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The Family Adaptability and Cohesion Scale III (FACES-III) has been widely used to measure an individual’s family functioning in terms of cohesion and adaptability. In Malaysia, the FACES-III has been translated into the Malay language for the community, but its psychometric properties in this context remain unknown. Thus, the purpose of this research is to examine the psychometric properties of the Malay version of the FACES-III in 852 adolescents attending secondary schools in Kuala Lumpur, Malaysia. Data were randomly split into two halves: the exploration sample and the validation sample. Exploratory factor analysis was conducted on the exploration sample and a two-factor model was discovered after removing nine items that showed low factor loading. Then, confirmatory factor analysis was conducted on the validation sample to compare the one-factor models, two-factor models, and three-factor models. Results showed that the 11-item two-factor model (FACES-III-M-SF) was superior to the other competing models. Both the exploratory and confirmatory factor analyses replicated the two-factor structure of the original version of FACES-III. The reliability of the overall scale was consistently good, but the subscale results were mixed. This suggests that researchers should use the overall score, but not the subscale scores, in analyses.

β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by β-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the β-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of β-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates β-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1β up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.严重急性呼吸系统综合症冠状病毒2型 (SARS-CoV-2) 是导致全球2019冠状病毒病 (COVID-19) 大流行的病原体。大量研究表明，心血管疾病可能会影响COVID-19的进展。在该研究中，我们使用感染了 SARS-CoV-2 的高血压小鼠模型研究了高血压对病毒复制和 COVID-19 进展的影响。结果显示，在高血压小鼠的肺中SARS-CoV-2的复制延迟。相比之下，用抗高血压药物卡托普利治疗的高血压小鼠的SARS-CoV-2 复制与感染了SARS-CoV-2 的正常血压小鼠的病毒复制相似。此外，抗高血压治疗减轻了由 SARS-CoV-2 复制引起的IL-1β上调和免疫细胞浸润增加。在感染 SARS-CoV-2 的血压正常小鼠和高血压小鼠之间没有观察到肺部炎症的差异。因此，我们的研究结果初步表明，卡托普利治疗可能会缓解COVID-19的进展，但不会影响病毒复制。.

The primary outbreak of severe acute respiratory syndrome coronavirus 2, causing pneumonia-like symptoms in patients named coronavirus disease 2019 (COVID-19) had evolved into a global pandemic. COVID-19 has surpassed Middle East respiratory syndrome and severe acute respiratory syndrome in terms of rate and scale causing more than one million deaths. Development of an effective vaccine to fight against the spread of COVID-19 is the main goal of many countries around the world and plant-based vaccines are one of the available methods in vaccine developments. Plant-based vaccine has gained its reputation among researchers for its known effective manufacturing process and cost effectiveness. Many companies around the world are participating in the race to develop an effective vaccine by using the plant system. This review discusses different approaches used as well as highlights the challenges faced by various companies and research groups in developing the plant-based COVID-19 vaccine.

Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy.

Marine fungi are potentially important resources for bioactive lead compounds for discovering new drugs for diseases such as Alzheimer’s disease. In this paper, the combined bioassay model of acetylcholinesterase (AChE) inhibition, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging, and Artemia larval lethality was used to evaluate the activity and toxicity of 35 marine fungal strains from seas around China. Their bioactive constituents were revealed by thin layer chromatography (TLC) autography, bioactivity coupled LC–MS/MS and Global Natural Products Social Molecular Networking (GNPS). The results show that the extracts of five strains exhibited higher AChE inhibition ratios than the positive control compound, ‘tacrine’, for which the ratio was 89.8% at 200 μg/ml. Six strains displayed both AChE inhibition (inhibition ratios > 20% at 200 μg/ml) and DPPH scavenging activity (scavenging ratios > 30% at 200 μg/ml) together with low Artemia larval toxicity (lethal rates Talaromyces sp. C21-1, Aspergillus terreus C23-3, Trichoderma harzianum DLEN2008005, and Penicillium corylophilum TBG1-17. From the most potent sample F-11-1-b (derived from Aspergillus terreus C23-3), five AChE inhibitors and seven antioxidants were recognized as bioactive molecules by AChE coupled ultrafiltration followed by LC–MS/MS, and LC–MS/MS coupled with DPPH incubation. Furthermore, with the aid of GNPS, the AChE inhibitors were plausibly annotated as territrem analogues including territrems A–C/D, arisugacin A and an unknown compound 4, and the seven antioxidants were assigned as butyrolactone Ι, aspernolide E, a phenolic derivative and possibly unknown compounds 8–10 and 12.

Background and aim: Adolescent suicide has become a central issue around the world, including in Malaysia, which needs attention. The current study investigated the mediating effect of coping strategy in the association between family functioning and suicidal ideation among adolescents in Kuala Lumpur, Malaysia. Method: A total of 852 school-attending adolescents aged 13-17 years were recruited by multistage cluster sampling. The relationships between all the study variables were analysed using Pearson's correlation. Moreover, the mediation model was tested using SPSS PROCESS macro, while sex differences in suicidal ideation were examined using independent samples t-test. Results: Results showed that family cohesion, family flexibility, and problem-focused coping negatively correlated with adolescents' suicidal ideation. Problem-focused coping also mediated the association between family flexibility and suicidal ideation. There was a significant difference in suicidal ideation for males and females. Conclusion: Family functioning and coping strategy are related to adolescents' suicidal ideation, while problem-focused coping plays a crucial role in the relationship between family flexibility and suicidal ideation.

