Design, Synthesis, Bioactive Evaluation, and Molecular Dynamics Simulation of Novel 4H-Pyrano[3,2-c]pyridine Analogues as Potential Sterol 14α-Demethylase (CYP51) Inhibitors.

To discover potential sterol 14α-demethylase (CYP51) inhibitors, thirty-four unreported 4H-pyrano[3,2-c]pyridine derivatives were designed and synthesized. The assay results indicated that most compounds displayed significant fungicidal activity against Sclerotinia sclerotiorum, Colletotrichum lagenarium, Botrytis cinerea, Penicillium digitatum, and Fusarium oxysporum at 16 µg/mL. The half maximal effective concentration (EC50) values of compounds 7a, 7b, and 7f against B. cinerea were 0.326, 0.530, and 0.610, respectively. Namely, they had better antifungal activity than epoxiconazole (EC50 = 0.670 µg/mL). Meanwhile, their half maximal inhibitory concentration (IC50) values against CYP51 were 0.377, 0.611, and 0.748 µg/mL, respectively, representing that they also possessed better inhibitory activities than epoxiconazole (IC50 = 0.802 µg/mL). The fluorescent quenching tests of proteins showed that 7a and 7b had similar quenching patterns to epoxiconazole. The molecular dynamics simulations indicated that the binding free energy of 7a and epoxiconazole to CYP51 was -35.4 and -27.6 kcal/mol, respectively.

Novel Pyrido[4,3-d]pyrimidine Derivatives as Potential Sterol 14α-Demethylase Inhibitors: Design, Synthesis, Inhibitory Activity, and Molecular Modeling.

Thirty-four new pyrido[4,3-d]pyrimidine analogs were designed, synthesized, and characterized. The crystal structures for compounds 2c and 4f were measured by means of X-ray diffraction of single crystals. The bioassay results showed that most target compounds exhibited good fungicidal activities against Pyricularia oryzae, Rhizoctonia cerealis, Sclerotinia sclerotiorum, Botrytis cinerea, and Penicillium italicum at 16 µg/mL. Compounds 2l, 2m, 4f, and 4g possessed better fungicidal activities than the commercial fungicide epoxiconazole against B. cinerea. Their half maximal effective concentration (EC50) values were 0.191, 0.487, 0.369, 0.586, and 0.670 µg/mL, respectively. Furthermore, the inhibitory activities of the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results displayed that they had prominent activities. Compounds 2l, 2m, 4f, and 4g also showed better inhibitory activities than epoxiconazole against CYP51. Their half maximal inhibitory concentration (IC50) values were 0.219, 0.602, 0.422, 0.726, and 0.802 µg/mL, respectively. The results of molecular dynamics (MD) simulations exhibited that compounds 2l and 4f possessed a stronger affinity to CYP51 than epoxiconazole.

Tao-Hong-Si-Wu-Tang Improves the Depressive-like Behaviors in Mice Experiencing Perimenopausal Depression Through Modulating Activity of the Hypothalamic-Pituitary-Adrenal-Ovary Axis and Activating the BDNF-TrkB-CREB Signaling Pathway.

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer's disease.

BACKGROUND: Epidemiological studies have revealed a correlation between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes. AIM: To determine the effects of KAT7 on insulin patients with AD. METHODS: APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aß stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aß, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3ß, total GSK3ß, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A. RESULTS: KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aß accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3ß to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion. CONCLUSION: We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

Exosomes derived from induced cardiopulmonary progenitor cells alleviate acute lung injury in mice.

