain the status of the surface soil heavy metal pollution in the southern area of Laizhou Bay, 263 surface soil samples were collected from seven different land use types in the study area and the contents and pH of eight soil heavy metals （As, Cr, Ni, Cu, Zn, Cd, Pb, and Hg） were determined. The pollution assessment was carried out using the geo-accumulation index method, Nemerow comprehensive index method, and potential ecological risk index method. Then, the source of heavy metal pollution was discussed using correlation analysis and the source analysis was carried out through positive matrix factorization （PMF）. The results showed that the surface soil in the study area was weakly alkaline； As, Ni, Zn, and Hg slightly exceeded the background values of Weifang and the spatial distribution of heavy metals showed a trend of low in the north and high in the south. The results of the geo-accumulation index indicated that the study area was pollution free and the geo-accumulation index of different land types was arranged in the order of As&gt;Ni&gt;Zn&gt;Cr&gt;Pb&gt;Hg&gt;Cu&gt;Cd. The results of the Nemerow comprehensive pollution index indicated that the study area was lightly polluted and the Nemerow comprehensive pollution index of different land types was arranged in the order of town&gt;grassland&gt;forest&gt;agricultural land&gt;vegetable land&gt;industrial land&gt;mudflat. The results of the potential ecological risk index indicated that the study area belonged to low ecological risk and the potential ecological risk index of different land types was arranged in the order of agricultural land&gt;town&gt;forest land&gt;grassland&gt;vegetable land&gt;industrial land&gt;mudflat. The results of PMF analysis indicated that the heavy metal pollution sources in the study area mainly included natural sources, transportation sources, agricultural sources, and industrial sources, with contribution rates of 38.06%, 26.38%, 26.21%, and 9.35%, respectively.

Context: Coix [ Coix lacryma-jobi L. var. mayuen (Roman.) Stapf (Poaceae)], a crop of medicinal and edible significance, contains coixol, which has demonstrated anticancer properties. However, the limited solubility of coixol restricts its potential therapeutic applications., Objective: This study prepared a water-soluble coixol-β-cyclodextrin polymer (CDP) inclusion compound and evaluated its anticancer effect., Materials and Methods: The coixol-CDP compound was synthesized through a solvent-stirring and freeze-drying technique. Its coixol content was quantified using HPLC, and its stability was tested under various conditions. The anticancer effects of the coixol-CDP compound (4.129, 8.259, 16.518, and 33.035 mg/L for 24, 48, and 72 h) on the proliferation of non-small cell lung cancer (NSCLC) A549 cells were evaluated using an MTT assay; cell morphology was examined by Hoechst nuclear staining; apoptosis and cell cycle was detected by flow cytometry; and the expression of apoptosis-related proteins was assessed by Western blots., Results: The water-soluble coixol-CDP inclusion compound was successfully prepared with an inclusion ratio of 86.6% and an inclusion yield rate of 84.1%. The coixol content of the compound was 5.63% and the compound remained stable under various conditions. Compared to coixol alone, all 24, 48, and 72 h administrations with the coixol-CDP compound exhibited lower IC 50 values (33.93 ± 2.28, 16.80 ± 1.46, and 6.93 ± 0.83 mg/L) in A549 cells; the compound also showed stronger regulatory effects on apoptosis-related proteins., Discussion and Conclusions: These findings offer a new perspective for the potential clinical application of Coix in NSCLC therapy and its future research.

Innate immunity is the first line of defence against pathogenic microorganisms and is nearly universal among eukaryotes. The innate immune system is composed of various organs, cells and immune molecules. MicroRNAs (miRs) are a class of small non‑coding RNAs (~22 nucleotides) that are widely involved in post‑transcriptional regulation of proteins within the innate immune system through the recognition of seed sequences. The present review summarizes the role of the miR‑29 family in innate immunity, with a focus on its specific functions in the differentiation of T cells, B cells, natural killer cells and macrophages, as well as the mechanisms by which the miR‑29 family participates in innate immune signalling. Additionally, this review discusses how the miR‑29 family helps the host combat infections by hepatitis B and C viruses, human immunodeficiency virus and influenza A virus through the regulation of specific signalling molecules. This comprehensive analysis of existing studies emphasizes the importance of the miR‑29 family in maintaining immune balance and defence against pathogens.

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with a poor prognosis. Therapeutic options for patients with advanced ACC who have failed standard treatments are limited. Single-agent immunotherapy as a second-line treatment has shown unsatisfactory clinical outcomes. This phase II trial (NCT04318730) evaluated the efficacy and safety of the PD-1 inhibitor camrelizumab combined with the VEGFR inhibitor apatinib in previously treated advanced ACC. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. A total of 21 patients with advanced ACC received at least one dose of camrelizumab and apatinib. The ORR was 52% (95% CI, 30-74%), meeting the primary endpoint, and the disease control rate (DCR) was 95% (95% CI, 76-100%). The median PFS was 13.3 months (95% CI, 8.4-NE), and the median OS was 20.9 months (95% CI, 11.0-NE). The most common grade 3-4 treatment-related adverse events were alanine aminotransferase elevation, aspartate aminotransferase elevation, and lymphopenia. Predefined exploratory analyses indicated that patients with higher peripheral blood CXCR3 + CD8 + T cell abundance, lower immunosuppressive CD4 + T cell abundance, and higher overlap of clonotypes between tumor-infiltrating T cells and circulating T cells, were more likely to respond favorably to the combined therapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Goutengsan (GTS) is a traditional Chinese medicine formula that can improve multiple nervous system diseases, such as methamphetamine (MA) dependence. However, the mechanism how GTS treats MA dependence remains unclear. This study was aimed to investigate the action mechanism of GTS on MA dependence using network pharmacology, in vivo / in vitro experimental validation, pharmacokinetics, and tissue distribution in the brain., Materials and Methods: The bioactive ingredients from GTS and possible targeted genes for treating MA dependence were predicted using network pharmacology. The binding of key components of GTS to the predicted proteins was studied using molecular docking, and the key components were verified by HPLC. The effects of GTS on an MA-induced model in rats and SH-SY5Y cells were studied. The regulatory effects of GTS on the expressions of predicted MAPK pathway-related proteins in rat brain tissues and SH-SY5Y cells were validated. Furthermore, the plasma exposure and brain tissue distribution of GTS ingredients for MA dependence treatment and MAPK pathway regulation were studied in mice., Results: Network pharmacology screened 53 active ingredients, and 287 potential targets of GTS, and showed the MAPK pathway was among the most relevant pathways. Molecular docking showed that key active ingredients (e.g., 6-gingerol, liquiritin and rhynchophylline) bound strongly with MAPK core targets, such as MAPK3, and MAPK8. Five compounds of GTS were detected by HPLC, including 6-gingerol, chlorogenic acid, liquiritin, 5-o-methylviscumaboloside and hesperidin. GTS had a therapeutic effect on MA-dependent rats, and reduced hippocampal CA1 damage and relative expressions of p-MAPK3/MAPK3, p-MAPK8/MAPK8 in brain tissues induced by MA. GTS counteracted aberrant alterations in cAMP, 5-TH and cellular morphology induced by MA induction and exerts therapeutic effects on MA-induced SH-SY5Y cell models. GTS also can antagonize the high expressions of MAPK-related proteins in MA-induced SH-SY5Y cells. Pharmacokinetic experiment revealed the four ingredients of GTS (e.g., chlorogenic acid, 5-o-methylviscumaboloside, hesperidin and rhynchophylline) were exposed in the plasma and brain, which demonstrates its pharmacological effect on MA dependence., Conclusion: GTS treats MA dependence by regulating the MAPK pathway via multiple bioactive ingredients. The network pharmacology, experimental validation and pharmacokinetics integrated strategy is efficient in discovering the key pharmacological mechanism of herbal formulae., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Li, Wang, Zeng, Wu, Chen, Kong, Chen, Wu, Mo, Zhang and Liu.)