A new isoflavone derivative compound 1 (psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreus C23-3, together with seven known compounds including isoflavones 2–6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitro anti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2 (genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5 (biochanin A), 6 (psoralenol), and 7 exhibited potent larvicidal activity against brine shrimp. Compounds 3 (daidzein), 4 (4ʹ-hydroxy-6,7-dimethoxyisoflavone), and 5–7 showed broad-spectrum anti-microbial activity, and compound 7 also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity.

Piebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SNAI2 genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. Herein, we report a 5-month-old Chinese girl with severe piebaldism but no family history thereof. She has white forelock and large patches of depigmentation in the jaw, central anterior trunk, perineum and extremities. We performed whole-exome and Sanger sequencing and identified a de novo KIT mutation (NM_000222.2: c.2657G>A, p.Gly886Val) in exon 18 of KIT in the proband. Currently, this mutation is located in the most extreme C-terminal of the tyrosine kinase domain 2 of the KIT gene amongst all reported mutations and causes a severe clinical phenotype. We further reviewed literature on piebaldism and summarized 79 KIT gene mutations that lead to this disease. Our study may expand knowledge on the genotype-phenotype correlation in piebaldism and serve as a reference for genetic counseling and prenatal diagnosis of affected families.

To observe the therapeutic effect of low-dose amitriptyline (AMT) on epigastric pain syndrome (EPS) in patients with functional dyspepsia. Sixty patients with EPS were randomly divided into the following two groups for a four-week clinical trial: routine treatment with pantoprazole (RT group) and the AMT group. The RT group was treated with 40 mg of pantoprazole once daily. The AMT group received 25 mg of AMT once daily before bedtime. The Nepean Dyspepsia Index (NDI) checklist, Hamilton Rating Scale of Anxiety/Depression (HAMA/HAMD), and Pittsburgh Sleep Quality Index (PSQI) were employed to evaluate dyspepsia symptoms, psychological distress, and sleep, respectively. All items were similar between the two groups before treatment (0 week). After 4 weeks of treatment, the NDI–symptom checklist score as well as the severity and bothersomeness of EPS in the AMT group was significantly decreased compared with those in the RT group (p

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium–enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti–programmed cell death protein 1 (anti–PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation., An endothelial cell subtype, expressing endomucin and CD31, has been reported to couple angiogenesis with osteogenesis. Here, the authors show that loss of ZEB1 in these cells epigenetically suppresses Notch signaling, leading to impaired angiogenesis and osteogenesis, and that Zeb1 delivery via liposomes ameliorates bone loss in osteoporotic mice

To investigate the role of NEAT1 and the microRNA (miR)-377/fibroblast growth factor receptor 1 (FGFR1) axis in cervical cancer (CC), the expression levels of NEAT1, FGFR1 and miR-377 were detected in CC tissues and cell lines. NEAT1 or FGFR1 was knocked down by transfection with short hairpin RNA (sh)-NEAT1 or sh-FGFR1, and miR-377 was overexpressed by transfection with miR-377 mimics in HeLa and C33A cells. Cell viability and migration were measured using MTT and Transwell assays, respectively. Cell apoptosis was determined by flow cytometry. A dual luciferase reporter assay was performed to confirm the presence of binding sites between miR-377 and FGFR1. The results revealed that the expression levels of NEAT1 and FGFR1 were significantly elevated, whereas miR-377 expression was markedly decreased in CC tissues and cell lines. In HeLa and C33A cells, after NEAT1 knockdown, miR-377 expression was increased, cell viability and migration were inhibited, and apoptosis was induced. Similarly, silencing FGFR1 inhibited cell viability and migration, and induced apoptosis of HeLa and C33A cells. A dual luciferase reporter gene assay verified a targeting relationship between NEAT1 and miR-377. Inhibition of miR-377 or overexpression of FGFR1 reversed the effects of NEAT1 knockdown on cell function in HeLa and C33A cells. Moreover, a dual luciferase reporter assay confirmed that FGFR1 was a direct target of miR-377. In conclusion, suppression of NEAT1 inhibited cell viability and migration, and promoted apoptosis of CC cells, and these effects were achieved through regulation of the miR-377/FGFR1 axis.

The 10-item Body Appreciation Scale-2 (BAS-2) is a measurement for individuals to self-report the extent to which they accept and respect their bodies. Although the BAS-2 has been translated into the Malay language and found to have promising qualities, the psychometric characteristics of the English version of BAS-2 remain unknown in the Malaysian context. The present study thus administered the English version BAS-2 and selfie-editing frequency scale to 797 individuals aged 18 to 56 years old in Malaysia. The dataset that was randomly divided into two halves were submitted to exploratory factor analysis and confirmatory factor analysis respectively. Both of the factor analyses consistently support a one-factor model. The Cronbach’s alpha and McDonald omega coefficients were greater than 0.90, indicating that the BAS-2 has good internal consistency. The incremental validity is also evident. A hierarchical multiple regression showed that the BAS-2 score had a positive relationship with selfie-editing frequency after controlling for age and gender. Moreover, the measurement invariance test supported scalar invariance between genders, and an analysis of covariance did not find significant gender differences. Overall, the findings replicate past findings and regularly support the usability of the BAS-2 in the Malaysian context. The implications of the BAS-2 and future directions are also discussed.