Cardiopulmonary progenitor cells (CPPs) constitute a minor subpopulation of cells that are commonly associated with heart and lung morphogenesis during embryonic development but completely subside after birth. This fact offers the possibility for the treatment of pulmonary heart disease (PHD), in which the lung and heart are both damaged. A reliable source of CPPs is urgently needed. In this study, we reprogrammed human cardiac fibroblasts (HCFs) into CPP-like cells (or induced CPPs, iCPPs) and evaluated the therapeutic potential of iCPP-derived exosomes for acute lung injury (ALI). iCPPs were created in passage 3 primary HCFs by overexpressing GLI1, WNT2, ISL1 and TBX5 (GWIT). Exosomes were isolated from the culture medium of passage 6-8 GWIT-iCPPs. A mouse ALI model was established by intratracheal instillation of LPS. Four hours after LPS instillation, ALI mice were treated with GWIT-iCPP-derived exosomes (5 × 109, 5 × 1010 particles/mL) via intratracheal instillation. We showed that GWIT-iCPPs could differentiate into cell lineages, such as cardiomyocyte-like cells, endothelial cells, smooth muscle cells and alveolar epithelial cells, in vitro. Transcription analysis revealed that GWIT-iCPPs have potential for heart and lung development. Intratracheal instillation of iCPP-derived exosomes dose-dependently alleviated LPS-induced ALI in mice by attenuating lung inflammation, promoting endothelial function and restoring capillary endothelial cells and the epithelial cells barrier. This study provides a potential new method for the prevention and treatment of cardiopulmonary injury, especially lung injury, and provides a new cell model for drug screening.

Resting-state functional connectivity of amygdala subregions predicts treatment outcome for cognitive behavioral therapy in obsessive-compulsive disorder at a 4-month follow-up.

BACKGROUND: Cognitive behavioral therapy (CBT) is considered as the first-line treatment for obsessive-compulsive disorder (OCD). However, the underlying neural mechanisms through which CBT exerts its effects in OCD remain unclear. This study aims to investigate whether the improvement of clinical symptoms in OCD patients after CBT treatment is associated with changes in resting-state functional connectivity (FC) of the amygdala subregion, and whether these changes can be served as potential predictors of four-months treatment efficacy. METHODS: We collected resting-state functional magnetic resonance imaging (rs-fMRI) data from 57 OCD patients and 50 healthy subjects at baseline. In the patient group, rs-fMRI was also obtained after completion of an 8-week CBT treatment and 4 months post-treatment. A whole-brain rsFC analysis was conducted using the amygdala subregion as the seed point. We analyzed the FC patterns in relation to 4 months clinical outcomes to elucidate the long-term efficacy of CBT in OCD patients. RESULTS: Treatment responseat at pre-treatment was found to be associated with reduced rsFC between the left basolateral amygdala(BLA)and left superior temporal gyrus(STG) at baseline. Lower pre-treatment FC were negatively correlated with the severity of OCD symptoms as measured by the Yale-Brown Obsessive Compulsive Severity Scale (Y-BOCS). Moreover, the area under the receiver operating characteristic (ROC) curve for the FC between the left BLA and STG at the end of treatment was 73.0% and 70.4% for the effective-ineffective and remitted or unremitted groups, respectively. At the 4-month follow-up, the area under the ROC curve for the effective-ineffective and remitted or unremitted groups was 83.9% and 76.5%, respectively. CONCLUSION: These findings suggest that brain functional activity in patients with OCD can predict treatment response to CBT, and longitudinal changes in relevant brain functional activity following CBT treatment are associated with treatment response in OCD.

The change of intimate relationship between people with Alzheimer's disease and their adult child caregivers: An interpretative phenomenological analysis.

This study aims to explore the change of intimate relationship between people with Alzheimer's disease and their adult child caregivers as the disease progresses. Twelve adult child caregivers were recruited through purposive sampling. Explanatory phenomenological analysis was conducted to analyse data collected by semi-structured in-depth interviews. This study found a dynamically changing relationship between adult child caregivers and their parents with Alzheimer's disease during care giving that evolved with the progress of the disease. The relationship was the most intimate in the middle stage of the disease for most caregivers and a new reciprocal relationship developed due to caregiving. Caregivers experienced different degrees of self-growth when providing care, though caregiver burdens were common. The positive experience and perception of caregivers were important for improving the quality of life for adult child caregivers of people with Alzheimer's disease.

