Blockade of TGF-ß and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses.

BACKGROUND: Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-ß (TGF-ß) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-ß and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models. METHODS: BA is a first-in-class bifunctional inhibitor of TGF-ß and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models. RESULTS: Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-ß and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls. CONCLUSIONS: Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer.

The poor prognosis of immunotherapy in patients with colorectal cancer (CRC) necessitates a comprehensive understanding of the immunosuppressive mechanisms within tumor microenvironment (TME). Undoubtedly, the anti-tumor immune cells play an indispensable role in immune tolerance. Therefore, it is imperative to investigate novel immune-related factors that have the capacity to enhance anti-tumor immunity. Here, we employed bioinformatic analysis using R and Cytoscape to identify the hub gene chemokine (C-X-C motif) ligand 8 (CXCL8), which is overexpressed in CRC, in the malignant progression of CRC. However, its specific role of CXCL8 in CRC immunity remains to be elucidated. For this purpose, we evaluated how tumor-derived CXCL8 promotes M2 macrophage infiltration by in vivo and in vitro, which can be triggered by IL-1ß within TME. Mechanistically, CXCL8-induced polarization of M2 macrophages depends on the activation of the STAT3 signaling. Finally, immunohistochemistry and multiplexed immunohistochemistry analysis identified that CXCL8 not only enhances PD-L1+ M2 macrophage infiltration but also attenuates the recruitment of PD-1+ CD8+ T cells in murine CRC models. Together, these findings emphasize the critical role for CXCL8 in promoting M2 macrophage polarization and inhibiting CD8+ T cell infiltration, thereby links CXCL8 to the emergency of immunosuppressive microenvironment facilitating tumor evasion. Overall, these findings may provide novel strategy for CRC immunotherapy.

The burden and predictors of 30-day unplanned readmission in patients with acute liver failure: a national representative database study.

BACKGROUND: Liver diseases were significant source of early readmission burden. This study aimed to evaluate the 30-day unplanned readmission rates, causes of readmissions, readmission costs, and predictors of readmission in patients with acute liver failure (ALF). METHODS: Patients admitted for ALF from 2019 National Readmission Database were enrolled. Weighted multivariable logistic regression models were applied and based on Directed Acyclic Graphs. Incidence, causes, cost, and predictors of 30-day unplanned readmissions were identified. RESULTS: A total of 3,281 patients with ALF were enrolled, of whom 600 (18.3%) were readmitted within 30 days. The mean time from discharge to early readmission was 12.6 days. The average hospital cost and charge of readmission were $19,629 and $86,228, respectively. The readmissions were mainly due to liver-related events (26.6%), followed by infection (20.9%). The predictive factors independently associated with readmissions were age, male sex (OR 1.227, 95% CI 1.023-1.472; P = 0.028), renal failure (OR 1.401, 95% CI 1.139-1.723; P = 0.001), diabetes with chronic complications (OR 1.327, 95% CI 1.053-1.672; P = 0.017), complicated hypertension (OR 1.436, 95% CI 1.111-1.857; P = 0.006), peritoneal drainage (OR 1.600, 95% CI 1.092-2.345; P = 0.016), etc. CONCLUSIONS: Patients with ALF are at relatively high risk of early readmission, which imposes a heavy medical and economic burden on society. We need to increase the emphasis placed on early readmission of patients with ALF and establish clinical strategies for their management.

Arsenite Mediates Selenite Resistance and Reduction in Enterobacter sp. Z1, Thereby Enhancing Bacterial Survival in Selenium Environments.

Arsenic (As) is widely present in the environment, and virtually all bacteria possess a conserved ars operon to resist As toxicity. High selenium (Se) concentrations tend to be cytotoxic. Se has an uneven regional distribution and is added to mitigate As contamination in Se-deficient areas. However, the bacterial response to exogenous Se remains poorly understood. Herein, we found that As(III) presence was crucial for Enterobacter sp. Z1 to develop resistance against Se(IV). Se(IV) reduction served as a detoxification mechanism in bacteria, and our results demonstrated an increase in the production of Se nanoparticles (SeNPs) in the presence of As(III). Tandem mass tag proteomics analysis revealed that the induction of As(III) activated the inositol phosphate, butanoyl-CoA/dodecanoyl-CoA, TCA cycle, and tyrosine metabolism pathways, thereby enhancing bacterial metabolism to resist Se(IV). Additionally, arsHRBC, sdr-mdr, purHD, and grxA were activated to participate in the reduction of Se(IV) into SeNPs. Our findings provide innovative perspectives for exploring As-induced Se biotransformation in prokaryotes.