The aim of skeletal muscle tissue engineering is to replace or repair skeletal muscle functions that have been injured or lost part of their functions. Skeletal muscle tissue engineering is an important strategy for muscle injury repair. The previous review on skeletal muscle tissue engineering was limited to the discussion of seed cells, biological materials and growth factors. In recent years, research results in this field have continued to emerge. This paper first briefly introduces the anatomy of skeletal muscle, and then combines the latest domestic and foreign study, from the basic problems of tissue engineering skeletal muscle construction to its vascularization, neuralization, etc., to review the current research status of skeletal muscle tissue engineering using three-dimensional (3D) printing, and look forward to its research prospects.

The aim of the present study was to determine the neuroimaging predictors of poor participation after acute ischemic stroke. A total of 443 patients who had acute ischemic stroke were assessed. At 1-year recovery, the Reintegration to Normal Living Index was used to assess participation restriction. We also assessed the Activities of Daily Living Scale and modified Rankin Scale (mRS) score. Brain MRI measurement included acute infarcts and pre-existing abnormalities such as enlarged perivascular spaces, white matter lesions, ventricular-brain ratio, and medial temporal lobe atrophy (MTLA). The study included 324 men (73.1%) and 119 women (26.9%). In the univariate analysis, patients with poor participation after 1 year were older, more likely to be men, had higher National Institutes of Health Stroke Scale (NIHSS) score on admission, with more histories of hypertension and atrial fibrillation, larger infarct volume, more severely enlarged perivascular spaces and MTLA, and more severe periventricular hyperintensities and deep white matter hyperintensities. Patients with participation restriction also had poor activities of daily living (ADL) and mRS score. Multiple logistic regression showed that, in model 1, age, male gender, NIHSS score on admission, and ADL on follow-up were significant predictors of poor participation, accounting for 60.2% of the variance. In model 2, which included both clinical and MRI variables, male gender, NIHSS score on admission, ADL on follow-up, and MTLA were significant predictors of poor participation, accounting for 61.2% of the variance. Participation restriction was common after acute ischemic stroke despite good mRS score. Male gender, stroke severity, severity of ADL on follow-up, and MTLA may be predictors of poor participation. Trial registration number ChiCTR1800016665.

Objective The aim of this study was to evaluate the predictive factors of central lymph node metastasis (CLNM) and BRAFV600E mutation in Chinese patients with papillary thyroid carcinoma (PTC). Methods A total of 943 PTC patients who underwent thyroidectomy from 2014 to 2016 at our hospital were enrolled. Those patients were divided into PTC > 10 mm and papillary thyroid microcarcinoma (PTMC) groups by tumor size. The BRAFV600E mutation was examined by quantitative real-time PCR. Univariate and multivariate analyses were used to examine risk factors associated with CLNM and the BRAFV600E mutation. Results The frequency of CLNM was 53% (505/943). Both univariate and multivariate analyses suggested that the risk factors for CLNM in PTC patients were male, younger age, and larger tumor size (P < 0.05). Coexistent Hashimoto thyroiditis (HT) was an independent protective factor against CLNM when the tumor was > 10 mm (P = 0.006). Stratified analysis revealed that male, age ≤ 30 years, and tumor size > 5 mm were independent risk factors for CLNM. The BRAFV600E mutation rate was 85%. Multivariate logistic regression analysis revealed that age (P < 0.001) and coexistent HT (P = 0.005) were independent predictive factors of BRAFV600E mutation in PTC patients. Only age was a risk factor for the BRAFV600E mutation when the tumor was > 10 mm (P = 0.004). In the PTMC group, the BRAFV600E mutation was significantly correlated with tumor size (P < 0.001) and coexistent HT (P = 0.03). Stratified analysis revealed that age > 30 years and tumor size > 5 mm were independent predictive factors of BRAFV600E mutation. Furthermore, the incidence of CLNM was significantly higher in BRAFV600E mutation-positive patients (P = 0.009) when the tumor was ≤ 5 mm. Conclusion The factors male, younger age (≤ 30 years), large tumor size (> 5 mm), and coexistent HT are independent predicative factors for CLNM. The BRAFV600E mutation is associated with both large size and without HT in PTMC patients, age > 30 years in the PTC > 10 mm group. The BRAFV600E mutation was an independent risk factor for CLNM when the tumor was ≤ 5 mm. For optimal management, these features should be comprehensively evaluated to determine the initial surgical approach for PTC patients.