Spinal manipulative therapy (SMT) has been shown to significantly alleviate pain in patients with lumbar disc herniation (LDH), with its effects closely associated with brain function modulation. This study investigates the neural biomarkers linked to pain relief efficacy following a complete SMT treatment cycle in LDH patients. A total of 59 LDH patients were randomized into two groups: SMT treatment (Group 1, n = 28) and sham treatment (ST) (Group 2, n = 31). A matched healthy control group (Group 3, n = 28) was also included. Functional magnetic resonance imaging (fMRI) was performed on LDH patients at two time points (TPs)-before (TP1) and after (TP2) treatment-while healthy controls were scanned once. Clinical assessments were conducted using the Visual Analogue Scale (VAS) and the Japanese Orthopaedic Association (JOA) scale. Post-treatment results indicated significant improvements in both VAS and JOA scores for Group 1, while the improvement was limited to VAS scores for Group 2. Graph properties analysis revealed notable differences in brain network connectivity between LDH patients and healthy controls, particularly between the left precentral gyrus (left PreCG) and left inferior frontal gyrus, opercular part (left IFGoperc). Enhanced functional connectivity (FC) was observed in Group 1, notably between the right angular gyrus (right ANG) and the left middle orbital gyrus (left ORBmid), with right ANG showing a significant positive correlation with clinical scores. This study identifies the sensorimotor network-salience network are significantly activated in chronic pain among LDH patients. The default mode network-dorsal attention network may serve as key neural biomarkers for the efficacy of SMT treatment in alleviating pain in LDH., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Previous metabolomics studies have indicated a close association between blood metabolites and pain. However, the causal relationship between blood metabolites and spinal pain (SP) remains unclear. This study employs a bidirectional two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between 452 blood metabolites and SP., Methods: We used bidirectional two-sample MR analysis to assess the causal relationship between blood metabolites and SP, including neck pain (NP), thoracic spine pain (TSP), low back pain (LBP), and back pain (BP). Genome-wide association studies (GWAS) data for 452 metabolites (7,824 participants) were used as exposure variables. Summary data for NP were obtained from the UK Biobank, for TSP from the FinnGen Biobank, and for LBP from both the UK Biobank and the FinnGen Biobank. Summary data for BP were obtained from the UK Biobank. Inverse-variance weighting (IVW) was used to estimate the causal relationships between metabolites and SP, complemented by various sensitivity analyses to account for pleiotropy and heterogeneity, ensuring robust results., Results: The IVW analysis identified 155 metabolites associated with SP risk and 142 metabolites influenced by SP. No significant heterogeneity or horizontal pleiotropy was observed through other analytical methods., Conclusion: This study demonstrates potential causal effects between blood metabolites and SP, providing new insights into the pathogenesis of SP. These findings lay a theoretical foundation for preventing and treating SP through targeted interventions on specific blood metabolites, potentially elucidating underlying biological mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wu et al.)

Introduction: Research increasingly links environmental exposure to toxic metals with health risks, yet the effect of combined metal exposure on Toxoplasma infection remains underexplored. This study investigates the relationship between concurrent heavy metal exposure and Toxoplasma infection in adults., Methods: We analyzed data from 10,746 adults aged 20-80 from NHANES, with 1,869 positive for Toxoplasma gondii IgG. The study assessed associations between lead (Pb), cadmium (Cd), and mercury (Hg) with Toxoplasma infection risk using single-metal logistic regression, RCS analysis, WQS regression, and qgcomp models., Results: Each metal showed an independent association with Toxoplasma infection risk. Pb had a non-linear association, while Hg had a linear one. Analysis of multiple metals indicated a positive correlation between heavy metal exposure and infection risk, particularly in younger and middle-aged adults, with Pb showing the strongest link., Discussion: Our findings reveal a significant association between heavy metal exposure and Toxoplasma infection risk, especially in younger demographics, with lead being a key factor. This highlights the importance of understanding environmental metal exposure's impact on public health and informs the development of prevention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Xing, Chen and Shen.)