Circ ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 increases the stability of G9a and ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 messenger RNA through recruiting eukaryotic translation initiation factor 4A3, transcriptionally inhibiting PDZ and homeobox protein domain protein 1, and promotes the metastasis of hepatocellular carcinoma.

BACKGROUND AND AIM: Circular ubiquitin-like, containing PHD and ring finger domains 1 (circUHRF1) is aberrantly upregulated in human hepatocellular carcinoma (HCC) tissues. However, the underlying molecular mechanisms remain obscure. The present study aimed at elucidating the interactive function of circUHRF1-G9a-ubiquitin-like, containing PHD and ring finger domains 1 (UHRF1) mRNA-eukaryotic translation initiation factor 4A3 (EIF4A3)-PDZ and LIM domain 1 (PDLIM1) network in HCC. METHODS: Expression of circUHRF1, mRNAs of G9a, UHRF1, PDLIM1, epithelial-mesenchymal transition (EMT)-related proteins, and Hippo-Yap pathway components was determined by quantitative polymerase chain reaction (Q-PCR), immunofluorescence, or Western blot analysis. Tumorigenic and metastatic capacities of HCC cells were examined by cellular assays including Cell Counting Kit-8, colony formation, wound healing, and transwell assays. Molecular interactions between EIF4A3 and UHRF1 mRNA were detected by RNA pull-down experiment. Complex formation between UHRF1 and PDLIM1 promoter was detected by chromatin immunoprecipitation assay. Co-immunoprecipitation was performed to examine the binding between UHRF1 and G9a. RESULTS: Circular ubiquitin-like, containing PHD and ring finger domains 1, G9a, and UHRF1 were upregulated, while PDLIM1 was downregulated in HCC tissue samples and cell lines. Cellular silencing of circUHRF1 repressed HCC proliferation, invasion, migration, and EMT. G9a formed a complex with UHRF1 and inhibited PDLIM1 transcription. CONCLUSION: Eukaryotic translation initiation factor 4A3 regulated circUHRF1 expression by binding to UHRF1 mRNA promoter. circUHRF1 increased the stability of G9a and UHRF1 mRNAs through recruiting EIF4A3. Overexpression of circUHRF1 aggravated HCC progression through Hippo-Yap pathway and PDLIM1 inhibition. By elucidating the molecular function of circUHRF1-G9a-UHRF1 mRNA-EIF4A3-PDLIM1 network, our data shed light on the HCC pathogenesis and suggest a novel therapeutic strategy for future HCC treatment.

Inhibition of nucleophosmin/B23 sensitizes ovarian cancer cells to immune check-point blockade via PD-L1 in ovarian cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) that against programmed cell death protein-1 (PD-1) and its ligand PD-L1 have been approved as a promising treatment of many human cancers. However, the responses to these ICIs were limited in patients with ovarian cancer. Studies have indicated that the response to PD-1/PD-L1 blockade might be correlated with the PD-L1 expression level in cancer cells. Nucleophosmin (NPM/B23) was found to be a potential target for immunotherapy. Whether NPM/B23 plays a role in cancer-associated immunity, such as PD-1/PD-L1 axis, and its underlying mechanisms remain largely unknown in ovarian cancer. METHODS: We applied ovarian cancer cell lines as research models. The effect of modulating PD-L1 by NPM/B23 was subsequently confirmed via Western blot, flow cytometry, qRT-PCR, luciferase reporter assays, and immunoprecipitation. Protein stability and ubiquitin assay assays were used to analyze the interplay between NPM/B23 and NF-ĸB/p65 in PD-L1 regulation. The MOSEC/Luc xenograft mouse model was used to validate the role of NPM/B23-PD-L1 through tumor growth in vivo. RESULTS: Our results revealed that NPM/B23 negatively regulates PD-L1 expression via a protein complex with NF-κB/p65 and through an IFN-γ pathway. Moreover, NPM/B23 inhibitor/modulator sensitized ovarian cancer cells to the anti-PD-1 antibody by regulating PD-L1 expression in the immunocompetent mouse model. Compared to anti-PD-1 antibody alone, a combination of anti-PD-1 antibody and NPM/B23 inhibitor/modulator showed reduced tumorigenesis and increased CD8+ T-cell expansion, thus contributing to prolonged survival on MOSEC/Luc-bearing mouse model. CONCLUSION: Targeting NPM/B23 is a novel and potential therapeutic approach to sensitize ovarian cancer cells to immunotherapy.