Purpose: Impairment of cortical cholinergic pathways (CCP) is an important risk factor for chronic vascular cognitive impairment. However, this phenomenon has rarely been studied in post-stroke cognitive impairment (PSCI). We investigated the relationship between PSCI and CCP lesions assessed by structural magnetic resonance imaging (MRI).Patients and methods: We prospectively enrolled 103 patients within 7 days of ischemic stroke onset. CCP was measured by the cholinergic pathways hyperintensities scale (CHIPS), which semiquantitatively grades MR lesions strategically located on the CCP identified in human brains. We also measured other MRI parameters, including the location and volumes of acute infarcts, cerebral microbleeds, medial temporal lobe atrophy, and white matter lesions. Neuropsychological assessments were performed using the 60-min modified vascular dementia battery (VDB) at 3 months after the index stroke, and PSCI was defined according to VDB as well as ADL.Results: Of all 103 patients, 69 men (67.0%) and 34 women (33.0%) with a mean age of 57.22 ± 12.95 years, 55 patients (53.4%) were judged to have PSCI at 3 months, including 43 (41.7%) patients with PSCI-no dementia and 12 (11.7%) patients with poststroke dementia. According to the VBD assessment, the most commonly impaired cognitive domain was visuomotor speed (27.2%) followed by verbal memory (25.2%). Univariate analysis showed that patients with PSCI were older; had higher informant questionnaire on cognitive decline in the elderly (IQCODE) scores; had more frequent previous stroke history and atrial fibrillation; and had higher CHIPS scores, more severe white matter lesions, and medial temporal lobe atrophy. PSCI patients also had higher depression scores at 3 months. In the multivariate regression analysis, age, IQCODE score, CHIPS score, and Hamilton depression rating scale score were independent predictors of PSCI. Ordinal regression analysis for risk factors of poor functional outcomes revealed that IQCODE scores and cognitive function status were related to mRS score at 3 months after stroke.Conclusion: In patients with early subacute ischemic stroke, the severity of lesions involving the CCP may be associated with cognitive impairment at 3 months.Clinical Trial Registration: Chinese Clinical Trial Registry, identifier: ChiCTR1800014982.

The pathophysiology of cardiac hypertrophy is complex and multifactorial. Both the store-operated Ca2+ entry (SOCE) and excessive autophagy are the major causative factors for pathological cardiac hypertrophy. However, it is unclear whether these two causative factors are interdependent. In this study, we examined the functional role of SOCE and Orai1 in angiotensin II (Ang II)-induced autophagy and hypertrophy using in vitro neonatal rat cardiomyocytes (NRCMs) and in vivo mouse model, respectively. We show that YM-58483 or SKF-96365 mediated pharmacological inhibition of SOCE, or silencing of Orai1 with Orail-siRNA inhibited Ang II-induced cardiomyocyte autophagy both in vitro and in vivo. Also, the knockdown of Orai1 attenuated Ang II-induced pathological cardiac hypertrophy. Together, these data suggest that Ang II promotes excessive cardiomyocyte autophagy through SOCE/Orai1 which can be the prime contributing factors in cardiac hypertrophy.

Zika virus (ZIKV) is a typical mosquito-borne flavivirus known to cause severe fetal microcephaly and adult Guillain-Barre syndrome. Currently, there are no specific drugs or licensed vaccines available for ZIKV infection, and further research is required to identify host cell proteins involved in the virus's life cycle. Viruses are known to use host cell membrane skeletal proteins, such as actin and spectrin, to complete cell entry, transportation, and release. Here, based on immunoprecipitation, the Axl and ZIKV envelope (E) protein were shown to interact with the cell membrane skeleton protein 4.1R. Furthermore, deletion of 4.1R significantly reduced virus titer and viral protein synthesis. Our study showed that 4.1R is an important host cell protein during ZIKV infection and may be involved in the process of viral entry into host cells.

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α1-adrenergic receptors (α1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α1-AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 μM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, α1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.

Objective: To evaluate the efficacy of multiparametric magnetic resonance imaging (mp-MRI) using Prostate Imaging Reporting and Data System version 2.0 (PI-RADSv2) definitions in detecting organ-confined prostate cancer. Methods: All patients who underwent radical prostatectomy between January 1, 2014 and December 30, 2014 were identified. All underwent mp-MRI within 180 days before surgery. Those with prior pelvic irradiation or androgen deprivation therapy were excluded. Fully embedded, whole-mount histopathology was centrally reviewed and correlated with imaging for tumour location, Gleason score (GS) and stage. Results: There were 39 patients included, of which 35 (90%) had mp-MRI done post-biopsy. A total of 93 cancer foci were identified on whole-mount pathology, of which mp-MRI detected 63 (68%). Of those detected by mp-MRI, 14 were PI-RADS 3 (n = 6 for GS 6, n = 8 for GS 7, no GS ≥ 8) and 49 were PI-RADS 4–5 (n = 7 for GS 6, n = 33 for GS 7, and n = 9 for GS ≥ 8). There were 30 (32%) cancer foci missed by mp-MRI (n = 15 for GS 6, n = 13 for GS 7 and n = 2 for GS ≥ 8). A lesion classified as PI-RADS 4–5 predicted a higher grade cancer on pathology as compared to PI-RADS 3 (for GS 7 lesions, odds ratio [OR] = 3.53, 95% CI: 0.93–13.45, p = 0.064). The mp-MRI size detection limit was 20 mm2 and 100 mm2 for 50% and 75% probability of cancer, respectively. In associating with radiological and pathologic stage, the weighted Kappa value was 0.69 (p

Objective: To analyze the frequency and spectrum of thalassemia mutations in amniotic fluid samples collected from Han and Li people in Hainan province of China. Methods: We carried out a retrospective analysis on prenatal diagnosis of amniotic fluid samples collected from pregnant women who may have next generation with high risks of medium or severe thalassemia between 2005 and 2016. Diverse fetal thalassemia genotypes and mutated alleles in Han and Li people were analyzed and cmpared. Results: We examined 536 amniotic fluid samples from Han people and 588 from Li people, among which 406 Han and 500 Li samples were found to carry at least one thalassemia gene mutation, with a detection rate of 75.75% and 85.03%, respectively. Among all α- and β-thalassemia mutant alleles detected, the most frequently found mutations in Han and Li samples were SEA-type of α-thalassemia and 41/42 (–CTTT) of β-thalassemia, respectively. A total of 75 severe thalassemia cases were identified in Han samples and 53 in Li samples. In most of these severe cases, parents chose to terminate pregnancy after being informed of thalassemia-related risks. Conclusions: The thalassemia mutations shows ethnic and area specificity, and that prenatal diagnosis for high-risk thalassemia carrier pregnant women is an efficient approach to prevent and control the occurrence of severe thalassemia in the high-prevalence areas.

