Chromatin accessibility during human first-trimester neurodevelopment.

The human brain develops through a tightly organized cascade of patterning events, induced by transcription factor expression and changes in chromatin accessibility. Although gene expression across the developing brain has been described at single-cell resolution1, similar atlases of chromatin accessibility have been primarily focused on the forebrain2-4. Here we describe chromatin accessibility and paired gene expression across the entire developing human brain during the first trimester (6-13 weeks after conception). We defined 135 clusters and used multiomic measurements to link candidate cis-regulatory elements to gene expression. The number of accessible regions increased both with age and along neuronal differentiation. Using a convolutional neural network, we identified putative functional transcription factor-binding sites in enhancers characterizing neuronal subtypes. We applied this model to cis-regulatory elements linked to ESRRB to elucidate its activation mechanism in the Purkinje cell lineage. Finally, by linking disease-associated single nucleotide polymorphisms to cis-regulatory elements, we validated putative pathogenic mechanisms in several diseases and identified midbrain-derived GABAergic neurons as being the most vulnerable to major depressive disorder-related mutations. Our findings provide a more detailed view of key gene regulatory mechanisms underlying the emergence of brain cell types during the first trimester and a comprehensive reference for future studies related to human neurodevelopment.

Vacancy-Defect Ternary Topological Insulators Bi2Se2Te Encapsulated in Mesoporous Carbon Spheres for High Performance Sodium Ion Batteries and Hybrid Capacitors.

Ternary topological insulators have attracted worldwide attention because of their broad application prospects in fields such as magnetism, optics, electronics, and quantum computing. However, their potential and electrochemical mechanisms in sodium ion batteries (SIBs) and hybrid capacitors (SIHCs) have not been fully studied. Herein, a composite material comprising vacancy-defects ternary topological insulator Bi2Se2Te encapsulated in mesoporous carbon spheres (Bi2Se2Te@C) is designed. Bi2Se2Te with ample vacancy-defects has a wide interlayer spacing to enable frequent insertion/extraction of Na+ and boost reaction kinetics within the electrode. Meanwhile, the Bi2Se2Te@C with optimized yolk-shell structure can buffer the volume variation without breaking the outer protective carbon shell, ensuring structural stability and integrity. As expected, the Bi2Se2Te@C electrode delivers high reversible capacity and excellent rate capability in half SIB cells. Various electrochemical analyses and theoretical calculations manifest that Bi2Se2Te@C anode confirms the synergistic effect of ternary chalcogenide systems and suitable void space yolk-shell structure. Consequently, the full cells of SIB and SIHC coupled with Bi2Se2Te@C anode exhibit good performance and high energy/power density, indicating its widespread practical applications. This design is expected to offer a reliable strategy for further exploring advanced topological insulators in Na+-based storage systems.

Native Approach to Controlled-Z Gates in Inductively Coupled Fluxonium Qubits.

The fluxonium qubits have emerged as a promising platform for gate-based quantum information processing. However, their extraordinary protection against charge fluctuations comes at a cost: when coupled capacitively, the qubit-qubit interactions are restricted to XX interactions. Consequently, effective ZZ or XZ interactions are only constructed either by temporarily populating higher-energy states, or by exploiting perturbative effects under microwave driving. Instead, we propose and demonstrate an inductive coupling scheme, which offers a wide selection of native qubit-qubit interactions for fluxonium. In particular, we leverage a built-in, flux-controlled ZZ interaction to perform qubit entanglement. To combat the increased flux-noise-induced dephasing away from the flux-insensitive position, we use a continuous version of the dynamical decoupling scheme to perform noise filtering. Combining these, we demonstrate a 20 ns controlled-z gate with a mean fidelity of 99.53%. More than confirming the efficacy of our gate scheme, this high-fidelity result also reveals a promising but rarely explored parameter space uniquely suitable for gate operations between fluxonium qubits.

The Warburg effect drives cachectic states in patients with pancreatobiliary adenocarcinoma.