Studies have shown an association between cardiovascular disease and abnormal copper metabolism. Cuproptosis is caused by the accumulation of copper in vivo, and is a newly identified form of cell death. It regulates cardiovascular diseases by affecting vascular endothelial function and myocardial energy metabolism through pathways such as oxidative stress, mitochondrial function, and gene expression. The treatment of copper accumulation in traditional Chinese medicine primarily involves heat-clearing and detoxification therapy, supplemented with diuretic therapy. In contrast, Western medicine mainly uses copper chelators. Flavonoids are common active ingredients used in the treatment of copper metabolism-related and cardiovascular diseases. In this article, we reviewed the relationship between copper metabolism, cuproptosis, and cardiovascular disease, providing novel strategies for preventing and treating cardiovascular disease; our ultimate aim is to encourage inspiration and contemplation among readers., Competing Interests: Competing interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of the study is to investigate the efficacy of amide proton transfer-weighted (APT) imaging combined with serum squamous cell carcinoma antigen (SCC-Ag) in grading cervical cancer., Methods: Sixty-three patients with surgically confirmed cervical SCC were enrolled and categorized into 3 groups: highly differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3). The diagnostic efficacies of APT imaging and serum SCC-Ag, alone or in combination, for grading cervical SCC were compared., Results: The APT values measured by the 2 observers were in excellent agreement (intraclass correlation coefficient >0.75). Mean (± standard deviation) APT values for the high, moderate, and poor differentiation groups were 2.542 ± 0.215% (95% confidence interval [CI]: 2.423-2.677), 2.784 ± 0.175% (95% CI: 2.701-2.856), and 3.120 ± 0.221% (95% CI: 2.950-3.250), respectively. APT values for groups G2 and G3 were significantly higher than those for G1 ( P < 0.05). APT values for identifying cervical SCC in groups G1 and G2, G2 and G3, and G1 and G3, had areas under the receiver operating characteristic curve, sensitivities, and specificities of 0.815 (95% confidence interval [CI]: 0.674-0.914), 82.1%, and 72.2%, 0.882 (95% CI: 0.751-0.959), 70.6%, and 92.7%, and 0.961 (95% CI: 0.835-0.998), 94.1%, and 94.4%, respectively. APT values were significantly and positively correlated with the histological grade of cervical SCC (Spearman's correlation [ rs ] = 0.731, P < 0.01). Serum SCC-Ag levels for the high, moderate, and poor differentiation groups were 1.60 (0.88-4.63) ng/mL, 4.10 (1.85-6.98) ng/mL, and 26.10 (9.65-70.00) ng/mL, respectively. The differences were statistically significant only between groups G1 and G3 and G2 and G3 ( P < 0.05), whereas the differences between groups G1 and G2 were not statistically significant ( P > 0.05). Spearman's analysis revealed a positive correlation between SCC-Ag levels and the histological grade of cervical SCC ( rs = 0.573, P < 0.01). The diagnostic efficacy of APT imaging for the histological grading of cervical SCC was better than that of serum SCC-Ag, and the discriminatory efficacy of the combination of the 2 parameters was better than that of either alone., Conclusions: The diagnostic efficacy of APT imaging was better than that of serum SCC-Ag, and the combined diagnostic utility of APT and SCC-Ag was better than that of the individual parameters., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This is the first study to evaluate the efficacy of short-term Spinal Cord Stimulation (st-SCS) versus debridement for treating Diabetic Foot Ulcers (DFU)., Methods: We retrospectively analyzed records from DFU patients treated at our hospital. Patients were divided into two groups: 62 received st-SCS with debridement (SCS group), and 43 received only debridement (debridement group). We recorded ulcer area, Ankle-Brachial Index, sleep and life quality indices, foot temperature, and visual analog pain scale, and at 2 and 6 weeks post-operation, monitoring adverse events as well. Compared these indicators between the two groups, and changes in the SCS group were specifically analyzed at different time points., Results: Initially, both groups were comparable (P > 0.05). At 2 weeks postoperatively, the ulcer area reduction rate in the SCS group was higher than debridement group (24.37 % vs 12.77 %, P = 0.025), but this advantage disappeared by 6 weeks (P = 0.110). Compared to baseline, therapeutic indicators in the SCS group showed significant improvement at 2 weeks postoperatively and were significantly better than debridement group (P < 0.001). However, by 6 weeks postoperatively, all indicators except ulcer area had returned to baseline levels and showed no significant difference from the debridement group (P > 0.05). The amputation rate was higher in the debridement group (16.28 % vs 3.23 %, P = 0.036), and there were no significant differences in complications (P=0.132)., Conclusion: St-SCS shows significant early benefits over debridement in ulcer healing, pain relief, circulation improvement, and lower amputation rates. However, these benefits did not persist at 6 weeks post-treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