Objective Postoperative complications adversely affected the prognosis in patients with gastric cancer. This study intends to investigate the feasibility of using machine-learning model to predict surgical outcomes in patients undergoing gastrectomy. Methods In this study, cancer patients who underwent gastrectomy at Shanghai Rui Jin Hospital in 2017 were randomly assigned to a development or validation cohort in a 9:1 ratio. A support vector classification (SVC) model to predict surgical outcomes in patients undergoing gastrectomy was developed and further validated. Results A total of 321 patients with 32 features were collected. The positive and negative outcomes of postoperative complication after gastrectomy appeared in 100 (31.2%) and 221 (68.8%) patients, respectively. The SVC model was constructed to predict surgical outcomes in patients undergoing gastrectomy. The accuracy of 10-fold cross validation and external verification was 78.17% and 78.12%, respectively. Further, an online web server has been developed to share the SVC model for machine-learning-assisted prediction of surgical outcomes in patients undergoing gastrectomy in the future procedures, which is accessible at the web address: http://47.100.47.97:5005/r_model_prediction. Conclusions The SVC model was a useful predictor for measuring the risk of postoperative complications after gastrectomy, which may help stratify patients with different overall status for choice of surgical procedure or other treatments. It can be expected that machine-learning models in cancer informatics research are possibly shareable and accessible via web address all over the world.

Prior studies have examined the influence of MTHFR C677T on autism susceptibility, however, there are no consensus conclusions and specific analyses of a Chinese population. This meta-analysis included a false-positive report probability (FPRP) test to comprehensively evaluate the association of MTHFR C677T polymorphism with autism susceptibility among a Chinese Han population. A large-scale literature retrieval was conducted using various databases including PubMed, Embase, Wan Fang, and the Chinese National Knowledge Infrastructure (CNKI) up to July 31, 2020, with a total of 2,258 cases and 2,073 controls included. The strength of correlation was assessed by odds ratios (ORs) and 95% confidence intervals (95% CIs). MTHFR C677T showed a significant correlation with increased ASD susceptibility under all genetic models (T vs. C, OR = 1.89, 95% CI 1.28 to 2.79; TT vs. CC: OR = 2.44, 95% CI 1.43 to 4.15; CT vs. CC, OR = 1.73; 95% CI 1.19 to 2.51; CT + TT vs. CC: OR = 2.03, 95% CI 1.31 to 3.15; TT vs. CT + CC, OR = 1.95, 95% CI 1.21 to 3.13). Stratification analysis by region also revealed a consistent association in the Northern Han subgroup, but not in the Southern Han subgroup. Pooled minor allele frequency (MAF) of 30 studies were 45% in Northern Han and 39% in Southern Han. To avoid a possible “false positive report,” we further investigated the significant associations observed in the present meta-analysis using the FPRP test, which consolidated the results. In conclusion, MTHFR C677T polymorphism is associated with the increased risk of autism in China, especially in Northern Han. For those mothers and children who are generally susceptible to autism, prenatal folate and vitamin B12 may reduce the risk that children suffer from autism, especially in Northern Han populations. In the future, more well-designed studies with a larger sample size are expected.

Pathological cardiac hypertrophy is commonly associated with an upregulation of fetal genes, fibrosis, cardiac dysfunction, and heart failure. Previous studies have demonstrated that gastrodin (GAS) exerts cardioprotective action in the treatment of cardiac hypertrophy. However, the mechanism by which GAS protects against cardiac hypertrophy is yet to be elucidated. A mouse model of myocardial hypertrophy was established using an angiotensin II (Ang II) induction. GAS (5 or 50 mg/kg/d) was orally administered every day starting 7 days prior to the Ang II infusion combined with sham-operated controls. Heart samples from each group were collected for RNA sequencing. Using bioinformatics analysis, the key differentially expressed genes (DEGs) that are involved in reversing cardiac function were identified. Through bioinformatics analysis, the key DEGs that are involved in GAS's inhibition of Ang II-induced abnormal gene expression within the heart were identified. This was further validated using quantitative real-time PCR and Western blotting in neonatal rat cardiomyocytes (NRCMs). Oral administration of GAS significantly suppressed the Ang II-induced increase in heart size and heart weight to body weight. Furthermore, pretreatment of the NRCMs with GAS led to a dose-dependent inhibition of Ang II-induced increases in Nppb mRNA expression. We identified 620 upregulated and 87 downregulated Ang II-induced DEGs II, among which the expression patterns of 58 and 146 genes were inverted by low-dose and high-dose GAS, respectively. These inverted DEGs were found to be mainly enriched in the biological processes of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism, and positive regulation of cell cycle. Among them, the insulin-like growth factor type 2 (Igf2) gene, which was found to be highly reversed and downregulated by GAS, served as a core gene linking energy metabolism, immune regulation, and systemic development. Subsequent functional verification demonstrated that IGF2, and its receptor IGF2R, is one of the targets of GAS that helps protect against cardiac hypertrophy. Taken together, we have identified, for the first time, IGF2/IGF2R as a potential target influenced by GAS in the prevention of cardiac hypertrophy.