Effect of long-term care insurance policy on depression in non-disabled people: evidence from China.

BACKGROUND: Policy effect might be multidimensional and spill over to non-recipients. It is unclear how the implementation of Long-Term Care Insurance (LTCI) policy affects depression in non-disabled people and how this effect differs in different non-disabled groups. METHODS: Using time-varying differences-in-differences method and nationally representative health survey data in wave 2011, wave 2013, wave 2015 and wave 2018 from the China Health and Retirement Longitudinal Study, we assessed the effect of LTCI policy on depression in non-disabled people aged 45 years and older, and discussed the heterogeneity of effect across different population characteristics: retirement, financial support and social participation status. RESULTS: We found LTCI policy statistically significant reduced depression by 0.76 units in non-disabled people compared to non-pilot cities. Depression in non-disabled people who unretired, with financial support and without social participation was reduced by 0.8267, 0.7079 and 1.2161 units, respectively. CONCLUSIONS: Depression in non-disabled people was statistically significant reduced because of LTCI policy in China, and non-disabled people who unretired, with financial support and without social participation benefited more from LTCI policy. Our findings highlight the depression-reducing effect of LTCI policy in non-recipients and suggest that non-disabled people who unretired, with financial support and without social participation should be concerned during LTCI policy progress.

Greater Pattern Similarity between Mother Tongue and Second Language in the Right ATL Facilitates Understanding of Written Language.

Previous research has mapped out the brain regions that respond to semantic stimuli presented visually and auditorily, but there is debate about whether semantic representation is modality-specific (only written or only spoken) or modality-invariant (both written and spoken). The mechanism of semantic representation underlying native (L1) and second language (L2) comprehension in different modalities as well as how this mechanism is influenced by L2 proficiency, remains unclear. We used functional magnetic resonance imaging (fMRI) data from the OpenNEURO database to calculate neural pattern similarity across native and second languages (Spanish and English) for different input modalities (written and spoken) and learning sessions (before and after training). The correlations between behavioral performance and cross-language pattern similarity for L1 and L2 were also calculated. Spanish-English bilingual adolescents (N = 24; ages 16-17; 19 girls) participated in a 3-month English immersion after-school program. As L2 proficiency increased, greater cross-language pattern similarity between L1 and L2 spoken words was observed in the left pars triangularis. Cross-language pattern similarity between L1 and L2 written words was observed in the right anterior temporal lobe. Brain-behavior correlations indicated that increased cross-language pattern similarity between L1 and L2 written words in the right anterior temporal lobe was associated with L2 written word comprehension. This study identified an effective neurofunctional predictor related to L2 written word comprehension.

CSF Findings in Chinese Patients with NMDAR, LGI1 and GABABR Antibody-Associated Encephalitis.

Purpose: CSF inflammation in subtypes of antibody-defined autoimmune encephalitis (AE) ranges in intensity from moderate to severe. In a retrospective, cross-sectional study, we characterized CSF findings in Chinese patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E), anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1-E), and anti-gamma aminobutyric acid-B receptor encephalitis (GABABR-E). Patients and Methods: The AE cases, including 102 NMDAR-E, 68 LGI1-E and 15 GABABR-E, were included. CSF inflammatory parameters consisted primarily of CSF leukocytes, oligoclonal bands (OCBs), and CSF/serum albumin ratios (QAlb). Ten serum cytokines were evaluated in order to classify AE subtypes. Results: 88% of NMDAR-E, 80% of GABABR-E, and 51% of LGI1-E patients had aberrant CSF features. In NMDAR-E, the CSF leukocyte count, CSF protein concentration, and age-adjusted QAlb were significantly higher than in LGI1-E, but did not differ from GABABR-E. Blood-CSF barrier dysfunction was less common in NMDAR-E patients with >40 years old. On admission, inflammatory CSF response was more prevalent in NMDAR-E patients with a higher CASE score. With age <60 years, CSF inflammatory changes were less frequent in LGI1-E patients, but more common in GABABR-E patients. MCP-1, IL-10, IL-1ß, and IL-4 were potential classifiers for NMDAR-E, LGI1-E, and GABABR-E, and correlated substantially with CSF leukocyte count and QAlb. Conclusion: Subtype-specific patterns are formed by the various inflammatory CSF parameters in NMDAR-E, LGI1-E, and GABABR-E, and their correlation with disease severity, age, and disease duration. CSF inflammatory characteristics associated with MCP-1, IL-10, IL-1ß, and IL-4 may be potential immunopathogeneses targeting markers for these AE subtypes.