A sniff in humans typically lasts one to three seconds and is commonly considered to produce a long-exposure shot of the chemical environment that sets the temporal limit of olfactory perception. To break this limit, we devised a sniff-triggered apparatus that controls odorant deliveries within a sniff with a precision of 18 milliseconds. Using this apparatus, we show through rigorous psychophysical testing of 229 participants (649 sessions) that two odorants presented in one order and its reverse become perceptually discriminable when the stimulus onset asynchrony is merely 60 milliseconds (Cohen's d = 0.48; 95% confidence interval, (55, 59); 120-millisecond difference). Discrimination performance improves with the length of stimulus onset asynchrony and is independent of explicit knowledge of the temporal order of odorants or the relative amount of odorant molecules accumulated in a sniff. Our findings demonstrate that human olfactory perception is sensitive to chemical dynamics within a single sniff and provide behavioural evidence for a temporal code of odour identity., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study evaluated the safety, tolerability, pharmacodynamics, and pharmacokinetics of recombinant neorudin (EPR-hirudin [EH]) in patients with acute coronary syndrome (ACS), providing a basis for further therapeutic research. This open-label, single-center, nonrandomized, nonblinded, and noncontrolled trial categorized 24 patients with nonprogressive ACS who met the screening criteria into 3 groups. They received an intravenous injection of neorudin (0.4 mg/kg), followed by an intravenous drip at doses of 0.15, 0.30, and 0.45 mg/kg/h for 3 days in the low-, medium-, and high-dose groups, respectively. The safety, tolerability, pharmacodynamics, and pharmacokinetics of EH were assessed after treatment, indicating that neorudin was safe and well tolerated in nonprogressive ACS. No serious adverse events or clinical composite end points were observed. The activated partial thromboplastin time and thrombin time increased significantly and dose dependently following EH administration across all groups compared to pretreatment values. Conversely, thrombin activity significantly decreased after drug administration but returned to baseline levels shortly after drug withdrawal. Within the administered dose range, neorudin exposure increased with the dose, and its half-life was approximately 2 hours. Neorudin was found to be safe and tolerable for treating patients with nonprogressive ACS, demonstrating therapeutic efficacy at doses up to 0.45 mg/kg/h over a 3-day period., (© 2024 The Author(s). Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Daurian ground squirrels (Spermophilus dauricus) experience various stress states during winter hibernation, but the impact on testicular function remains unclear. This study focused on the effects of changes in testicular autophagy, apoptosis, and mitochondrial homeostasis signaling pathways at various stages on the testes of Daurian ground squirrels. Results indicated that: (1) During winter hibernation, there was a significant increase in seminiferous tubule diameter and seminiferous epithelium thickness compared to summer. Spermatogonia number and testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were higher during inter-bout arousal, suggesting that the testes remained stable during hibernation. (2) An increased number of mitochondria with intact morphology were observed during hibernation, indicating that mitochondrial homeostasis may contribute to testicular stability. (3) DNA fragmentation was evident in the testes during the hibernation and inter-bout arousal stages, with the highest level of caspase3 enzyme activity detected during inter-bout arousal, together with elevated levels of Bax/Bcl-2 and Lc3 II/Lc3 I, indicating an up-regulation of apoptosis and autophagy signaling pathways during hibernation. (4) The abundance of DRP1, MFF, OPA1, and MFN2 proteins was increased, suggesting an up-regulation of mitochondrial dynamics-related pathways. Overall, testicular autophagy, apoptosis, and mitochondrial homeostasis-related signaling pathways were notably active in the extreme winter environment. The well-maintained mitochondrial morphology may favor the production of reproductive hormones and support stable testicular morphology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To investigate the effectiveness and safety of separation surgery for Epidural Spinal Cord Compression (ESCC) graded ≥ 2 in patients with Multiple Myeloma (MM), analyze factors influencing surgical outcomes, and develop a preliminary treatment decision framework for these patients., Methods: A retrospective analysis was conducted on clinical data from 35 MM patients who underwent separation surgery for ESCC graded ≥ 2 between 2013 and 2018. Patient data, including baseline information, surgical details, complications, and pre-operative as well as one-month post-operative efficacy evaluation indicators were recorded. Statistical analysis was performed on pre-operative and post-operative efficacy indicators to determine if there were significant improvements (p < 0.05). Ordered logistic regression was utilized to assess factors associated with an unfavorable post-operative quality of life outcome., Results: Compared to pre-operative values, at one-month post-surgery, patients showed significant improvements in Frankel Score Classification (4 vs 5, p < 0.05), Karnofsky Performance Score (30 vs 70, p < 0.05), and Visual Analogue Scale (8 vs 3, p < 0.05). Complications occurred in 7 cases (20%). The number of segments with ESCC (OR = 0.171, p < 0.05) and pre-operative chemotherapy (OR = 5.202, p = 0.05) were identified as independent factors influencing patient outcomes. Patients with more than two vertebral segments with ESCC exhibited significantly worse post-operative conditions., Conclusions: Separation surgery effectively alleviates pain, improves neurological function, and enhances the quality of life in patients with ESCC graded ≥ 2 due to MM., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacological Relevance: The Shenlian formula (SL) is a Chinese medicine formula used to curb the development of atherosclerosis (AS) and cardiovascular disease in clinical practice. However, owing to the complexity of compounds and their related multiple targets in traditional Chinese medicine (TCM), it remains difficult and urgent to elucidate the underlying mechanisms at a holistic level., Aim: To investigate the intrinsic mechanisms by which SL suppresses AS progression and to gain new insight into its clinical use., Methods: We proposed a network pharmacology-based workflow to evaluate the mechanism by which SL affects AS via data analysis, target prediction, PPI network construction, GO and KEGG analyses, and a "drug-core ingredient-potential target-key pathway" network. Then, non-targeted lipidomic analysis was performed to explore the differential lipid metabolites in AS rats, revealing the possible mechanism by which SL affects atherosclerotic progression. Moreover, an AS rabbit model was constructed and gavaged for SL intervention. Serum lipid profiles and inflammatory cytokine indices were tested as an indication of the mitigating effect of SL on AS., Results: A total of 89 bioactive compounds and 298 targets related to SL and AS, which play essential roles in this process, were identified, and a component-target-disease network was constructed. GO and KEGG analyses revealed that SL regulated metabolic pathway, lipids and atherosclerosis, the PI3K-Akt pathway, the MAPK pathway and so on. In vivo experimental validation revealed that a total of 43 different lipid metabolites regulated by SL were identified by non-targeted lipidomics, and glycerophospholipid metabolism was found to be an important mechanism for SL to interfere with AS. SL reduced the plaque area and decreased the levels of inflammatory cytokines (TNF-α and IL-4) and blood lipids (TC, TG, LDL-C, and ApoB) in HFD-induced AS models. In addition, HDL and ApoA 1 levels are increased. PLA2 and Lipin1 are highly expressed in AS model, indicating their role in destabilizing glycerophosphatidylcholine metabolism and contributing to the onset and progression of ankylosing spondylitis. Moreover, SL intervention significantly reduced the level of pro-inflammatory cytokines; significantly down-regulated NF-kB/p65 expression, exhibiting anti-inflammatory activity., Conclusion: The Shenlian formula (SL) plays a pivotal role in the suppression of AS progression by targeting multiple pathways and mechanisms. This study provides novel insights into the essential genes and pathways associated with the prognosis and pathogenesis of AS., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled ‘Mechanistic exploration of the Shenlian formula in the suppression of atherosclerosis progression via network pharmacology and in vivo experimental validation’., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Limited activation and infiltration of CD8 + T cells are major challenges facing T cell-based immunotherapy for most solid tumors, of which the mechanism is multilayered and not yet fully understood., Methods: Levels of CD93 expression on monocytes from paired non-tumor, peritumor and tumor tissues of human hepatocellular carcinoma (HCC) were evaluated. The underlying mechanisms mediating effects of CD93 + monocytes on the inhibition and tumor exclusion of CD8 + T cells were studied through both in vitro and in vivo experiments., Results: In this study, we found that monocytes in the peritumoral tissues of HCC significantly increased levels of CD93 expression, and these CD93 + monocytes collocated with CD8 + T cells, whose density was much higher in peritumor than intratumor areas. In vitro experiments showed that glycolytic switch mediated tumor-induced CD93 upregulation in monocytes via the Erk signaling pathway. CD93 on the one hand could enhance PD-L1 expression through the AKT-GSK3β axis, while on the other hand inducing monocytes to produce versican, a type of matrix component which interacted with hyaluronan and collagens to inhibit CD8 + T cell migration. Consistently, levels of CD93 + monocytes positively correlated with the density of peritumoral CD8 + T cells while negatively correlated with that of intratumoral CD8 + T cells. Targeting CD93 on monocytes not only increased the infiltration and activation of CD8 + T cells but also enhanced tumor sensitivity to anti-PD-1 treatment in mice in vivo., Conclusion: This study identified an important mechanism contributing to the activation and limited infiltration of CD8 + T cells in solid tumors, and CD93 + monocytes might represent a plausible immunotherapeutic target for the treatment of HCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We study a hybrid system of a plasmonic cavity coupled to a pair of different molecular vibration modes with the strong optomechanical-like interactions. Here, this plasmonic cavity is considered as a quantum data bus and then assist several applications. For instance, it can first establish a bimolecular interface to ensure the reciprocal or non-reciprocal information transmission, and then engineer both molecules into the steady-state quantum entanglement of the continuous variable through the dissipative method. In contrast to the traditional optomechanical system, this hybrid system can provide the stronger optomechanical-like interactions and more convenient controls to the molecular quantum units. This investigation is believed to be able to further expand the practical application range of quantum technology., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Our previous study has shown that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs-exo) alleviated burn-induced acute lung injury (ALI). In this study, we explored a novel mechanism by which hUCMSCs-exo contributed to the inhibition of burn-induced ALI. The ALI rat model with severe burn was established for the in vivo experiments, and rats PMVECs were stimulated with the serum from burn-induced ALI rats for the in vitro experiments. The pathological changes of lung tissues were evaluated by HE staining; the cell viability was measured using CCK-8; the iron level and Fe 2+ concentration were assessed using Iron Assay Kit and Fe 2+ fluorescence detection probe; the mRNA expression of SLC7A11 and GPX4 were measured by qRT-PCR; the protein levels of SLC7A11, GPX4, Nrf2 and HO-1 were detected by western blot. Both the in vivo and in vitro experiments revealed that ferroptosis was significantly induced in burn-induced ALI, which as verified by increased iron level and Fe 2+ concentration, and decreased SLC7A11 and GPX4 mRNA and protein levels. Furthermore, both hUCMSCs-exo and Fer-1 (the inhibitor of ferroptosis) alleviated lung inflammation and up-regulated protein levels of Nrf2 and HO-1 in the lung tissues of burn-induced ALI rats. These results suggested that hUCMSCs-exo exhibited a protective role against burn-induced ALI by inhibiting ferroptosis, partly owing to the activation of Nrf2/HO-1 pathway, thus providing a novel therapeutic strategy for burn-induced ALI., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The aim of this article is to investigate the stability of sampled-data systems (SDSs) by introducing a sawtooth-characteristic-based hierarchical integral inequality (SCBHII) and to obtain the maximum allowable sampling period that maintains the stability of the system. First, by associating the sawtooth characteristics of the input delay in SDSs with free matrices, an SCBHII is proposed; its accuracy improves as the hierarchy increases. Subsequently, a high-order two-sided looped-functional, which considers both the sampling multi-integral states and the sawtooth pattern, is introduced to cater to the aforementioned inequality. In addition, the system variables are augmented by sawtooth pattern-related terms, which eliminates the need for additional secondary processing when determining the negative-definiteness of derivatives with high-order terms. By combining the high-order two-sided looped-functional with the proposed SCBHII, a stability criterion for SDSs with reduced conservatism is achieved, presented in the form of linear matrix inequalities. The proposed inequality technique and the stability criterion are shown to be effective and superior through three numerical examples and a real-world simplified power market model.