Objective:The aim of the study is to evaluate the association of the BRAFV600E mutation with the clinicopathologic characteristics in Chinese population with papillary thyroid carcinoma (PTC).MethodsA total of 943 PTC patients who underwent thyroidectomy from 2014 to 2016 at Henan Provincial People’s Hospital were included in the present study. The BRAFV600E mutation was examined in each resected specimen by quantitative Real-time PCR (qRT-PCR) technique. Results The PTC patients were subclassified into the overall, PTC>10mm and papillary thyroid microcarcinoma(PTMC) groups. The positive rate of BRAFV600E mutation was 85.4% in Chinese patients with PTC. In both overall PTC and PTC> 10mm groups, the BRAFV600E mutation was much more frequently detected in elderly patients and patients at T1 stage (P< 0.05). In addition, the positive rate of BRAFV600E mutation was significantly higher in PTC patients without concomitant Hashimoto’s thyroiditis in overall PTC and PTMC groups (P< 0.05). Furthermore, logistic regression analysis suggested that the risk of having a larger tumor diameter was increased by 6-fold when BRAFV600E mutation in the PTMC group. No association between the BRAFV600E mutation and other clinicopathologic factors was observed. ConclusionThe BRAFV600E mutation was significantly associated with patients age and T stage. Furthermore, the risk of having a larger tumor size was significantly increased when BRAFV600E mutation in the PTMC group. which suggests that BRAFV600E mutation might play an important role in the activation of early thyroid carcinogenesis, the effect might weaken in the progression of PTC.

Objectives An artificial intelligence model was adopted to identify mild COVID-19 pneumonia from computed tomography (CT) volumes, and its diagnostic performance was then evaluated. Methods In this retrospective multicenter study, an atrous convolution-based deep learning model was established for the computer-assisted diagnosis of mild COVID-19 pneumonia. The dataset included 2087 chest CT exams collected from four hospitals between 1 January 2019 and 31 May 2020. The true positive rate, true negative rate, receiver operating characteristic curve, area under the curve (AUC) and convolutional feature map were used to evaluate the model. Results The proposed deep learning model was trained on 1538 patients and tested on an independent testing cohort of 549 patients. The overall sensitivity was 91.5% (195/213; p < 0.001, 95% CI: 89.2–93.9%), the overall specificity was 90.5% (304/336; p < 0.001, 95% CI: 88.0–92.9%) and the general AUC value was 0.955 (p < 0.001). Conclusions A deep learning model can accurately detect COVID-19 and serve as an important supplement to the COVID-19 reverse transcription–polymerase chain reaction (RT-PCR) test. Key Points • The implementation of a deep learning model to identify mild COVID-19 pneumonia was confirmed to be effective and feasible. • The strategy of using a binary code instead of the region of interest label to identify mild COVID-19 pneumonia was verified. • This AI model can assist in the early screening of COVID-19 without interfering with normal clinical examinations. Supplementary Information The online version contains supplementary material available at 10.1007/s00330-021-07797-x.

Background: Early neurological deterioration (END) is common in acute ischemic stroke (AIS), but its effect on functional outcomes is not well understood. The aim of the present study was to explore the effects of END on multiple dimensions of functional outcomes.Methods: In the present study, 256 patients with AIS were analyzed. All patients were followed up for 1 year. We used the modified Rankin Scale (mRS) to assess body function impairment, the Lawton activities of daily living scale to assess activity limitations, and the reintegration to normal living index (RNLI) to assess participation restrictions. Brain magnetic resonance imaging was performed to identify acute infarcts and preexisting abnormalities, such as white matter lesions, medial temporal lobe atrophy, microbleeds, and silent lacunae. To reduce the effects of a lack of randomization, we conducted a propensity score analysis. Results: The study sample consisted of 185 men (72.3%) and 71 women (27.7%). Sixty-one patients (23.8%) had END. Before matching, patients with END had higher levels of small artery-type stroke, higher National Institutes of Health Stroke Scale scores on arrival, higher systolic blood pressure on admission, and larger infarct volumes. After matching, there were no significant differences between the two groups in any clinical or neuroimaging variables, except for stroke subtype and cortical region infarct. Logistic regression analysis revealed that END was a significant predictor of poor mRS (odds ratio [OR], 3.829; 95% confidence interval [CI], 1.367–10.723, p = 0.011) and poor RNLI (OR, 2.777; 95% CI, 1.133–6.806, p = 0.026) scores after adjusting for confounding factors.Conclusions: END is relatively common in AIS, with an incidence of 23.8%. END might be able to predict poor functional outcomes, including body function impairment and reduced social participation.