We have studied whether the Warburg effect (uncontrolled glycolysis) in pancreatobiliary adenocarcinoma triggers cachexia in the patient. After 74 pancreatobiliary adenocarcinomas were removed by surgery, their glucose transporter-1 and four glycolytic enzymes were quantified using Western blotting. Based on the resulting data, the adenocarcinomas were equally divided into a group of low glycolysis (LG) and a group of high glycolysis (HG). Energy homeostasis was assessed in these cancer patients and in 74 non-cancer controls, using serum albumin and C-reactive protein and morphometrical analysis of abdominal skeletal muscle and fat on computed tomography scans. Some removed adenocarcinomas were transplanted in nude mice to see their impacts on host energy homeostasis. Separately, nude mice carrying tumor grafts of MiaPaCa-2 pancreatic adenocarcinoma cells were treated with the glycolytic inhibitor 3-bromopyruvate and with emodin that inhibited glycolysis by decreasing hypoxia-inducible factor-1α. Adenocarcinomas in both group LG and group HG impaired energy homeostasis in the cancer patients, compared to the non-cancer reference. The impaired energy homeostasis induced by the adenocarcinomas in group HG was more pronounced than that by the adenocarcinomas in group LG. When original adenocarcinomas were grown in nude mice, their glycolytic abilities determined the levels of hepatic gluconeogenesis, skeletal muscle proteolysis, adipose-tissue lipolysis, and weight loss in the mice. When MiaPaCa-2 cells were grown as tumors in nude mice, 3-bromopyruvate and emodin decreased tumor-induced glycolysis and cachexia, with the best effects being seen when the drugs were administered in combination. In conclusion, the Warburg effect in pancreatobiliary adenocarcinoma triggers cancer cachexia.

Allogeneic stem cell transplantation is still a highly curative therapy in adults with philadelphia chromosome-positive acute lymphoblastic leukaemia.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Four undescribed coumarin derivatives, with ten amides from the roots of Ficus hirta and their cytotoxic activities.

Four undescribed coumarin derivatives, ficusalt A (1) and ficusalt B (2), a pair of racemic coumarins, (±) ficudimer A (3a/3b), along with ten known amides, were isolated from the roots of Ficus hirta. Their structures were elucidated by several spectroscopic data analyses, including HRESIMS, NMR, and X-ray single-crystal diffraction. The cytotoxic activities of all compounds against HeLa, HepG2, MCF-7, and H460 cell lines were detected using the MTT assay. Among these, 5 showed the highest activity against HeLa cells. Subsequently, the apoptotic, anti-invasive, and anti-migration effects of 5 on HeLa cells were determined by flow cytometer, transwell invasion assay, and wound-healing assay, respectively. The result suggested that 5 distinctly induced the apoptosis in HeLa cells and inhibited their invasion and migration. Further studies on anticancer mechanisms were conducted using Western blotting. As a result, 5 increased the cleavage of PARP and the expression of pro-apoptotic protein Bax. Moreover, 5 notably upregulated the phosphorylation of p38 and JNK, whereas inhibited the expression of p-ERK and p-AKT. Our results demonstrated that 5 could be a potential leading compound for further application in the treatment of cervical cancer.

High lipoprotein(a) concentration is associated with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) has attracted the attention of scholars because of its rarity and unknown etiology. METHODS: Data for this study were sourced from the Second Affiliated Hospital of Nanchang University. Regression analyses were conducted to examine the association in Lipoprotein [Lp(a)] and MMD. R and IBM SPSS were conducted. RESULTS: A cohort comprising 1012 MMD patients and 2024 controls was established through the propensity score matching method. Compared with controls, MMD patients showed higher median Lp(a) concentrations [18.5 (9.6-37.8) mg/dL vs. 14.9 (7.8-30.5) mg/dL, P < 0.001]. The odds ratios and 95% confidence intervals for Lp(a) were calculated in three models: unadjusted model, model 1 (adjusted for body mass index and systolic blood pressure), and model 2 (adjusted for model 1 plus triglyceride, C-reactive protein, homocysteine, and low-density lipoprotein cholesterol). Results were [1.613 (1.299-2.002), P < 0.001], [1.598 (1.286-1.986), P < 0.001], and [1.661 (1.330-2.074), P < 0.001], respectively. Furthermore, age, sex, or hypertension status had nothing to do with this relationship. CONCLUSIONS: Positive relationship exists between Lp(a) and MMD.

Efficacy of acellular fish skin graft in the management of chronic ulcer: a systematic review and meta-analysis.