Background: To analyze the learning curve of novices in mastering short-term Spinal cord stimulation (st-SCS) for diabetic foot, evaluating the efficacy, safety, and difficulty of this technique., Methods: A retrospective review of diabetic foot patients treated with st-SCS at our hospital was conducted. All procedures were performed by the same physician and patients were sequentially numbered according to the order of surgery. Learning curves were plotted using segmented linear regression and cumulative sum curves based on surgery duration. Patients were divided into 2 groups according to the inflection points on the learning curve: the learning group and the mastery group. Pre- and postoperative efficacy indicators were recorded and compared, along with general patient data, perioperative parameters, and incidence of complications., Results: A total of 36 patients were included. Significant improvements were observed post-st-SCS in ulcer size (from 7.00 cm 2 to 4.00 cm 2 ), visual analog scale (from 7.00 to 3.00), foot temperature (from 30.06°C to 32.37°C), and Pittsburgh Sleep Quality Index (from 14.42 to 8.36) (P < 0.05). The physician could proficiently perform st-SCS after 9 cases. Surgery time was significantly shorter in the mastery group (1-9 cases) compared to the learning group (10-36 cases) (28.04 vs. 43.56 min, P < 0.05). There were no significant differences between the 2 groups in baseline data, improvement in efficacy indicators, or complications (P > 0.05)., Conclusions: St-SCS is beneficial for wound healing, pain relief, improving peripheral circulation, and improving sleep quality. Surgeons can master this simple and safe technique in about 9 cases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Nonrestorative sleep (NRS) is related to numerous adverse outcomes. There is rare evidence of its associated factors, especially in Chinese adolescents. This study aimed to explore the factors associated with NRS in Chinese adolescents and the potential moderation effects of coffee or tea consumption., Methods: This cross-sectional study invited adolescents attending Grades 7-11 in Nanjing, China, to complete a self-administered questionnaire, including their NRS, stress, anxiety, physical symptoms, depression, sociodemographics, and lifestyles. Linear regressions were applied to investigate the associated factors of their NRS, with the moderation effects of coffee or tea consumption and other characteristics being tested by additionally including their interactions., Results: Totally 481 adolescents (49% male, age 15.5 ± 1.5 years) were enrolled, with the average global NRS score of 42.16 ± 7.57. Higher family income (β = 2.01, P = 0.007), longer sleep duration (β = 2.33, P = 0.011), and moderate after-class activity (β = 1.50, P = 0.044) contributed less NRS, while higher educational level (β = -2.60, P = 0.033), more coffee or tea consumption (β = -1.68, P = 0.013), physical symptoms (β = -3.85, P < 0.001), stress (β = -0.23, P = 0.005), anxiety (β = -1.54, P = 0.045), and depression (β = -0.13, P = 0.014) contributed more NRS. Females (β = 0.82, P = 0.005), older age (β = -0.46, P = 0.029), and higher education level (β = -1.68, P < 0.001) contributed less refreshment from sleep, more physical/medical symptoms of NRS, and less daytime function, respectively. Coffee or tea consumption moderated the associations of somatic symptoms (β = 0.25, P = 0.021), stress (β = 0.29, P = 0.022), anxiety (β = 0.27, P = 0.005), and depression (β = 0.17, P = 0.021) with NRS., Conclusions: Longer sleep duration, moderate after-class activity, reduced coffee or tea consumption, and promotion of physical and mental health may help reduce adolescents' NRS. Coffee or tea consumption may help buffer the negative associations of somatic symptoms, stress, anxiety, and depression with NRS., (© 2024. The Author(s).)