Incremental Value of Stroke-Induced Structural Disconnection in Predicting Global Cognitive Impairment After Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) is highly prevalent in stroke survivors and correlated with unfavorable clinical outcomes. This study aimed to identify the neural substrate of PSCI using atlas-based disconnectome analysis and assess the value of disconnection score, a baseline measure for stroke-induced structural disconnection, in PSCI prediction. METHODS: A multicenter prospective cohort of 676 first-ever patients with acute ischemic stroke was enrolled from 3 independent hospitals in China. Sociodemographic, clinical, and neuroimaging data were collected at acute stage of stroke. Cognitive assessment was performed at 3 months after stroke. Voxel-wise and tract-wise disconnectome analysis were performed to uncover the strategic structural disconnection pattern for global PSCI. Disconnection score was calculated for each participant in leave-one-dataset-out cross-validation. Multivariable logistic regression was performed for the association between disconnection score and PSCI. Prediction models with and without disconnection score were developed, cross-validated, and compared in terms of discrimination and goodness-of-fit. RESULTS: Compared with lesions of non-PSCI, those of PSCI were more likely to have fiber connections with left prefrontal cortex and left deep structures (thalamus and basal ganglia). Disconnection score could predict the risk and severity of PSCI during cross-validation, and was independently associated with PSCI after controlling for all baseline covariates (odds ratio, 1.38 [95% CI, 1.17-1.64]; P<0.001). Incorporating disconnection score into a reference model with 6 known predictors resulted in significant improvement in both discrimination and goodness-of-fit throughout cross-validation. CONCLUSIONS: A strategic structural disconnection pattern centered on left prefrontal cortex, thalamus, and basal ganglia is identified for global PSCI using indirect disconnectome analysis. The baseline disconnection score is independently predictive of PSCI and has significant incremental value to preexisting sociodemographic, clinical, and neuroimaging predictors. REGISTRATION: URL: http://www.chictr.org.cn/enIndex.aspx; Unique identifier: ChiCTR-ROC-17013993.

Croceibacterium selenioxidans sp. nov., isolated from seleniferous soil.

A Gram-negative, aerobic bacterial strain, designated LX-88T, was isolated from seleniferous soil in Enshi, Hubei Province, PR China. Strain LX-88Toxidized elemental selenium to selenite, and produced carotenoids but not bacteriochlorophyll. The isolate grew optimally at 28 °C, pH 8.0 and with 0.5 % (w/v) NaCl. Phylogenetic analysies of the organism's 16S rRNA and bacterial core gene set sequences indicated that LX-88T belongs to the genus Croceibacterium, and has the highest degree of 16S rRNA gene sequence similarity to Croceibacterium soli MN-1T (97.4 %). The LX-88T genome was 3.4 Mbp and had a G+C content of 63.6 mol%. The average nucleotide identity and digital DNA-DNA hybridization values showed low relatedness (below 95 and 70 %, respectively) between strain LX-88T and other strains in the genus Croceibacterium. Ubiquinone-10 was the predominant quinone. The polar lipid profile was dominated by diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, an unidentified aminolipid, an unidentified phospholipid and an unidentified lipid. The major fatty acid was summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c). These physiological and biochemical tests facilitated the differentiation of strain LX-88T from other members of the genus Croceibacterium. The results of this multifaceted taxonomic study indicate that strain LX-88T represents a novel species in the genus Croceibacterium, for which the name Croceibacterium selenioxidans sp. nov. is proposed. The type strain is LX-88T (=MCCC 1K08007T=LMG 32570T).

Birth outcomes following pelvic ring injury: A retrospective study.