BACKGROUND: The wounds failing to heal through a timely and orderly standard of care (SOC) treatment are considered as chronic wounds, which add significant burden to healthcare systems around the world. SOC treatment has been commonly applied for management of chronic wounds, but SOC alone may not be adequate to heal all ulcers effectively. Fish skin graft (FSG) is a xenogenic skin substitute which could be used for accelerating skin healing. The current study was performed with the view of evaluating the effectiveness of FSG as an adjuvant treatment of SOC for chronic ulcer treatment. METHODS: Two authors independently searched the following electronic databases: PubMed, Embase, and CENTRAL, using keywords including "diabetic foot ulcer," "fish skin graft," and "wound healing." Clinical studies that evaluated the clinical outcomes of FSG in treatment of chronic ulcers were included in this meta-analysis. Random- or fixed-effect modeled meta-analyses were performed according to the heterogeneity test result (i.e., I2), to analyze the clinical outcome of FSG. RESULTS: A total of 8 studies were included in qualitative synthesis and meta-analysis, with 145 patients treated by SOC and 245 patients treated by SOC plus FSG. There was no significant difference between two groups for time to healing (MD = 1.99, 95% CI: -3.70~7.67, p = 0.493). The complete healing rate was significantly higher in FSG group compared with SOC alone (OR = 3.44, 95% CI: 2.03~5.82, p < 0.001***). Mean percentage area reduction (PAR) was reported in six studies, with a range of 71.6~97.3%. However, many of these studies did not report the value of standard deviation (SD), so we could not pool the data. No significantly different ulcer recurrence rate (RR = 0.60, 95% CI: 0.07~5.27, p = 0.645) and severe adverse events (SAEs) risk (RR = 1.67, 95% CI: 0.42~6.61, p = 0.467) were found between two groups. CONCLUSIONS: The application of FSG treatment for patients with chronic ulcers that do not respond well to SOC management could significantly increase the complete healing rate compared with SOC alone, without increased recurrence rate and SAEs risk.

Effects and long-term outcomes of endurance versus resistance training as an adjunct to standard medication in patients with stable COPD: a multicenter randomized trial.

BACKGROUND: Comparisons between endurance training (ET) and resistance training (RT) have produced equivocal findings in chronic obstructive pulmonary disease (COPD) patients. The purpose of our study is to investigate the effectiveness and long-term outcomes of adding ET and RT to conventional medical treatment in patients with COPD. A secondary objective is to investigate the clinical improvements resulting from exercise training in patients with different disease severities. METHODS: The study was a multicenter, prospective trial in people with stable COPD. The cohort was randomized to three groups: individualized medical treatment group (MT), MT + endurance training group (MT + ET) and MT + resistance training group (MT + RT). Exercise was performed 3 times weekly over a 12-week period. The endpoints of exercise capacity, health-related quality of life, COPD symptoms, lung function, and anxiety and depression questionnaires were re-evaluated at baseline, at the completion of the intervention and at 6 and 12-month follow-up. According to the COPD assessment tool offered by GOLD guidelines, patients were stratified into GOLD A and B groups and GOLD C and D groups for further subgroup analysis. RESULTS: The intention-to-treat (ITT) population included 366 patients, 328 of them completed the study protocol over 12 months (the PP-population). There were no significant differences in the primary outcome, quality of life, between patients who underwent medical treatment (MT) alone, MT + endurance training (MT + ET), or MT + resistance training (MT + RT) at the completion of the intervention, 6-, or 12-month follow-up. Additionally, no significant differences were observed between MT, MT + RT, or MT + ET groups concerning the primary outcome, exercise capacity (3MWD), after initial 3 months of intervention. However, a small statistically significant difference was noted in favor of MT + ET compared to MT + RT at 12 months (ITT: Δ3MWD in ET vs RT = 5.53 m, 95% confidence interval: 0.87 to 13.84 m, P = 0.03) (PP: Δ3MWD in ET vs RT = 7.67 m, 95% confidence interval: 0.93 to 16.27 m, P = 0.04). For patients in the GOLD C and D groups, improvement in quality of life following ET or RT was significantly superior to medical intervention alone. Furthermore, upon completion of the exercise regimen, RT exhibited a greater improvement in anxiety compared to ET in these patients (ITT: ΔHAD-A at 3-month: RT = -1.63 ± 0.31 vs ET = -0.61 ± 0.33, p < 0.01) (PP: ΔHAD-A at 3-month: RT = -1.80 ± 0.36 vs ET = -0.75 ± 0.37, p < 0.01). CONCLUSIONS: Our study presents evidence of the beneficial effects of ET and RT in combination with standard medical treatment, as well as the long-term effects over time after the intervention. While the statistically significant effect favoring ET over RT in terms of exercise capacity was observed, it should be interpreted cautiously. Patients in severe stages of COPD may derive greater benefits from either ET or RT and should be encouraged accordingly. These findings have implications for exercise prescription in patients with COPD. TRIAL REGISTRATION: ChiCTR-INR-16009892 (17, Nov, 2016).