Background: Preoperative prediction of lymphovascular space invasion (LVSI) is crucial for improving the prognosis of patients with cervical cancer., Purpose: To evaluate the value of preoperative amide proton transfer (APT) imaging combined with serum CA125 levels for predicting LVSI in cervical cancer., Material and Methods: This retrospective study included 80 patients with cervical cancer who underwent preoperative magnetic resonance imaging, including APT imaging. Serum CA125 levels were measured using a fully automated immunoassay analyzer and chemiluminescence method. The presence of LVSI was determined based on the pathological results after surgery., Results: Among the 40 patients who met the requirements, 29 had postoperative pathological confirmation of LVSI, while 11 did not. The areas under the receiver operating characteristic curves (AUC) of preoperative APT and CA125 levels predicting LVSI were 0.889 and 0.687, respectively. When the APT value was 2.9%, the corresponding Youden index was the highest (0.702), with a sensitivity of 79.3% and specificity of 90.9%. When the critical value of the preoperative serum CA15 level was 25.3 u/mL, the corresponding Youden index was the highest (0.508), with a sensitivity of 69.0% and a specificity of 81.8%. The sensitivity and specificity of preoperative APT imaging combined with serum CA125 in predicting LVSI were 82.7% and 100%, respectively, with a Youden's index of 0.828 and an AUC of 0.923., Conclusion: The combination of preoperative APT imaging and serum CA125 levels is valuable for predicting LVSI in cervical cancer. Diagnostic efficacy is highest when the APT value is >2.9% and the serum CA125 level is >25.3 u/mL., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs., (© 2024. The Author(s).)

Sleep is critical for maintaining overall health. Insufficient sleep duration and poor sleep quality are associated with various physical and mental health risks and chronic diseases. To date, plenty of epidemiological research has shown that sleep disorders are associated with the risk of obesity, which is usually featured by the expansion of adipose tissue. However, the underlying mechanism of increased fat accumulation upon sleep disorders remains unclear. Here we demonstrated that sleep deprivation (SD) caused triglycerides (TG) accumulation in the visceral white adipose tissue (vWAT), accompanied by a remarkable decrease in the expression of adipose triglyceride lipase (ATGL) and other two rate-limiting lipolytic enzymes. Due to the key role of ATGL in initiating and controlling lipolysis, we focused on investigating the signaling pathway leading to attenuated ATGL expression in vWAT upon SD in the following study. We observed that ATGL downregulation resulted from the suppression of ATGL transcription, which was mediated by the reduction of the transcriptional factor FOXO1 and its upstream regulator SIRT1 expression in vWAT after SD. Furthermore, impairment of SIRT1/FOXO1/ATGL pathway activation and lipolysis induced by SIRT1 inhibitor EX527 in the 3 T3-L1 adipocytes were efficiently rescued by the SIRT1 activator resveratrol. Most notably, resveratrol administration in SD mice revitalized the SIRT1/FOXO1/ATGL pathway activation and lipid mobilization in vWAT. These findings suggest that targeting the SIRT1/FOXO1/ATGL pathway may offer a promising strategy to mitigate fat accumulation in vWAT and reduce obesity risk associated with sleep disorders., (© 2024. The Author(s) under exclusive licence to University of Navarra.)

