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Objective: This study aimed to evaluate the role of miRNA-492 in the progression of mycoplasma pneumoniae (MP) infection in pediatric patients. Methods: Forty-six children admitted to the present study’s hospital and diagnosed with mycoplasma pneumonia were recruited as the study group from March 2018 to August 2019, and 40 healthy children were selected as the control group. Results: The expression levels of miRNA-492, TNF-α, IL-6 and IL-18 in the study group were significantly higher than those in the control group (p < 0.05). There was no significant correlation between miRNA-492 and most of the immune-correlated indicators in the study group, except for IL-6, IL-18 and HMGB1. Meanwhile, overexpression of miRNA-492 increased IL-6 secretion in PMA-activated monocytes (p < 0.01). Conclusion: The present study’s results suggested that miRNA-492 might play a role in the pathogenesis of mycoplasma pneumoniae pneumonia in children by regulating the secretion of immune-inflammatory factors such as IL-6 and IL-18 in the mononuclear macrophages.

Organic cathode materials (OCMs) for rechargeable Li and Na batteries show great advantages in resource sustainability and huge potential in electrochemical performance but suffer from dissolution problems and costly synthesis. Herein, for the first time, we investigated the copolymer of benzoquinone (BQ) and pyrrole (Py), namely, poly(benzoquinone-pyrrole) (PBQPy), as an OCM for Li batteries. The low-cost raw materials and solvent-free synthesis provide PBQPy much brighter prospects in large-scale production compared to other carbonyl-based polymer cathode materials. Nevertheless, PBQPy showed one of the best electrochemical performances among all OCMs, including excellent energy density (2.32 V × 255 mAh g

By continuously alloying Nb with Mn, it transferred from an FM metal to an FIM metal to an AFM half-metal to an AFM semiconductor. These theoretical results provide keystone knowledge of regulating the electronic and magnetic properties by the alloying effect.

DNA double-strand breaks (DSBs) are highly toxic lesions that occur during the cellular metabolic process. DNA Polymerase theta (Polθ) is an error-prone polymerase that has been implicated in the repair of chromosome breaks, recovery of broken replication forks, and translesion synthesis. The inhibition of Polθ activity has been implicated in killing HR-deficient tumor cellsin vitroandin vivo. We present the first biochemical evidence that the antibiotics novobiocin (NVB) noncompetitively inhibit ATP hydrolysis by the ATPase domain of the Polθ helicase domain (Polθ-HLD). We report the Cryo-EM structure of apo dimeric Polθ helicase domain (Polθ-HLD), and the first inhibitor occupied Polθ-HLD structure. Our structure identifies a non-canonical novobiocin binding pocket, distinct from the canonical site that partially overlaps with the ATP in the ATPase domain. Comparison with the homolog helicase Hel308-DNA duplex complex suggests that the novobiocin competitively binds to a triangle hub on the DNA translocation pathway and blocks the ssDNA binding and translocation. Furthermore, the first dimeric structure of Polθ-HLD also provides a structural framework for revealing the microhomology-mediated end-joining mechanism. Our results demonstrate that the inhibitor-occupied structure combined with rational, structure-based drug design will undoubtedly accelerate the discovery of potent inhibitors with better efficacy and target selectivity to human Polθ.

With reversible O redox and increased Ni content, a Li-rich layered Mn-based cathode achieves a high-energy-density of 947 W h kg−1.