OBJECTIVE: To report obstetric outcomes in pregnant women with previous pelvic ring injury (PRI) and investigate the correlation between residual pelvic deformity and the mode of delivery. DESIGN: Retrospective cohort study. SETTING: Single medical centre in Taiwan. POPULATION: Forty-one women with PRI histories from 2000 to 2021 who subsequently underwent pregnancy and delivery. METHODS: All patients had complete PRI treatment and radiological follow up for at least 1 year. The demographic data, radiological outcomes after PRI and obstetric outcomes were collected to investigate the potential factors of delivery modes using non-parametric approaches and logistic regression. Caesarean section (CS) rates among different subgroups were reported. MAIN OUTCOME MEASURES: Comparisons of demographic data and radiological outcomes (Matta/Tornetta criteria and Lefaivre criteria) after PRI among patients who had subsequent pregnancy and underwent vaginal deliveries (VD) or CS. RESULTS: There were 14 VD and 27 CS in 41 patients. Nine patients underwent CS because of their PRI history, 12 patients underwent CS for other obstetric indications and 20 underwent trial of labour. Based on the logistic regression model, retained trans-iliosacral implants did not significantly increase the risk of CS (odds ratio [OR] 1.20; 95% CI 0.17-8.38). Higher pelvic asymmetry value by Lefaivre criteria was a potential risk factor for CS after previous PRI (OR 1.52; 95% CI 1.043-2.213). CONCLUSIONS: VD is possible after PRI. Retained trans-iliosacral implants do not affect the delivery outcome. Residual pelvic asymmetry after PRI by Lefaivre criteria is a potential risk factor for CS.

Myricetin improves apoptosis after ischemic stroke via inhibiting MAPK-ERK pathway.

BACKGROUND: Neuronal apoptosis is the main cause for the disabilities and deaths of patients suffered with stroke. Neuroprotectants are clinically used to reduce neuronal apoptosis in ischemic stroke. However, the current neuroprotectants have multiple limitations. Myricetin is beneficial for multiple neurodegenerative diseases, but the role of myricetin as a neuroprotective agent in ischemic stroke is still not fully understood. METHODS AND RESULTS: Middle cerebral artery occlusion, Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and Western blots were used to explore the anti-apoptotic effects of myricetin in vivo. Flow cytometry, Western blots and Ca2+ staining were used to study the neuroprotective effects of myricetin in vitro. In this study, we first demonstrated that myricetin reduced neuronal apoptosis after ischemia in vivo and in vitro. And, among the factors of apoptosis after ischemic stroke, excitotoxicity, oxidative stress and inflammation-induced apoptosis can be alleviated by myricetin. Moreover, we further demonstrated that myricetin was able to improve neuronal intrinsic apoptosis by inhibiting the phosphorylation of extracellular signal-regulated kinase in the oxygen and glucose deprivation in vitro. CONCLUSIONS: Summarily, our results support myricetin as a novel neuroprotectant for the prevention or treatment of ischemic stroke via MAPK-ERK signaling pathway.

Simultaneous removal of antibiotic-resistant Escherichia coli and its resistance genes by dielectric barrier discharge plasma.

As emerging contaminants, antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) have been widely detected in various aqueous environments. For antibiotic resistance to be inhibited in the environment, it is essential to control ARB and ARGs. In this study, dielectric barrier discharge (DBD) plasma was used to inactivate antibiotic resistant Escherichia coli (AR E. coli) and remove ARGs simultaneously. Within 15 s of plasma treatment, 108 CFU/mL of AR E. coli were inactivated by 97.9%. The rupture of the bacterial cell membrane and the increase of intracellular ROS are the main reasons for the rapid inactivation of bacteria. Intracellular ARGs (i-qnrB, i-blaCTX-M, i-sul2) and integron gene (i-int1) decreased by 2.01, 1.84, 2.40, and 2.73 log after 15 min of plasma treatment, respectively. In the first 5 min of discharge, extracellular ARGs (e-qnrB, e-blaCTX-M, e-sul2) and integron gene (e-int1) decreased by 1.99, 2.22, 2.66, and 2.80 log, respectively. The results of the ESR and quenching experiments demonstrated that ·OH and 1O2 played important roles in the removal of ARGs. This study shows that DBD plasma is an effective technique to control ARB and ARGs in waters.