[Effect of Naotaifang on microglial polarization and glial scar following cerebral ischemia reperfusion injury].

This study aims to investigate the effect of Naotaifang(NTF) on the proteins associated with microglial polarization and glial scar in the rat model of cerebral ischemia reperfusion injury(CIRI). The CIRI model was established by middle cerebral artery occlusion/reperfusion. The 48 successfully modeled rats were randomized into model 7 d, model 14 d, NTF 7 d, and NTF 14 d groups(n=12). In addition, 12 SD rats were selected as the sham group. The NTF group was administrated with NTF suspension at 27 g·kg~(-1)·d~(-1) by gavage, and the sham, model 7 d, and model 14 d groups were administrated with the same volume of normal saline every day by gavage for 7 and 14 days, respectively. After the intervention, Longa score was evaluated. The infarct volume was measured by 2,3,5-triphenyl-2H-tetrazolium chloride(TTC) staining. Morris water maze and open field tests were carried out to evaluate the spatial learning, memory, cognitive function, and anxiety degree of rats. Hematoxylin-eosin(HE) staining was employed to observe the morphological structure and damage of the brain tissue. The immunofluorescence assay was employed to measure the expression of glial fibrillary acidic protein(GFAP) and glial scar. Western blot was employed to determine the protein levels of GFAP, neurocan, phosphacan, CD206, arginase-1(Arg-1), interleukin(IL)-1ß, IL-6, and IL-4. Compared with the sham, model 7 d and model 14 d groups showed cerebral infarction of different degrees, severe pathological injury of cerebral cortex and hippocampus, neurological impairment, reduced spatial learning and memory, cognitive dysfunction, severe anxiety, astrocyte hyperplasia, thickening penumbra glial scar, and up-regulated protein levels of IL-1ß, IL-6, GFAP, neurocan, phosphacan, CD206, and Arg-1(P<0.01). Compared with the model group, NTF 7 d and NTF 14 d groups improved spatial learning, memory, and cognitive function, reduced anxiety, improved nerve function, reduced cerebral infarction volume, reduced astrocyte hyperplasia, thinned penumbra glial scar, down-regulated the protein levels of GFAP, neurocan, phosphacan, IL-6, and IL-1ß, and up-regulated the protein levels of IL-4, CD206, and Arg-1(P<0.05 or P<0.01). NTF exerts a neuroprotective effect on CIRI by inducing the M2 polarization of microglia, inhibiting inflammatory response, and reducing the formation of glial scar.

Insight into the lncRNA-mRNA Co-Expression Profile and ceRNA Network in Lipopolysaccharide-Induced Acute Lung Injury.

Long non-coding RNAs (lncRNAs) participate in acute lung injury (ALI). However, their latent biological function and molecular mechanism have not been fully understood. In the present study, the global expression profiles of lncRNAs and mRNAs between the control and lipopolysaccharide (LPS)-stimulated groups of human normal lung epithelial cells (BEAS-2B) were determined using high-throughput sequencing. Overall, a total of 433 lncRNAs and 183 mRNAs were differentially expressed. A lncRNA-mRNA co-expression network was established, and then the top 10 lncRNAs were screened using topological methods. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis results showed that the key lncRNAs targeting mRNAs were mostly enriched in the inflammatory-related biological processes. Gene set variation analysis and Pearson's correlation coefficients confirmed the close correlation for the top 10 lncRNAs with inflammatory responses. A protein-protein interaction network analysis was conducted based on the key lncRNAs targeting mRNAs, where IL-1ß, IL-6, and CXCL8 were regarded as the hub genes. A competing endogenous RNA (ceRNA) modulatory network was created with five lncRNAs, thirteen microRNAs, and twelve mRNAs. Finally, real-time quantitative reverse transcription-polymerase chain reaction was employed to verify the expression levels of several key lncRNAs in BEAS-2B cells and human serum samples.