Increased mitochondrial reactive oxygen species (mROS) and glycolysis have been established in pulmonary hypertension (PH). However, the effect of elevated mROS on glycolytic shift and how increased glycolysis promotes hypoxic pulmonary artery smooth muscle cell (PASMC) proliferation and vascular remodeling remain elusive. Here, we reported that hypoxia-induced mROS inhibit HIF-1α hydroxylation and further trigger PASMC glycolytic switch through the upregulated HIF-1α/PDK1&PDK2/p-PDH-E1α axis, which facilitates lactate accumulation and histone lactylation. Through H3K18la and HIF-1α ChIP–seq analysis, we found that the enhanced histone lactylation of HIF-1α targets, such as Bmp5, Trpc5, and Kit, promotes PASMC proliferation. Knockdown of Pdk1&2 blunts lactate production, histone lactylation marks, and PASMC proliferation. Moreover, pharmacological intervention with lactate dehydrogenase inhibitor diminishes histone lactylation and ameliorates PASMC proliferation and vascular remodeling in hypoxic PH rats. Taken together, this study provides proof of concept for anti-remodeling therapy through lactate manipulation.

Mesocentrotus nudus is an economically important mariculture species. Identification of sex-related markers and candidate genes has potential implications for sex-control breeding of Mesocentrotus nudus. The aim of this study was to identify the molecular markers and genes associated with the sex of M. nudus. Initial GWAS analysis based on 80 individuals genotyped by using GBS identified 22 sex-related SNPs located on 9 GBS tags. Further targeted sequencing in another population of 124 individuals confirmed that 7 SNPs located on 7 GBS tags displayed complete associations with sex, suggesting a ZW/ZZ sex-determination system in M. nudus. Besides, genome and transcriptome annotations presented that the heat shock protein 75 kDa, mitochondrial (trap1), and protein furry homolog-like (fryl) may be important candidate genes involved in sex determination and differentiation in M. nudus. However, further studies are needed to elucidate the functions of these genes. Overall, the current results not only provide molecular markers that may contribute to the sex-control breeding for M. nudus, but also provide new insights to understand the regulatory mechanism of sea urchin sex.

Background Dual antiplatelet therapy is considered beneficial in acute ischemic stroke (AIS) patients with intracranial artery stenosis (ICAS), with more bleeding events. Ginkgolide is shown to reduce platelet activation after infarction, which might be of benefit in AIS. We aimed to explore the effect of Ginkgolide in AIS patients with ICAS. Methods This was a randomized, double‐blinded, placebo‐controlled trial conducted at 61 centers in China. Within 72 h after onset, consecutive patients diagnosed as AIS with ICAS were randomized to either Ginkgolide or placebo treatment. The primary outcome was the composite of mortality and recurrent stroke (ischemic or hemorrhagic) during first 4 weeks in an intention‐to‐treat analysis. Secondary functional outcome was assessed by modified Rankin Scale and improvement of stroke severity was assessed by National Institution of Health Stroke Scale at day 28. Safety outcome was measured by the rate of severe adverse event (SAE). Results There were 936 patients randomized to either Ginkgolide or placebo treatment. Their average age was 64.2 ± 10.4 years old and 36.0% of the patients were female. The composite index event occurred in six patients in placebo group, and none occurred in Ginkgolide group (risk ratio 1.01; 95% CI 1.00–1.02). There were more patients who achieved favorable outcome in Ginkgolide group, compared with that of the placebo group (OR 2.16, 95%CI 1.37–3.41). SAE occurred in five (1.1%) patients in the Ginkgolide group and three (0.6%) in the placebo group (OR0.60, 95CI% 0.14–2.53). Intracranial hemorrhage occurred in 1/473 (0.2%) in the placebo group. Conclusions Ginkgolide, working as PAF antagonist, may reduce recurrent stroke in AIS with ICAS patients within 72 hours after onset. It might be an optional treatment in moderate‐to‐severe AIS patients with ICAS. (http://www.chictr.org.cn Number as ChiCTR‐IPR‐17012310)., Although dual antiplatelet therapy is considered benefit in acute ischemic stroke (AIS) patients with intracranial artery stenosis (ICAS), there are more bleeding events. Ginkgolide, works as PAF antagonist, may reduce recurrent and mortality in AIS with large artery stenosis within 72 hours atfer onset during 90 days follow‐up. It might play a role of neuroprotection in AIS patients with ICAS