Impact of the COVID-19 and psychological risk factors on non-suicidal self-injury behavior among high school students: a one-year follow-up study.

OBJECTIVES: Non-suicidal self-injury (NSSI) behavior is a severe public health issue in adolescents. This study investigated the possible impact of the coronavirus disease 2019 (COVID-19) and analyzed psychological risk factors on adolescent NSSI. METHODS: A one-year follow-up study was conducted in September 2019 (Time 1) and September 2020 (Time 2) among 3588 high school students. The completed follow-up participants (N = 2527) were classified into no NSSI (negative at both time points), emerging NSSI (negative at Time 1 but positive at Time 2), and sustained NSSI (positive at both time points) subgroups according to their NSSI behaviors before and during the COVID-19 pandemic. Perceived family functioning, perceived school climate, negative life events, personality traits (neuroticism, impulsivity, and self-control) were assessed using self-report scales. RESULTS: The data indicated an increase (10.3%) in the incidence of NSSI. Compared to no NSSI subjects, the emerging NSSI and sustained NSSI subgroups had lower perceived family functioning, higher neuroticism, higher impulse-system but lower self-control scores, and more negative life events. Logistic regressions revealed that after controlling for demographics, neuroticism and impulse-system levels at Time 1 positively predicted emerging NSSI behavior, and similarly, higher neuroticism and impulsivity and lower self-control at Time 1 predicted sustained NSSI behavior. CONCLUSIONS: These findings highlighted the aggravated impact of the COVID-19 on NSSI, and suggested that individual neuroticism, impulsivity, and self-control traits might be crucial for the development of NSSI behavior among adolescent students.

Psychopathological network for early-onset post-stroke depression symptoms.

BACKGROUND: Post-stroke depression (PSD) can be conceptualized as a complex network where PSD symptoms (PSDS) interact with each other. The neural mechanism of PSD and interactions among PSDS remain to be elucidated. This study aimed to investigate the neuroanatomical substrates of, as well as the interactions between, individual PSDS to better understand the pathogenesis of early-onset PSD. METHODS: A total of 861 first-ever stroke patients admitted within 7 days poststroke were consecutively recruited from three independent hospitals in China. Sociodemographic, clinical and neuroimaging data were collected upon admission. PSDS assessment with Hamilton Depression Rating Scale was performed at 2 weeks after stroke. Thirteen PSDS were included to develop a psychopathological network in which central symptoms (i.e. symptoms most strongly correlated with other PSDS) were identified. Voxel-based lesion-symptom mapping (VLSM) was performed to uncover the lesion locations associated with overall PSDS severity and severities of individual PSDS, in order to test the hypothesis that strategic lesion locations for central symptoms could significantly contribute to higher overall PSDS severity. RESULTS: Depressed mood, Psychiatric anxiety and Loss of interest in work and activities were identified as central PSDS at the early stage of stroke in our relatively stable PSDS network. Lesions in bilateral (especially the right) basal ganglia and capsular regions were found significantly associated with higher overall PSDS severity. Most of the above regions were also correlated with higher severities of 3 central PSDS. The other 10 PSDS could not be mapped to any certain brain region. CONCLUSIONS: There are stable interactions among early-onset PSDS with Depressed mood, Psychiatric anxiety and Loss of interest as central symptoms. The strategic lesion locations for central symptoms may indirectly induce other PSDS via the symptom network, resulting in higher overall PSDS severity. TRIAL REGISTRATION: URL: http://www.chictr.org.cn/enIndex.aspx ; Unique identifier: ChiCTR-ROC-17013993.

The Role of the Cerebellum in Drug Reward: A Review.