COVID-19 infection in patients with haematological malignancies: A single-centre survey in the latest Omicron wave in China.

As the COVID-19 variant Omicron surge in Beijing, China, a better understanding of risk factors for adverse outcomes may improve clinical management in patients with haematological malignancies (HM) diagnosed with COVID-19. The study sample includes 412 cases, mainly represented by acute leukaemia, chronic myeloid leukaemia (CML), plasma cell disorders and lymphoma and chronic lymphocytic leukaemia. COVID-19 pneumonia was observed in 10.4% (43/412) of patients, and severe/critical illness was observed in 5.3% (22/412). Among the 86 cases with advanced malignancies, 17.6% (12/86) of patients developed severe/critical COVID-19, which was significantly higher than reported in patients with stable malignancies (9/326, 2.70%, p < 0.001). Similarly, the advanced malignancy cohort had a higher mortality rate (9/86, 10.5% vs. 0/326, 0%, p < 0.001) and a poor 30-day overall survival (OS) compared with the stable malignancy cohort (74.2% vs. 100.0%, p < 0.0001). Overall, nine patients (2.2%) died. The primary cause of death was progressive HM in four patients and a combination of both COVID-19 and HM in five patients. In the multivariable analysis, over 65 years of age, comorbidities and advanced malignancy were correlated with severe/critical COVID-19 in HM patients. This study sheds light on the poor outcomes among COVID-19 HM patients with the leading cause of advanced malignancy.

Improvement of vaginal probiotics Lactobacillus crispatus on intrauterine adhesion in mice model and in clinical practice.

BACKGROUND: Intrauterine adhesion (IUA) is a frequent acquired endometrial condition, for which there is no effective preventive or treatment. Previous studies have found that vaginal microbiota dysregulation is closely related to endometrial fibrosis and IUA. Therefore, we wondered whether restoration of vaginal microbiota by vaginal administration of L. crispatus could prevent endometrial fibrosis and ameliorate IUA. RESULTS: First, we created a mechanically injured mouse model of IUA and restored the mice's vaginal microbiota by the addition of L. crispatus convolvulus. The observations suggested that intrauterine injections of L. crispatus significantly decreased the degree of uterine fibrosis, the levels of IL-1ß and TNF-α in blood, and downregulated the TGF-ß1/SMADs signaling pathway in IUA mice. A therapy with L. crispatus considerably raised the abundance of the helpful bacteria Lactobacillus and Oscillospira and restored the balance of the vaginal microbiota in IUA mice, according to high-throughput sequencing. Then we conducted a randomized controlled trial to compare the therapeutic effect of L. crispatus with estrogen after transcervical resection of adhesion (TCRA). And the results showed that vaginal probiotics had a better potential to prevent intrauterine adhesion than estrogen. CONCLUSIONS: This study confirmed that L. crispatus could restore vaginal microbiota after intrauterine surgery, inhibit endometrial fibrosis, and finally play a preventive and therapeutic role in IUA. At the same time, it is a new exploration for the treatment of gynecological diseases with vaginal probiotics. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn/ , identifier (ChiCTR1900022522), registration time: 15/04/2019.

Comparison of efficacy between homoharringtonine, aclarubicin, cytarabine (HAA) and idarubicin, cytarabine (IA) regimens as induction therapy in patients with de novo core binding factor acute myeloid leukemia.