This study analyzed the correlation between the Notch3 mutation and stroke by testing an effective nanoparticle-loaded aspirin in stroke therapy. Fifty patients with ischemic stroke were followed for two years, and fifty healthy persons served as the control group. By RT-PCR, this study revealed that the Notch3 mutation existed in ischemic stroke patients who were more likely to have a family history, small vessel lesions, relatively frequent cerebral hemorrhage, and poor long-term prognosis. Liposome-aspirin-chitosan nanoparticle (LACN) was constructed as a nano-composite for stroke treatment. Notch3 Arg170Cys knock-in mice were prepared as a mutant Notch3 mouse model to test the LACN infiltration efficiency and observe the anti-stroke capacity. We found that LACN could better transport aspirin into brain vessels than the Polyethyleneimine (PEI) delivery system. However, in the Notch3 mutation mouse model, cerebral infarction and hemorrhage often occurred after being treated with aspirin. Still, LACN better prolongs the half-life of aspirin, rescues the pathological alteration of stroke in the brain, and reduces inflammatory reaction and oxidative stress response. In conclusion, the Notch3 mutation is closely related to stroke occurrence, and LACN may be a better choice for stroke therapy in the future.

The objective of this research is to study the effects of static resistance training of neck muscles on neck-type cervical spondylosis (NTCS) with upper cross syndrome (UCS). The NTCS patients with UCS were randomly divided into an observation group and a control group. The observation group was given conventional therapy plus static resistance training of neck muscles, while the control group was given conventional therapy plus ordinary cervical exercises. The scores of the visual analogue scale (VAS), neck disability index (NDI), and clinical assessment scale for cervical spondylosis (CASCS) and the cervical physiological curve were compared, and the overall efficacy was analyzed. After treatment, the VAS and NDI scores were lower in the observation group than in the control group. The cervical physiological curve was more significant in the observation group. The CASCS score was higher in the observation group than the control group after treatment. The observation group had obviously superior clinical efficacy. Therefore, in the treatment of NTCS with UCS, static resistance training of neck muscles can ameliorate the clinical symptoms of patients and restore the cervical physiological curve, with definite short-term efficacy, making it superior to ordinary cervical exercises, so it is worthy of clinical popularization.

Background Breast cancer (BRCA) has the highest incidence among female malignancies. Increasing evidence has confirmed that chromatin regulators (CRs) are involved in cancer progression. We aim to develop a chromatin regulators signature to predict the prognosis of BRCA patients. Methods The mRNA expression profiles and corresponding clinical data of BRCA patients were downloaded from TCGA databases, and then the differentially expressed CRs genes were screened. We also used the least absolute shrinkage and selection operator (LASSO) Cox regression model to construct a multigene signature with CRs genes of BRCA patients and evaluated the efficacy of the CRs prognostic signature with GEO validation cohort. Then, we explored the differences of tumor immune cell infiltration, tumor mutation burden (TMB), and patients’ response to chemotherapy between the different risk group. Results This CRs prognostic signature consisted of 8 chromatin regulators related genes, which was an independent prognostic factor of BRCA. The prognostic signature was further validated in GSE42568 cohort. According to the signature, patients with BRCA were divide into two risk groups. Functional annotation and the pathway analysis showed that the high-risk group had an enrichment of many tumor features, including cGMP-PKG signaling pathway, chromatin remodeling, DNA repair, thyroid cancer, cell cycle, homologous recombination, lysine degradation, pathways in cancer. Moreover, the immune cell types of tumor immune microenvironment and the TMB value of patients in the high-risk group was significantly different from those in low-risk group. ROC curves and nomogram indicated that the risk score had a good accuracy for predicting the survival of BRCA patients. Conclusions We identified a novel CRs prognostic signature which could precisely predict the prognosis of breast cancer patients. Our work elucidated that the CRs genes may serve as an indispensable player in complexity and diversity of tumor progression.