Drug abuse remains a global problem; nonetheless, its mechanism has not yet been fully understood. Recent studies have reported on the non-motor functions of the cerebellum, and evidence from neuroimaging and behavioral studies has suggested the role of cerebellum in drug reward, which has received increasing attention. Furthermore, emerging technological developments have aided in clarifying the various circuits and functions of the cerebellum. Exploring the role of the cerebellum in drug reward can improve our understanding of the mechanism underlying addiction and facilitate the development of new treatment schemes. This review summarizes the anatomy of the cerebellum and its connections to brain regions considered important in addiction. Subsequently, we investigate the neurological reasons elucidating why the cerebellum is a potential target for drug reward. Additionally, we expound the molecular targets of addictive drugs in the cerebellum, mainly glutamate and endocannabinoids. Unlike previous studies, this article focuses on the influence of alcohol, nicotine, morphine, cannabis, and cocaine on the cerebellum from multiple viewpoints, including imaging and behavioral changes, molecular signals, neurotransmitters, and synaptic transmission. We aim to clarify some drug-induced cerebellar changes to supplement the previous research regarding the relationship between addiction and the cerebellum. Finally, we discuss the limitations and prospects of drug reward research on the cerebellum to provide novel insights into studying the cerebellum and its role in addiction. We recommend that future addiction network models should include the cerebellum to provide new therapeutic targets for treating addiction.

[Study of the association of lncRNA-GAS5 gene polymorphisms with systemic lupus erythematosus in Guangxi population].

OBJECTIVE: To assess the association of rs55829688 and rs75315904 polymorphisms of the lncRNA-GAS5 gene with susceptibility to systemic lupus erythematosus (SLE) in Guangxi population. METHODS: Peripheral venous blood samples were collected from the SLE group and control group. Following extraction of genomic DNA, SNPscan and Sanger sequencing were carried out to determine the genotypes for the rs55829688 and rs75315904 loci of the lncRNA-GAS5 gene. RESULTS: No difference was found between the two groups with regard to the genotypic frequencies for rs55829688 and rs75315904 (P > 0.05). However, the frequencies of C allele of rs55829688 between the two groups was significantly different (P < 0.05). In the SLE group, the frequencies of C allele and CT+CC genotype for rs55829688 among SLE patients with nephritis were significantly lower than those of SLE patients without nephritis (P < 0.05). In addition, haplotype analysis showed that the frequency of rs55829688 C/rs75315904 A allele in the SLE group was lower than that of the control group (P < 0.05). CONCLUSION: In Guangxi population, the carrier status of rs55829688 C allele of the lncRNA-GAS5 gene may reduce the risk of SLE and its complicated nephritis, and the rs55829688 C/rs75315904 A haplotype may reduce the risk for SLE.

Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality.

The human brain is a complex, three-dimensional structure. To better recapitulate brain complexity, recent efforts have focused on the development of human-specific midbrain organoids. Human iPSC-derived midbrain organoids consist of differentiated and functional neurons, which contain active synapses, as well as astrocytes and oligodendrocytes. However, the absence of microglia, with their ability to remodel neuronal networks and phagocytose apoptotic cells and debris, represents a major disadvantage for the current midbrain organoid systems. Additionally, neuroinflammation-related disease modeling is not possible in the absence of microglia. So far, no studies about the effects of human iPSC-derived microglia on midbrain organoid neural cells have been published. Here we describe an approach to derive microglia from human iPSCs and integrate them into iPSC-derived midbrain organoids. Using single nuclear RNA Sequencing, we provide a detailed characterization of microglia in midbrain organoids as well as the influence of their presence on the other cells of the organoids. Furthermore, we describe the effects that microglia have on cell death and oxidative stress-related gene expression. Finally, we show that microglia in midbrain organoids affect synaptic remodeling and increase neuronal excitability. Altogether, we show a more suitable system to further investigate brain development, as well as neurodegenerative diseases and neuroinflammation.

Clinical Outcomes of Taiwanese Patients with Resected Oral Cavity Squamous Cell Carcinoma Who Underwent Reconstruction with Free Versus Local Flaps.