To compare efficacy between homoharringtonine combined with cytarabine and aclarubicin (HAA) and idarubicin and cytarabine (IA) regimens as first induction chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML). Cox regression model and propensity score matching (PSM) were used to identify the regimen associated with a better remission rate and outcomes. In total, 374 patients with CBF-AML (243 with RUNX1::RUXN1T1 and 131 with CBFB::MYH11) were included in this study. The patients received the HAA or IA regimen (187 each) as the first induction therapy. For patients with RUNX1::RUXN1T1, multivariate analyses showed that the HAA regimen was significantly associated with a higher CR/CRi rate after the first induction (hazard ratio [HR] = 5.3 [95% CI 2.3, 12.2]; p < 0.001) and more favorable relapse-free survival (RFS) (HR = 0.5 [0.3, 0.8], p = 0.01). In PSM analysis, the HAA regimen also had a higher CR/CRi rate (96% vs. 77%, p < 0.001), especially for those harboring wild-type KIT (KITWT) (96% vs. 83%, p = 0.02) or non-D816 KIT mutation (100% vs. 63%, p = 0.002), as well as more favorable RFS (p = 0.01), compared with the IA regimen. However, there was no difference in the remission rate or outcomes between the two regimens for patients with CBFB::MYH11. The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KITWT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

Inhibition of gp130 alleviates LPS-induced lung injury by attenuating apoptosis and inflammation through JAK1/STAT3 signaling pathway.

BACKGROUND AND OBJECTIVE: Acute lung injury or acute respiratory distress syndrome (ALI/ARDS) is a life-threatening respiratory disease. Gp130 is a signal transduction receptor that participates in a variety of essential biological processes. The biological function of gp130 in ALI/ARDS is unclear. This study aims to investigate the roles and potential mechanisms of gp130 in lung injury induced by lipopolysaccharide (LPS). METHODS: The ALI/ARDS mouse model was established using intratracheal LPS administration. Hematoxylin and eosin staining and bronchoalveolar lavage fluid analysis were used to evaluate the degree of lung injury. Cell apoptosis was assessed by TUNEL staining, flow cytometry, and western blot. Then the expression of gp130, IL-6, IL-10, TNF-α, and the JAK1/STAT3 signaling pathway-related proteins was assessed by RT-PCR, western blot, and immunohistochemistry. RESULTS: The expression of gp130 increased after 24 h of LPS treatment. Inhibiting gp130 improved inflammatory infiltration and alveolar collapsed, decreased IL-6 and TNF-α levels, raised IL-10 levels, and decreased cell apoptosis in LPS-induced mice. Meanwhile, suppressing gp130 reduced the inflammatory response and cell apoptosis in LPS-induced Beas-2B cells. Furthermore, p-JAK1 and p-STAT3 expressions were elevated after LPS stimulation and decreased following gp130 inhibition, suggesting that gp130 may regulate the JAK1/STAT3 signaling pathway in LPS-induced mice and Beas-2B cells. CONCLUSION: The findings suggest that gp130 regulates the inflammatory response and cell apoptosis through the JAK1/STAT3 signaling pathway, thereby mitigating LPS-induced lung injury. Gp130 may be a potential therapeutic target for ALI/ARDS.

SIRT6 ameliorates LPS-induced apoptosis and tight junction injury in ARDS through the ERK1/2 pathway and autophagy.

Sirtuin6 (SIRT6) has been demonstrated to be involved in a range of physiological processes and diseases, while its role in acute respiratory distress syndrome (ARDS) remains unclear. Therefore, this study focused on the role and underlying mechanism of SIRT6 in ARDS with the aim of identifying potential therapeutic targets. In this study, we found that SIRT6 was significantly decreased in lipopolysaccharide (LPS)-induced A549 cells and a murine model. In vitro overexpression of SIRT6 restored the expression of tight junction proteins (ZO-1 and occludin) and alleviated cell apoptosis and inflammation, while knockdown of SIRT6 aggravated the loss of tight junction proteins (ZO-1 and occludin) and promoted cell apoptosis and inflammation in LPS-induced A549 cells. Furthermore, the overexpression of SIRT6 enhanced autophagy and inhibited the ERK1/2 pathway, while the knockdown of SIRT6 inhibited autophagy and activated the ERK1/2 pathway. The autophagy activator rapamycin and the ERK1/2 inhibitor PD98059 rescued the effects of SIRT6 knockdown on tight junction proteins, apoptosis, and inflammation. Mechanistically, SIRT6 deacetylated histone 3 at Lys9 to negatively regulate the ERK1/2 pathway. In vivo, the SIRT6-specific inhibitor OSS_128167 also significantly accelerated LPS-induced loss of tight junction proteins, lung inflammation, and apoptosis. Meanwhile, the SIRT6-specific inhibitor OSS_128167 also activated the ERK1/2 pathway and inhibited lung autophagy. These results suggested that SIRT6 could ameliorate the loss of tight junction proteins, inflammation, and apoptosis in LPS-induced ARDS by inhibiting the ERK1/ 2 pathway and enhancing autophagy, indicating that SIRT6 plays a beneficial role in ARDS and might be a potential therapeutic target for ARDS.