Congenital heart disease (CHDs) is the leading cause of mortality from birth defects, affecting up to 1% of live births. However, there have been inconsistent results of the relationship between aluminum (Al) /iron (Fe) level and risk of CHDs. We performed a pair-matched case–control study and included 97 cases and 194 controls to investigate the association and interaction between Al/Fe exposure and the risk of CHDs in a birth cohort study conducted in Lanzhou, China. Compared to 75th percentile of Al in total CHDs (aOR = 2.826, 95% CI: 1.009–7.266) and isolated CHDs (aOR = 10.713, 95% CI: 1.017–112.851). Although a similar pattern was not detected in MB of Al and Fe in both MB and CB, a significant dose-effect was observed between the Al level and total CHDs in both MB and CB (Ptrend

The purpose of this study is to investigate the unsafe conditions of pedestrian crossings at signalized intersections under the mixed traffic environment in Changsha, China. For this purpose, based...

Background and Purpose: Whether imaging parameters would independently predict stroke recurrence in low-risk minor ischemic stroke (MIS) or transient ischemic attack (TIA) according to traditional score system (such as ABCD 2 score, which was termed on the basis of the initials of the five factors: age, blood pressure, clinical features, duration, diabetes) remains unclear. We sought to evaluate the association between imaging parameters and 1-year stroke recurrence in patients with TIA or MIS in different risk stratum stratified by ABCD 2 score. Methods: We included patients with TIA and MIS (National Institutes of Health Stroke Scale score ≤3) with complete baseline vessel and brain imaging data from the Third China National Stroke Registry III. Patients were categorized into different risk groups based on ABCD 2 score (low risk, 0–3; moderate risk, 4–5; and high risk, 6–7). The primary outcome was stroke recurrence within 1 year. Multivariable Cox proportional-hazards regression models were used to assess whether imaging parameters (large artery stenosis, infarction number) were independently associated with stroke recurrence. Results: Of the 7140 patients included, 584 patients experienced stroke recurrence within 1 year. According to the ABCD 2 score, large artery stenosis was associated with higher stroke recurrence in both low-risk (adjusted hazard ratio, 1.746 [95% CI, 1.200–2.540]) and moderate-risk group (adjusted hazard ratio, 1.326 [95% CI, 1.042–1.687]) but not in the high-risk group ( P >0.05). Patients with multiple acute infarctions or single acute infarction had a higher risk of recurrent stroke than those with no infarction in both low- and moderate-risk groups, but not in the high-risk group. Conclusions: Large artery stenosis and infarction number were independent predictors of 1-year stroke recurrence in low-moderate risk but not in high-risk patients with TIA or MIS stratified by ABCD 2 score. This finding emphasizes the importance of early brain and vascular imaging evaluation for risk stratification in patients with TIA or MIS.

We aimed to identify whether

Although there has been enormous progress in the last half-century in the drug discovery targeting obesity and associated co-morbidities, the clinical treatment of obesity remains tremendously challenging. GPR75 is an orphan receptor and is suggested to be a potential novel target for the control of obesity and related metabolic disorders. Inhibition of the GPR75 signaling pathway by small molecules, antibodies, or genetic manipulations may provide a therapeutic strategy for obesity. Here, we report the active-like Cryo-EM structure of human GPR75 with an intracellular nanobody, which reveals the receptor activation mechanism. The extensive interaction network required to achieve the active structure helps explain the allosteric coupling between the orthosteric pocket and the G-protein coupling domain. The well-defined orthosteric ligand binding pocket of human GPR75 provides a structural basis for anti-obesity drug discovery.