Acute sympathetic stress quickly induces cardiac inflammation and injury, suggesting that pathogenic signals rapidly spread among cardiac cells and that cell-to-cell communication may play an important role in the subsequent cardiac injury. However, the underlying mechanism of this response is unknown. Our previous study demonstrated that acute β-adrenergic receptor (β-AR) signaling activates inflammasomes in the heart, which triggers the inflammatory cascade. In the present study, β-AR overactivation induced inflammasome activation in both the cardiomyocytes and cardiac fibroblasts (CFs) of mice hearts following a subcutaneous injection of isoproterenol (ISO, 5 mg/kg body weight), a selective agonist of β-AR. In isolated cardiac cells, ISO treatment only activated the inflammasomes in the cardiomyocytes but not the CFs. These results demonstrated that inflammasome activation was propagated from cardiomyocytes to CFs in the mice hearts. Further investigation revealed that the inflammasomes were activated in the cocultured CFs that connected with cardiomyocytes via membrane nanotubes (MNTs), a novel membrane structure that mediates distant intercellular connections and communication. Disruption of the MNTs with the microfilament polymerization inhibitor cytochalasin D (Cyto D) attenuated the inflammasome activation in the cocultured CFs. In addition, the MNT-mediated inflammasome activation in the CFs was blocked by deficiency of the inflammasome component NOD-like receptor protein 3 (NLRP3) in the cardiomyocytes, but not NLRP3 deficiency in the CFs. Moreover, ISO induced pyroptosis in the CFs cocultured with cardiomyocytes, and this process was inhibited by disruption of the MNTs with Cyto D or by the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Z-YVAD-FMK (FMK). Our study revealed that MNTs facilitate the rapid propagation of inflammasome activation among cardiac cells to promote pyroptosis in the early phase of β-adrenergic insult. Therefore, preventing inflammasome transfer is a potential therapeutic strategy to alleviate acute β-AR overactivation-induced cardiac injury.

Background Low-dose amitriptyline (AMT) is an effective treatment for diarrhea-dominant irritable bowel syndrome (IBS-D). Its efficacy depends upon its serum concentration and the patient's CYP2C19 genotype. Aims To identify the association between serum AMT and nortriptyline (NT) concentration and CYP2C19 polymorphism and the clinical response in IBS-D patients. Methods Ninety IBS-D patients were treated of AMT for 6 weeks. Efficacy was evaluated by the results of the Adequate Relief question each week and an IBS severity scoring system (IBS-SSS) at 0, 3, and 6 weeks. CYP2C19 genotyping was performed by direct sequencing. AMT and NT steady-state serum concentrations were detected by high-performance liquid chromatography. Results The CYP2C19 polymorphism exhibited a significant influence on the NT serum concentration but did not predict the clinical efficacy of AMT for treating IBS-D. The NT steady-state and dose-corrected serum concentrations were significantly correlated with an improvement in the IBS-SSS score after 6 weeks, whereas the AMT serum concentration was not correlated with clinical improvement. The cut-off NT steady-state serum concentration of 2.91 ng/ml may help distinguish responders from non-responders. Conclusions NT serum concentration but not CYP2C19 polymorphism may be correlated with the clinical efficacy of AMT for treating IBS-D, and such a response may occur at the upper NT threshold of 2.91 ng/ml.

Whether autonomic dysfunction contributes to cerebral small vessel disease (CSVD) remains unclear. This study aimed to explore the relationship between CSVD and blood pressure variability (BPV) and heart rate variability (HRV).This case-control study recruited 50 patients with CSVD and 50 non-CSVD hypertensive age- and gender-matched controls. All participants completed a 24-h ambulatory electrocardiogram recording and ambulatory BP monitoring (ABPM). Differences in HRV and BPV between the two groups were examined. BPV indices assessed by ABPM included mean systolic BP (SBP), mean diastolic BP (DBP), coefficient of variation and weighted standard deviation of SBP and DBP.CSVD patients had significant higher 24-h mean systolic BP (SBP), 24-h mean diastolic BP (DBP), daytime mean SBP, nocturnal mean SBP, and nocturnal mean DBP (P.05 for all). CSVD patients had a significant lower nocturnal SBP fall rate compared with controls (median: 1.0 versus 6.2, respectively; P.001) and were more likely to be non-dippers and reverse dippers. There were no differences in HRV variables between the two groups. Five logistic models were built to explore the correlations between BPV indices and CSVD. BPV indices were separately entered into the logistic regression models, together with hyperlipidemia, ischemic stroke history, current use of anti-hypertensive agents, and serum blood urea nitrogen. In models 1-3, 24-h mean SBP and nocturnal mean SBP and DBP were significantly correlated with CSVD (rLower nocturnal SBP fall rate is associated with CSVD. Non-dipper and reverse dipper hypertensive patients have a higher risk of CSVD.

Activating transcription factor 4 (ATF4), which regulates genes associated with endoplasmic reticulum stress, apoptosis, autophagy, the gut microbiome, and metabolism, has been implicated in many diseases. However, its mechanistic role in hypertension remains unclear. In the present study, we investigated its role in salt-sensitive hypertensive mice. Wild-type (WT) C57BL/6J mice were used to establish Atf4 knockout (KO) and overexpression mice using CRISPR-Cas9 and lentiviral overexpression vectors. Then, fecal microbiota transplantation from Atf4+/− mice and vitamin K2 (VK2) supplementation were separately carried out in high-salt-diet (8% NaCl)-induced mice for 4 weeks. We found that Atf4 knockout inhibited and Atf4 overexpression enhanced the increase in blood pressure and endothelial dysfunction induced by high salt intake in mice, while regulating the gut microbiota composition and VK2 expression. It was further verified that ATF4 is involved in the regulation of salt-sensitive hypertension and vascular endothelial function, which is achieved through association with gut microbiota and may be related to VK2 and different bacteria such as Dubosiella. In addition, we found that VK2 supplementation prevents the development of salt-sensitive hypertension and maintains vascular endothelial function; moreover, VK2 supplementation increases the abundance of intestinal Dubosiella and downregulates the relative expression of Atf4 in the thoracic aorta of mice. We conclude that ATF4 plays an important role in regulating gut microbiota and VK2 production, providing new insights into the association between ATF4 and development of salt-induced hypertension in mice, meanwhile contributing to the development for a new preventive strategy of hypertension.