Transcriptomic analysis reveals key genes and pathways corresponding to Cd and Pb in the hyperaccumulator Arabis paniculata.

Soil and water are increasingly at risk of contamination from the toxic heavy metals lead (Pb) and cadmium (Cd). Arabis paniculata (Brassicaceae) is a hyperaccumulator of heavy metals (HMs) found widely distributed in areas impacts by mining activities. However, the mechanism by which A. paniculata tolerates HMs is still uncharacterized. For this experiment, we employed RNA sequencing (RNA-seq) in order to find Cd (0.25 mM)- and Pb (2.50 mM)-coresponsive genes A. paniculata. In total, 4490 and 1804 differentially expressed genes (DEGs) were identified in root tissue, and 955 and 2209 DEGs were identified in shoot tissue, after Cd and Pb exposure, respectively. Interestingly in root tissue, gene expression corresponded similarly to both Cd and Pd exposure, of which 27.48% were co-upregulated and 41.00% were co-downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that the co-regulated genes were predominantly involved in transcription factors (TFs), cell wall biosynthesis, metal transport, plant hormone signal transduction, and antioxidant enzyme activity. Many critical Pb/Cd-induced DEGs involved in phytohormone biosynthesis and signal transduction, HM transport, and transcription factors were also identified. Especially the gene ABCC9 was co-downregulated in root tissues but co-upregulated in shoot tissues. The co-downregulation of ABCC9 in the roots prevented Cd and Pb from entering the vacuole rather than the cytoplasm for transporting HMs to shoots. While in shoots, the ABCC9 co-upregulated results in vacuolar Cd and Pb accumulation, which may explain why A. paniculata is a hyperaccumulator. These results will help to reveal the molecular and physiological processes underlying tolerance to HM exposure in the hyperaccumulator A. paniculata, and aid in future efforts to utilize this plant in phytoremediation.

Identification of potential prognostic biomarkers in vulval squamous cell carcinoma based on human papillomavirus infection Status-Analysis of GSE183454.

This study aimed to elucidate the differences in vulval squamous cell carcinomas (VSCC) based on the HPV infection status. The sequencing data GSE183454 which contains 23 VSCC samples based on its HPV infection status was obtained from the Gene Expression Omnibus (GEO) database. We comprehensively dissected the differences of genomic and tumour microenvironment (TME) immune cell infiltration landscapes between HPV + and HPV- VSCC. The potential molecular mechanisms of prognostic genes were explored by functional enrichment analysis. Five novel key molecules (SYCP2, SMC1B, RNF212, MAJIN and C14orf39) with significantly up-regulated expression in HPV + VSCC were identified while protein-protein interaction (PPI) networks were created upon Cytoscape software. Additionally, VSCC with up-regulated expression of these key molecules exhibited a significantly decreased TME immune cell infiltration. SYCP2 is overexpressed in HPV + VSCC and could be a candidate therapy target for further research.IMPACT STATEMENTWhat is already known on this subject? VSCC are characterised by two aetiological pathways. The former occurs in the background of lichen sclerosus, while the latter is related to HPV infection. VSCC most commonly arises from the non-HPV related pathway portends worse prognosis than VSCC derived from HPV infection.What do the results of this study add? Five key molecules are identified and significantly up-regulated in HPV + VSCC. In which, SYCP2 is overexpressed in HPV + VSCC and exhibited a significantly decreased TME immune cell infiltration. SYCP2 constant expression could be a potential biomarker of neoplasms associated with HPV and could be a candidate therapy target in VSCC especially HPV + VSCC for further research.What are the implications of these findings for clinical practice and/or further research? SYCP2 could be a candidate therapy target in VSCC especially with HPV + for further research.

Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.

BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study. METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo. RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo. CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.