Cardiopulmonary progenitors facilitate cardiac repair via exosomal transfer of miR-27b-3p targeting the SIK1-CREB1 axis.

Ischemic heart disease, especially myocardial infarction (MI), is one of the leading causes of death worldwide, and desperately needs effective treatments, such as cell therapy. Cardiopulmonary progenitors (CPPs) are stem cells for both heart and lung, but their repairing role in damaged heart is still unknown. Here, we obtained CPPs from E9.5 mouse embryos, maintained their stemness while expanding, and identified their characteristics by scRNA-seq, flow cytometry, quantitative reverse transcription-polymerase chain reaction, and differentiation assays. Moreover, we employed mouse MI model to investigate whether CPPs could repair the injured heart. Our data identified that CPPs exhibit hybrid fibroblastic, endothelial, and mesenchymal state, and they could differentiate into cell lineages within the cardiopulmonary system. Moreover, intramyocardial injection of CPPs improves cardiac function through CPPs exosomes (CPPs-Exo) by promotion of cardiomyocytic proliferation and vascularization. To uncover the underlying mechanism, we used miRNA-seq, bulk RNA-seq, and bioinformatic approaches, and found the highly expressed miR-27b-3p in CPPs-Exo and its target gene Sik1, which can influence the transcriptional activity of CREB1. Therefore, we postulate that CPPs facilitate cardiac repair partially through the SIK1-CREB1 axis via exosomal miR-27b-3p. Our study offers a novel insight into the role of CPPs-Exo in heart repair and highlights the potential of CPPs-Exo as a promising therapeutic strategy for MI.

Cross-Spatiotemporal Graph Convolution Networks for Skeleton-Based Parkinsonian Gait MDS-UPDRS Score Estimation.

Gait impairment in Parkinson's Disease (PD) is quantitatively assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a well-established clinical tool. Objective and efficient PD gait assessment is crucial for developing interventions to slow or halt its advancement. Skeleton-based PD gait MDS-UPDRS score estimation has attracted increasing interest in improving diagnostic efficiency and objectivity. However, previous works ignore the important cross-spacetime dependencies between joints in PD gait. Moreover, existing PD gait skeleton datasets are very small, which is a big issue in deep learning-based gait studies. In this work, we collect a sizable PD gait skeleton dataset by multi-view Azure Kinect sensors. The collected dataset contains 102 PD patients and 30 healthy older adults. In addition, gait data from 16 young adults (aged 24-50 years) are collected to further examine the effect of age on PD gait assessment. For skeleton-based automatic PD gait analysis, we propose a novel cross-spatiotemporal graph convolution network (CST-GCN) to learn complex features of gait patterns. Specifically, a gait graph labeling strategy is designed to assemble and group cross-spacetime neighbors of the root node according to the spatiotemporal semantics of the gait skeleton. Based on this strategy, the CST-GCN module explicitly models the cross-spacetime dependencies among joints. Finally, a dual-path model is presented to realize the modeling and fusion of spatial, temporal, and cross-spacetime gait features. Extensive experiments validate the effectiveness of our method on the collected dataset.