BACKGROUND: We sought to compare the clinical outcomes of Taiwanese patients with resected oral cavity squamous cell carcinoma (OCSCC) who underwent reconstruction with free versus local flaps. METHODS: From 2011 to 2017, we examined 8646 patients with first primary OCSCC who received surgery either with or without adjuvant therapy. Of these patients, 7297 and 1349 received free and local flap reconstruction, respectively. Two propensity score-matched groups of patients who underwent free versus local flap (n = 1268 each) reconstructions were examined. Margin status was not included as a propensity score-matched variable. RESULTS: Compared with local flaps, patients who received free flaps had a higher prevalence of the following variables: male sex, age < 65 years, pT3-4, pN1-3, p-Stage III-IV, depth ≥ 10 mm, margin > 4 mm, extranodal extension (ENE), and adjuvant therapy (all p < 0.0001). Multivariable analysis identified the reconstruction method (local vs. free flaps, only overall survival [OS]), age ≥ 65 years, pT3-4, pN1-3, p-Stage III-IV, depth ≥ 10 mm (only OS), margins ≤ 4 mm, and ENE as independent adverse prognosticators for disease-specific survival (DSS) and OS. The results of propensity score-matched analyses revealed that, compared with free flaps, patients who underwent local flap reconstruction showed less favorable 5-year DSS (hazard ratio [HR] 1.26, 82%/77%; p = 0.0100) and OS (HR 1.21, 73%/68%; p = 0.0079). CONCLUSIONS: After adjusting for covariates using multivariate models, and also by propensity score modeling, OCSCC patients who underwent free flap reconstruction showed a higher frequency of clear margins and a significant survival advantage compared with those who received local flaps.

Nonreciprocal light transmission via optomechanical parametric interactions.

Nonreciprocal transmission of optical or microwave signals is indispensable in various applications involving sensitive measurements. In this paper, we study optomechanically induced directional amplification and isolation in a generic setup including two cavities and two mechanical oscillators by exclusively using blue-sideband drive tones. The input and output ports defined by the two cavity modes are coupled through coherent and dissipative paths mediated by the two mechanical resonators, respectively. By choosing appropriate transfer phases and strengths of the driving fields, either a directional amplifier or an isolator can be implemented at low thermal temperature, and both of them show bi-directional nonreciprocity working at two mirrored frequencies. The nonreciprocal device can potentially be demonstrated by opto- and electromechanical setups in both optical and microwave domains.

Systemic low-grade inflammation and depressive symptomology at chronic phase of ischemic stroke: The chain mediating role of fibrinogen and neutrophil counts.

BACKGROUND: Post-stroke depression (PSD) is the most common psychological consequence of stroke. Increased inflammatory markers resulting from ischemic stroke may played an important role in the pathogenesis of depressive symptomology. The present study was conducted to further elucidate the relationship between stroke severity, systemic low-grade inflammation and chronic phase post-stroke depressive symptomology (CP-PSDS). METHODS: A total of 897 stroke patients were consecutively recruited in this multicenter prospective cohort study and followed up for 1 year. The analytical sample consisted of 436 patients with ischemic stroke (23.4% female, median age = 57 years) from this cohort. Serum concentrations of inflammatory markers were measured in all 436 patients with ischemic stroke, from fasting morning venous blood samples on admission. Stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) on admission and post-stroke depressive symptomology (PSDS) was evaluated by 17-item Hamilton Rating Scale for Depression (HRSD). RESULTS: In the fully adjusted models, we observed that 1) NIHSS (Model 2: ß = 0.200, 95%CI, 0.057 ∼ 0.332), fibrinogen (Model 2: ß = 0.828, 95%CI, 0.269 ∼ 1.435), white blood cell counts (WBC, model 2: ß = 0.354, 95%CI, 0.122 ∼ 0.577) and neutrophil counts (Model 2: ß = 0.401, 95%CI, 0.126 ∼ 0.655) can independently predict the CP-PSDS after ischemic stroke onset; 2) fibrinogen (Indirect effect = 0.027, 95%CI, 0.007 ∼ 0.063, 13.4% mediated), WBC (Indirect effect = 0.024, 95%CI, 0.005 ∼ 0.058, 11.8% mediated) and neutrophil counts (Indirect effect = 0.030, 95%CI, 0.006 ∼ 0.069, 14.8% mediated) could partially mediate the association between stroke severity and CP-PSDS, and 3) stroke severity might cause CP-PSDS partly through the chain-mediating role of both fibrinogen and neutrophil counts (chain mediated effect = 0.003, 95%CI, 0.000 ∼ 0.011, p = 0.025, 1.6% mediated). CONCLUSIONS: Findings revealed that fibrinogen, WBC and neutrophil counts may be independent predictors of CP-PSDS and partial mediators of the relationship between stroke severity and CP-PSDS among patients with ischemic stroke. In addition, the chain mediating effect of fibrinogen and neutrophil counts might play an important role in the occurrence of CP-PSDS. However, no inflammatory markers were associated with CP-PSDS in females.