The purpose of this study is to explore the levels of aluminum (Al) and iron (Fe) levels in maternal peripheral blood (MB) and cord blood (CB) and the relationship to the risk of congenital heart defects (CHDs) in the offspring. This matched-based birth cohort study with 194 controls and 97 CHDs-cases (proportion = 2:1) was included in this study. Serum concentrations of Al and Fe were measured by inductively coupled plasma mass spectroscopy. Conditional logistic regression model was employed to evaluate the influence of Al/Fe and its interaction on risk of fetal CHDs, adjusted for confounders. Compared to the low quartiles of Al level in CB, risk differences were significantly detected in the highest quartiles of Al in total CHDs (aOR = 2.826, 95% CI: 1.009–7.266) and isolated CHDs (aOR = 10.713, 95% CI: 1.017–112.851). A significant dose-effect was observed between the Al level and total CHDs in both MB and CB (Ptrend

Background: Hypertension is a risk factor of poor stroke outcomes and associated with antiplatelet resistance. This study aimed to explore the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in patients with different hypertension status, using randomized trial data from the CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II). Methods: A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles were enrolled and randomized to either ticagrelor-aspirin or clopidogrel-aspirin group. Hypertension status were classified into no, newly diagnosed, and previously diagnosed hypertension according to medical history, blood pressure, and antihypertensive medications during hospitalization. The primary efficacy and safety outcomes were stroke recurrence and moderate to severe bleeding risk within 90-day follow-up. Results: Ticagrelor-aspirin was associated with reduced risk of new stroke in patients without hypertension (32 [4.8%] versus 60 [7.2%]; hazard ratio, 0.55 [95% CI, 0.35–0.86]), but not in those with a newly diagnosed hypertension (20 [5.3%] versus 36 [9.1%]; hazard ratio 0.59 [95% CI, 0.33–1.07]), or those with a previously diagnosed hypertension (139 [7.0%] versus 147 [7.4%]; hazard ratio, 0.93 [95% CI, 0.74–1.18]) compared with clopidogrel-aspirin ( P =0.04 for interaction). The risk of bleeding for ticagrelor-aspirin was not associated with hypertension status (0.1% versus 0.4%; 0.3% versus 0.5%, 0.4% versus 0.3%, P =0.50 for interaction). All the efficacy and safety outcomes between treatments did not differ by blood pressure levels on admission. Conclusions: In the CHANCE-2 trial, patients without hypertension received a significantly greater benefit from ticagrelor- aspirin than those with previous hypertension after minor stroke or transient ischemic attack, and a similar benefit trend was observed in those with newly diagnosed hypertension. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04078737.

BackgroundHypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. Alveolar epithelial cells (AECs) primarily sense alveolar hypoxia, but the role of AECs in HPH remains unclear. In this study, we explored whether AECs are involved in pulmonary vascular remodeling and constriction.MethodsIn the constructed rat HPH model, hemodynamic and morphological characteristics were measured. By treating AECs with hypoxia, we further detected the levels of superoxide dismutase 2 (SOD2), catalase (CAT), reactive oxygen species (ROS) and hydrogen peroxide (H2O2), respectively. To detect the effects of AECs on pulmonary vascular remodeling and constriction, AECs and pulmonary artery smooth cells (PASMCs) were co-cultured under hypoxia, and PASMCs and isolated pulmonary artery (PA) were treated with AECs hypoxic culture medium. In addition, to explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used.ResultsHypoxia caused pulmonary vascular remodeling and increased pulmonary artery pressure, but had little effect on non-pulmonary vessels in vivo. Meanwhile, in vitro, hypoxia promoted the imbalance of SOD2 and CAT in AECs, leading to increased ROS and hydrogen peroxide (H2O2) production in the AECs culture medium. In addition, AECs caused the proliferation of co-cultured PASMCs under hypoxia, and the hypoxic culture medium of AECs enhanced the constriction of isolated PA. However, treatment with ROS inhibitor NAC effectively alleviated the above effects.ConclusionThe findings of present study demonstrated that AECs were involved in pulmonary vascular remodeling and constriction under hypoxia by paracrine H2O2into the pulmonary vascular microenvironment.