Effects of short-term second language learning on the development of individual semantic networks in written and spoken language.

Previous studies have primarily focused on the relationship between native language (L1) and second language (L2) in the brain, specifically in one language modality, such as written or spoken language. However, there is limited research on how L2 proficiency impacts both modalities. This study aimed to investigate the functional networks involved in reading and speech comprehension for both L1 and L2, and observe changes in these networks as L2 proficiency improves. The dataset used in this study was obtained from a previous research conducted by Gurunandan et al., which involved Spanish-English bilingual participants undergoing a three-month English training program. Participants underwent fMRI scanning and performed a semantic animacy judgment task in both spoken and written language before and after training. Through analysis, distinct neural networks associated with spoken and written language were found between individuals' L1 and L2, both before and after training. Moreover, as L2 proficiency improved, the spoken and written networks for L2 remained distinct from those of the L1. These findings suggest that short-term L2 learning experiences can modify neural networks, but may not be enough to achieve native-like proficiency, supporting the accommodation hypothesis. These results have important implications for language learning and education, indicating that additional short-term training and exposure alone may not bridge the gap between L1 and L2 processing networks.

Abnormalities of structural covariance of insular subregions in drug-naïve OCD patients.

The insula plays a significant role in the neural mechanisms of obsessive-compulsive disorder. Previous studies have identified functional and structural abnormalities in insula in obsessive-compulsive disorder patients. The predictive coding model in the context of interoception can explain the psychological and neuropathological manifestations observed in obsessive-compulsive disorder. The model is based on the degree of laminar differentiation of cerebral cortex. The interindividual differences in a local measure of brain structure often covary with interindividual differences in other brain regions. We investigated the anatomical network involving the insula in a drug-naïve obsessive-compulsive disorder sample. We recruited 58 obsessive-compulsive disorder patients and 84 matched health controls. The cortical thickness covariance maps between groups were compared at each vertex. We also evaluated the modulation of Yale-Brown Obsessive-Compulsive Scale scores and obsessive-compulsive disorder duration on thickness covariance. Our findings indicated that the thickness covariance seeded from granular and dysgranular insula are different compared with controls. The duration and severity of obsessive-compulsive disorder can modulate the thickness covariance of granular and dysgranular insula with posterior cingulate cortex and rostral anterior cingulate cortex. Our results revealed aberrant insular structural characteristics and cortical thickness covariance in obsessive-compulsive disorder patients, contributing to a better understanding of the involvement of insula in the pathological mechanisms underlying obsessive-compulsive disorder.

The Modified Exenatide Microspheres: PLGA-PEG-PLGA Gel and Zinc-Exenatide Complex Synergistically Reduce Burst Release and Shorten Platform Stage.

The existing exenatide microspheres have the problem of burst release in the early stage, and minimal release in the middle stage which makes it difficult to achieve effective blood drug concentration (platform period). In this study, the modified exenatide microspheres were constructed to address the aforementioned issues. Poly(D,L-lactic-co-glycolic acid) (PLGA) and triblock copolymer with sol-gel conversion characteristics (PLGA-PEG-PLGA gel) were introduced as carriers to prepare microspheres. The hot gel characteristics and hydrophilicity of PLGA-PEG-PLGA gel were utilized to decline the burst release and shorten the platform period. Simultaneously, zinc acetate and exenatide were combined to generate an insoluble complex to further reduce the burst release. Herein, we prepared three types of exenatide microspheres using the solvent evaporation method and investigated their characterization as well as in vitro and in vivo release. According to the experimental findings, the modified exenatide microspheres, i.e., PLGA-PEG-PLGA gel and PLGA co-loaded zinc-exenatide insoluble complex microspheres (Zn-EXT-Gel-MS), had smooth and rounded surfaces, with a particle size of 24.7 µm, and the encapsulation rate reached 89.43%. And it was released for 40 days in vitro, behaving better than the other two microspheres in terms of release behavior. When this product was administered subcutaneously to rats, it produced a comparatively constant plasma exenatide concentration that lasted for 24 days and superior bioavailability than the exenatide microspheres (EXT-MS). The creation of modified exenatide microspheres may serve as a heuristic method for other long-acting medications. Schematic diagram of the synthesis process and release curves of three types of exenatide microspheres in vitro and in vivo.