Over the past years, the application potential of ferroelectric nanomaterials with unique physical properties for modern electronics is highlighted to a large extent. However, it is relatively challenging to fabricate inorganic ferroelectric nanomaterials, which is a process depending on a vacuum atmosphere at high temperatures. As significant complements to inorganic ferroelectric nanomaterials, the nanomaterials of molecular ferroelectrics are rarely reported. Here a low-cost room-temperature antisolvent method is used to synthesize free-standing 2D organic-inorganic hybrid perovskite (OIHP) ferroelectric nanosheets (NSs), that is, (CHA) 2 PbBr 4 NSs (CHA = cyclohexylammonium), with an average lateral size of 357.59 nm and a thickness ranging from 10 to 70 nm. This method shows high repeatability and produces NSs with excellent crystallinity. Moreover, ferroelectric domains in single NSs can be clearly visualized and manipulated using piezoresponse force microscopy (PFM). The domain switching and PFM-switching spectroscopy indicate the robust in-plane ferroelectricity of the NSs. This work not only introduces a feasible, low-cost, and scalable method for preparing molecular ferroelectric NSs but also promotes the research on molecular ferroelectric nanomaterials., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Alkaline phosphatase (ALP) reflects changes in the condition of multiple myeloma (MM) patients to some extent. However, the relationship of ALP in MM remains uncertain. Our study aimed to determine the association between initial ALP levels and overall survival in newly diagnosed MM patients., Methods: Clinical data from 202 newly diagnosed MM patients at Beijing Chaoyang Hospital between 2012 and 2016 were collected. Baseline characteristics, disease progression staging, serum markers, and patient survival data were recorded. The cut-off value for ALP was calculated based on patient survival data, and patients were divided into groups. Differences in patients' 3- and 5-year survival rates, liver function, bone disease and other indicators among different groups were compared. Independent risk factors influencing newly diagnosed MM patients were identified using COX regression analysis., Results: Patients were categorized into three groups based on ALP cut-off points: Group 1 (ALP <70 U/L), Group 2 (ALP 70 to <120 U/L), and Group 3 (ALP ≥120 U/L). Significant differences were observed in lactate dehydrogenase, serum calcium, white blood cell count, hemoglobin, and liver function indicators (including alanine aminotransferase, aspartate aminotransferase, albumin, and γ-glutamyl transferase) among different ALP groups (P<0.05). ALP levels varied significantly among patients with different bone disease grades (P<0.05). Median survival times for Groups 1, 2, and 3 were 25, 52, and 31 months, respectively. Group 2 exhibited significantly higher 3-year survival compared to the other two groups (P=0.006), while no significant difference was observed in 5-year survival among the three groups (P=0.51). Age, International Staging System staging, aspartate aminotransferase, β2-microglobulin, ALP grading, and severe bone disease were identified as independent factors influencing survival in newly diagnosed patients (P<0.05)., Conclusions: ALP levels are correlated with the prognosis of MM patients, and an ALP range of 70 to <120 U/L reflects a better survival expectation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-330/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Background: The role of Mast cells has not been thoroughly explored in the context of prostate cancer's (PCA) unpredictable prognosis and mixed immunotherapy outcomes. Our research aims to employs a comprehensive computational methodology to evaluate Mast cell marker gene signatures (MCMGS) derived from a global cohort of 1091 PCA patients. This approach is designed to identify a robust biomarker to assist in prognosis and predicting responses to immunotherapy., Methods: This study initially identified mast cell-associated biomarkers from prostate adenocarcinoma (PRAD) patients across six international cohorts. We employed a variety of machine learning techniques, including Random Forest, Support Vector Machine (SVM), Lasso regression, and the Cox Proportional Hazards Model, to develop an effective MCMGS from candidate genes. Subsequently, an immunological assessment of MCMGS was conducted to provide new insights into the evaluation of immunotherapy responses and prognostic assessments. Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and pathway analysis to explore the biological pathways and mechanisms associated with MCMGS., Results: MCMGS incorporated 13 marker genes and was successful in segregating patients into distinct high- and low-risk categories. Prognostic efficacy was confirmed by survival analysis incorporating MCMGS scores, alongside clinical parameters such as age, T stage, and Gleason scores. High MCMGS scores were correlated with upregulated pathways in fatty acid metabolism and β-alanine metabolism, while low scores correlated with DNA repair mechanisms, homologous recombination, and cell cycle progression. Patients classified as low-risk displayed increased sensitivity to drugs, indicating the utility of MCMGS in forecasting responses to immune checkpoint inhibitors., Conclusion: The combination of MCMGS with a robust machine learning methodology demonstrates considerable promise in guiding personalized risk stratification and informing therapeutic decisions for patients with PCA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: To investigate the prognosis of patients with Multiple Myeloma (MM) after surgery, analyze the risk factors leading to adverse postoperative outcomes, and establish a nomogram., Methods: Clinical data from 154 patients with MM who underwent surgery at our institution between 2007 and 2019 were retrospectively analyzed. Assessing and comparing patients' pain levels, quality of life, and functional status before and after surgery (P < 0.05) were considered statistically significant. The Kaplan-Meier survival curve was used to estimate the median survival time. Adverse postoperative outcomes were defined as worsened symptoms, lesion recurrence, complication grade ≥ 2, or a postoperative survival period < 1 year. Logistic regression analysis was used to determine the prognostic factors. Based on the logistic regression results, a nomogram predictive model was developed and calibrated., Results: Postoperative pain was significantly alleviated in patients with MM, and there were significant improvements in the quality of life and functional status (P < 0.05). The median postoperative survival was 41 months. Forty-nine patients (31.8%) experienced adverse postoperative outcomes. Multivariate logistic regression analysis identified patient age, duration of MM, International Staging System, preoperative Karnofsky Performance Status, and Hb < 90 g/L as independent factors influencing patient prognosis. Based on these results, a nomogram was constructed, with a C-index of 0.812. The calibration curve demonstrated similarity between the predicted and actual survival curves. Decision curve analysis favored the predictive value of the model at high-risk thresholds from 10% to-69%., Conclusion: This study developed a nomogram risk prediction model to assist in providing quantifiable assessment indicators for preoperative evaluation of surgical risk., (© 2024. The Author(s).)

Introduction: The clinical symptoms of Lumbar Disc Herniation (LDH) can be effectively ameliorated through Lever Positioning Manipulation (LPM), which is closely linked to the brain's pain-regulating mechanisms. Magnetic Resonance Imaging (MRI) offers an objective and visual means to study how the brain orchestrates the characteristics of analgesic effects. From the perspective of multimodal MRI, we applied functional MRI (fMRI) and Magnetic Resonance Spectrum (MRS) techniques to comprehensively evaluate the characteristics of the effects of LPM on the brain region of LDH from the aspects of brain structure, brain function and brain metabolism. This multimodal MRI technique provides a biological basis for the clinical application of LPM in LDH., Methods and Analysis: A total of 60 LDH patients and 30 healthy controls, matched by gender, age, and years of education, will be enrolled in this study. The LDH patients will be divided into two groups (Group 1, n = 30; Group 2, n = 30) using a random number table method. Group 1 will receive LPM treatment once every two days, for a total of 12 times over 4 weeks. Group 2 will receive sham LPM treatment during the same period as Group 1. All 30 healthy controls will be divided into Group 3. Multimodal MRI will be performed on Group 1 and Group 2 at three time points (TPs): before LPM (TP1), after one LPM session (TP2), and after a full course of LPM treatment. The healthy controls (Group 3) will not undergo LPM and will be subject to only a single multimodal MRI scan. Participants in both Group 1 and Group 2 will be required to complete clinical questionnaires. These assessments will focus on pain intensity and functional disorders, using the Visual Analog Scale (VAS) and the Japanese Orthopaedic Association (JOA) scoring systems, respectively., Discussion: The purpose of this study is to investigate the multimodal brain response characteristics of LDH patients after treatment with LPM, with the goal of providing a biological basis for clinical applications., Trial Registration Number: https://clinicaltrials.gov/ct2/show/NCT05613179 , identifier: NCT05613179., (© 2024. The Author(s).)

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC 50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