Altered brain functional network topology in Obsessive-Compulsive Disorder: A comparison of patients with varying severity of depressive symptoms and the impact on psychosocial functioning.

BACKGROUND: Obsessive-compulsive disorder (OCD) is associated with psychosocial impairment, which can be exacerbated by depressive symptoms. In this study, we employed graph theory analysis to investigate the association among neuroimaging, clinical features, and psychosocial functioning in OCD patients, with a specific focus on the differential impact of depressive symptoms. METHODS: 216 OCD patients were divided into two subgroups based on depressive symptoms. Resting-state functional MRI data were acquired from a subset of 106 OCD patients along with 77 matched healthy controls (HCs). We analyzed the topological characteristics of the entire brain and the cognition-related subnetworks and performed Pearson correlation analyses to further explore the relationship with psychosocial functioning. RESULTS: OCD patients with more severe depressive symptoms exhibited greater impairment across all dimensions of psychosocial functioning. Graph theory analysis revealed more pronounced reductions in network efficiency within the entire brain, the default mode network (DMN), and the cingulo-opercular network (CON) among patients with non or mild depressive symptoms. Lower nodal efficiency and degree centrality of the right superior temporal gyrus (STG) were found in OCD patients and these variables were positively correlated with psychosocial functioning impairment. CONCLUSIONS: This study revealed that the presence of depressive symptoms generally exacerbated psychosocial functioning impairment in OCD patients. Abnormalities in the functional integration of the entire brain, the DMN, and the CON in OCD patients may comprise the basis of cognitive deficits, while dysfunction of the right STG may affect the psychosocial functioning through its role in emotion, intention perception, and insight.

The construction and validation of ECM-related prognosis model in laryngeal squamous cell carcinoma.

Background: Laryngeal squamous cell carcinoma (LSCC) is a kind of common and aggressive tumor with high mortality. The application of molecular biomarkers is useful for the early diagnosis and treatment of LSCC. Methods: The expression and clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Principal components analysis (PCA) was used to discriminate between LSCC and normal samples. The hub genes were screened out through univariate and multivariate cox analyses. The Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curve was used to validate the predictive performance. The single sample gene set enrichment analysis (ssGSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to determine the enrichment function. Protein-Protein Interaction (PPI) network was constructed in STRING. The immune analysis was performed by ESTIMATE, IPS and xCELL. The drug sensitivity was identified with GSCA database. Results: We identified that 47 extracellular matrix (ECM) genes were differentially expressed in LSCC compared with normal group. Univariate and multivariate cox analysis determined that leucine-rich glioma-inactivated 4 (LGI4), matrilin 4 (MATN4), microfibrillar-associated protein 2 (MFAP2) and fibrinogen like 2 (FGL2) were closely related to the disease free survival (DSS) of LSCC. ROC curve determined that the risk model has a good predictive performance. PPI network showed the top 100 genes with high correlation of hub genes. The ssGSEA, GO and KEGG enrichment analyses determined that immune response was significantly involved in the development of LSCC. Immune infiltration analysis showed that most immune cells and immune checkpoints were inhibited in high risk score group. Drug sensitivity analysis showed that MATN4, FGL2 and LGI4 were negatively related to various drugs, while MFAP2 was positively related to many drugs. Conclusion: We established a risk model constructed with four ECM-related genes, which could effectively predict the prognosis of LSCC.

Health spillover studies of long-term care insurance in China: evidence from spousal caregivers from disabled families.

BACKGROUND: To alleviate the shortage of caregivers associated with disabled persons, China has implemented a pilot policy for long-term care insurance. This policy has the characteristics of "familialization" and "de-familialization" policy orientation, and it is indeed essential to clarify whether the policy has a positive spillover effect on the health of family caregivers, which is of great value to the pilot from local practice to national institutional arrangement. METHODS: Based on the China Health and Retirement Longitudinal Study microdata and time-varying DID method, our study used the implementation of the pilot policy as a "quasi-natural experiment" to assess the health spillover effects of the pilot policy on family spousal caregivers. RESULTS: This policy significantly improved the health of spousal caregivers, increasing self-rated health and life satisfaction, and reducing depression; Compared with female, urban and central-western spousal caregivers, male, rural and eastern spousal caregivers were "beneficiaries" in more dimensional health. CONCLUSIONS: Our research indicated that spousal caregivers of disabled people, particularly male, rural and eastern spousal caregivers, experienced positive health spillovers after implementing long-term care insurance. These results suggest that the imbalance between supply and demand of nursing staff could be solved in terms of de-familialization and familialization, spousal caregivers should be promoted to equally enjoy the policy benefits on gender, urban-rural and regions.

Influence of konjac glucomannan and its derivatives on the oral pharmacokinetics of antimicrobial agent in antibiotics cocktails: Keep vigilant on dietary fiber supplement.

In this study, konjac glucomannan (KGM) and its derivatives were gavaged as dietary fiber supplements, followed by a single dose of antibiotic cocktail (Abx) containing amoxicillin, neomycin, metronidazole and vancomycin in mice. The effects of dietary fiber on the pharmacokinetics and tissue distribution of each antibiotic were investigated. The results showed that the specific effects of KGM and its derivatives on the absorption, distribution, and elimination of certain antibiotics varied and depended on the nature of the fibers and the characteristics of the antibiotics. Explicitly, the ingestion of KGM and its derivatives enhanced the absorption of metronidazole by 1.7 times and hindered that of amoxicillin by nearly 36 % without affecting the absorption of neomycin sulfate and vancomycin. KGM and its derivatives had no effect on the distribution of amoxicillin and metronidazole, but DKGM and KGM hindered the distributions of neomycin sulfate (from 1.25 h to 1.62 h) and vancomycin (from 0.95 h to 1.14 h), respectively. KGM and its derivatives promoted the elimination of amoxicillin by nearly 38 % while prolonging that of metronidazole by >50 %. KOGM boosted the elimination of neomycin sulfate and vancomycin, but KGM differed from DKGM in acting on the elimination of both.

Factors associated with disease relapse rate in the Neuromyelitis optica spectrum disorder.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a group of demyelinating diseases of the nervous system with high relapse rate and high disability rate without treatment, and we aimed to explore the influencing factors related to the recurrence of NMOSD and provide basis for clinical treatment in this study. METHODS: Referring to the diagnostic criteria for NMOSD issued in 2015, 259 patients were enrolled. Clinical information, cerebrospinal fluid (CSF) and serum analysis results, brain and spinal cord magnetic resonance imaging (MRI) findings, treatment details, and prognosis were all recorded. RESULTS: 176 (68.00%) participants were found to be AQP4 Ab-positive in serum or CSF, and the relapse rate was 36.67% (95/259). These 259 individuals were separated into two groups: non-release (n = 164) and relapse (n = 95). In terms of EDSS scores at onset, EDSS score after treatment, lesion location, serum creatinine (Cr) and treatment strategy, there were statistical differences between the two groups. Multivariable logistic regression analyses revealed five predictors for recurrence of NMOSD patients within two years: EDSS scores at onset, transverse myelitis, brain/brainstem, Cr, and Rituximab/immunosuppressants. CONCLUSION: It is essential to explore the risk factors related to recurrence and prevent them to reduce the risk of disability and improve the prognosis, and the recurrence rate of NMOSD may be affected by several factors.