This study examines the effects of mass media and mobile media on civil behaviors in China during COVID-19 outbreaks. It explores the media practices of the Chinese public and the psychological mechanisms that led to their protests and boycotts against the government's COVID policies. Chinese official media has a reputation for depoliticizing natural disasters and censoring the online mobilization of collective actions. Based on previous research and theories regarding media multitasking and political communication, this study demonstrates the psychological mechanism by which a special type of media multitasking-second screening-contributed to political participation in a politically restrictive environment. This study contributes to existing research on media multitasking by proposing a unique theoretical framework that entails an issue-based typology of second screening. The framework expands knowledge by highlighting the importance of issue-switching and investigating its psychological influence on political participation. Previous studies have primarily focused on device-switching and its effects, so this study offers fresh insights in this field. Drawing on a nationwide online survey ( N  = 1180) conducted during the late-2022 wave of COVID-19 in China, this study reveals that second screening on official televised COVID-19 news can elicit simultaneous issue-switching among Chinese audiences: from the de-politicalized COVID-19 propaganda toward politics. Further, second screening on different issues (i.e., politics vs. health sciences) may instigate political participation through cognitive and emotion channels differently. That is, both political efficacy (cognitive) and negative emotions (emotion) facilitate the process, with the former making a greater contribution., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Industrial hemp (Cannabis sativa L.) has great application potential in heavy metal-polluted soils owing to its safe non-food utilization. However, the fate of heavy metals in different varieties of hemp planted in strongly contaminated natural soils remains unknown. Here, we investigated the growth, heavy metal uptake, distribution, and transfer of nine hemp varieties in soils strongly contaminated with Cu, As, Cd, and Pb. Hemp variety and metal type were the main factors affecting the growth and heavy metal uptake in hemp. The nine hemp varieties grew well in the contaminated soils; however, differences existed among the varieties. The biomass of Z3 reached 5669.1 kg hm -1 , whereas that of Yunma No. 1 was only 51.8 % of Z3. The plant height, stalk diameter, and stalk bark thickness of Z3 were greater than those of the other varieties, reaching 168 cm, 9.2 mm, and 0.56 mm, respectively. Permanova's analysis revealed that the total effects of Cu, As, Cd, and Pb on the growth of the nine hemp varieties reached 60 %, with leaf As having the greatest effect, reaching 16 %. , Even in strongly contaminated soils, the nine varieties showed poor Cu, As, Cd, and Pb uptake. Most of the Cu, As, Cd, and Pb were retained in the root, reaching 57.7-72.4, 47.6-64.7, 76.0-92.9, and 70.0-87.8 %, respectively. Overall, the Cu, As, Cd, and Pb uptake of Wanma No.1 was the highest among the nine varieties, whereas that of Guangxi Bama was the lowest. These results indicate that hemp is a viable alternative for phytoattenuation in soils contaminated with heavy metals because of its ability to tolerate and accumulate Cu, As, Cd, and Pb in its roots, and Guangxi Bama is superior to the other varieties considering the safe utilization of hemp products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: According to the reactivity hypothesis and the diathesis-stress model, repeated activation of the stress system has a negative effect on health, and this effect may differ because of individual characteristics. Thus, the present study explores the effect of chronic stress on fatigue and investigates its mechanism., Methods: A questionnaire survey of 288 participants selected from the northwest part of China was conducted (13.89% females; ages ranged from 18 to 34 years, with M  ±  SD  = 23.14 ± 3.79 years) on chronic stress, fatigue, depression, anxiety, and negative emotion differentiation. SPSS 28.0 was used to process descriptive statistics and correlation analysis and the PROCESS macro was used to analyze the moderated chained multi-mediation., Results: Chronic stress was found to be positively correlated with fatigue, depression, and anxiety; depression and anxiety played a chained multi-mediating role between chronic stress and fatigue, and negative emotion differentiation played a moderating role in the chained multi-mediation model., Discussion: Compared with depression, anxiety plays a more important role in the influence of chronic stress on fatigue. Therefore, it is necessary to pay more attention to anxiety symptoms and take appropriate intervention measures. Negative emotion differentiation plays a moderating role. Improving negative emotion differentiation through mindfulness and adaptive emotion regulation is an effective way to reduce the influence of chronic stress on fatigue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lv, Qiu, Lu, Yajuan, Yongjie, Xing and Zhu.)

The theories of relational regulation and compensatory Internet use suggest that intolerance of uncertainty influences smartphone addiction (SPA), which in turn is influenced by other aspects. This study used previous results to examine how intolerance of uncertainty affects SPA in PhD and master's degree programs. A convenience sample comprising 1727 master's and PhD students (99.9 %; 50.7 % female; M age  = 27.71; SD  = 3.80; range = 21-43) was recruited. Using established questionnaires, we measured SPA, anxiety, positive coping style, perceived social support, and intolerance of uncertainty. The results demonstrated that intolerance of uncertainty positively affects SPA in terms of predictive power. Furthermore, anxiety and positive coping style mediate that link in a cascade fashion. A greater SPA indicates that the individual is less likely to use a positive coping style, has a higher anxiety level, and has a lower tolerance for uncertainty. While thinking about how intolerance of uncertainty affects anxiety and positive coping style, perceived social support mediates the relationship. Intolerance of uncertainty has less impact on anxiety and positive coping style when perceived social support is high. These results indicate the possibility of examining SPA prevention and intervention from several angles. Therefore, emotional regulation, which modifies anxiety and the tendency to use a positive coping style, may reduce the impact of intolerance of uncertainty on SPA. Another successful strategy for reducing smartphone addiction is to provide social support from loved ones and the community at large., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Ambient air temperature is a key factor affecting human health. Female reproductive disorders are representative health risk events under low temperature. However, the mechanism involving in cold-induced female reproductive disorders remains largely unknown. Female mice were intermittently exposed to cold conditions (4 °C) to address the health risk of low temperature on female reproductive system. Primary granulosa cells (GCs) were prepared and cultured under low temperature (35 °C) or exposed to β3-adrenoreceptor agonist, isoproterenol, to mimic the condition of cold exposure. Western-blot, RT-PCR, co-IP, ELISA, pharmacological inhibition or siRNA-mediated knockdown of target gene were performed to investigate the possible role of hormones, gap conjunction proteins, and ER stress sensor protein in regulating female reproductive disorders under cold exposure. Cold exposure induced estrous cycle disorder and follicular dysplasia in female mice, accompanying with abnormal upregulation of progesterone and its synthetic rate-limiting enzyme, StAR, in the ovarian granulosa cells. Under the same conditions, an increase in connexin 43 (CX43) expressions in the GCs was also observed, which contributed to elevated progesterone levels in the ovary. Moreover, ER stress sensor protein, PERK, was activated in the ovarian GCs after cold exposure, leading to the upregulation of downstream NRF2-dependent CX43 transcription and aberrant increase in progesterone synthesis. Most importantly, blocking PERK expression in vivo significantly inhibited NRF2/CX43/StAR/progesterone pathway activation in the ovary and efficiently rescued the prolongation of estrous cycle and the increase in follicular atresia of the female mice induced by cold stress. We have elucidated the mechanism of ovarian PERK/NRF2/CX43/StAR/progesterone pathway activation in mediating female reproductive disorder under cold exposure. Targeting PERK might be helpful for maintaining female reproductive health under cold conditions., (© 2024. The Author(s).)