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.

Background: Acupuncture points are commonly used by Traditional Chinese Medicine to treat throat discomfort. Transcutaneous electroacupuncture (TEA) is a new therapy combining transcutaneous electrical nerve stimulation with meridian theory. The efficacy and mechanism of Transcutaneous electroacupuncture for globus pharyngeus has not been reported. The aim of our study was to explore the effect and possible mechanisms of TEA at CV22/LI3/LU11/ST36 for patients with globus.Methods: A total of 80 patients with globus pharyngeus were randomly allocated into eight groups. The intervention order in Groups A1/B1/C1/D1 was firstly TEA at CV22/LI3/LU11/ST36 during the first period and sham-TEA in the second period. For participants in Groups A2/B2/C2/D2, the intervention order was the reverse. Before the test, the participants were asked to complete the Glasgow Edinburgh Throat Scale (GETS), visual analog scale (VAS), and the Hamilton Rating Scale Anxiety/Depression and were then asked to test and measure the heart rate variability and serum hormone levels of SP and NPY. At the end of the second period, these tests were manipulated again.Results: D-values of GETS and VAS following stimulation at CV22/LU11 were significantly higher than those of sham-stimulating (CV22: 13.5 ± 13.09 vs. 1 ± 9.68, P

Compound CYD19 has been identified as a CBP/p300-Snail interaction inhibitor that exhibits potent anticancer efficacy., The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered “undruggable,” and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail’s interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

BACKGROUNDThere is little information about the coronavirus disease 2019 (Covid-19) during pregnancy. This study aimed to determine the clinical features and the maternal and neonatal outcomes of pregnant women with Covid-19.METHODSIn this retrospective analysis from five hospitals, we included pregnant women with Covid-19 from January 1 to February 20, 2020. The primary composite endpoints were admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Secondary endpoints included the clinical severity of Covid-19, neonatal mortality, admission to neonatal intensive care unit (NICU), and the incidence of acute respiratory distress syndrome (ARDS) of pregnant women and newborns.RESULTSThirty-three pregnant women with Covid-19 and 28 newborns were identified. One (3%) pregnant woman needed the use of mechanical ventilation. No pregnant women admitted to the ICU. There were no moralities among pregnant women or newborns. The percentages of pregnant women with mild, moderate, and severe symptoms were 13 (39.4%),19(57.6%), and 1(3%). One (3.6%) newborn developed ARDS and was admitted to the NICU. The rate of perinatal transmission of SARS-CoV-2 was 3.6%.CONCLUSIONSThis report suggests that pregnant women are not at increased risk for severe illness or mortality with Covid-19 compared with the general population. The SARS-CoV-2 infection during pregnancy might not be associated with as adverse obstetrical and neonatal outcomes that are seen with the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infection during pregnancy. (Funded by the National Key Research and Development Program.)

Cardiac fibroblast (CF) differentiation plays a crucial role in cardiac fibrosis, which is a specific manifestation distinguishing pathological cardiac hypertrophy from physiological hypertrophy. The DNA-binding activity of paired box 6 (Pax6) has been shown to be oppositely regulated in physiological and pathological hypertrophy; however, it remains unclear whether Pax6 is involved in CF differentiation during cardiac fibrosis. We found that Pax6 is expressed in the heart of and CFs isolated from adult mice. Moreover, angiotensin II (Ang II) induced the downregulation of Pax6 mRNA and protein expression in fibrotic heart tissue and cardiac myofibroblasts. Pax6 knockdown in CFs promoted the expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and the synthesis of the extracellular matrix (ECM) proteins collagen I and fibronectin. Furthermore, we validated the ability of Pax6 to bind to the promoter regions of Cxcl10 and Il1r2 and the intronic region of Tgfb1. Pax6 knockdown in CFs decreased CXC chemokine 10 (CXCL10) and interleukin-1 receptor 2 (IL-1R2) expression and increased transforming growth factor β1 (TGFβ1) expression, mimicking the effects of Ang II. In conclusion, Pax6 exerts an inhibitory effect on CF differentiation and ECM synthesis by transcriptionally activating the expression of the anti-fibrotic factors CXCL10 and IL-1R2 and repressing the expression of the pro-fibrotic factor TGFβ1. Therefore, maintaining Pax6 expression in CFs is essential for preventing CF differentiation, and provides a new therapeutic target for cardiac fibrosis.

Differentiation therapies have been proposed to overcome the impaired cell differentiation in acute myeloid leukemia (AML). However, thus far the all-trans retinoic acid-based differentiation therapy has been the only successful modality in treating acute promyelocytic leukemia. Here, we showed that vibsanin A, a novel protein kinase C (PKC) activator, sensitized AML cells to tyrosine kinase inhibitor (TKI)-induced differentiation. Vibsanin A augmented the ability of TKIs to induce growth inhibition and G1 cell cycle arrest of AML cells. Mechanistically, PKC activation was involved in the differentiation-inducing effects of combining vibsanin A with TKIs. Moreover, we found that vibsanin A enhanced TKI-induced Lyn expression and suppression of Lyn interfered with AML cell differentiation, indicating an essential role for Lyn expression in the combination-induced differentiation. Finally, combining vibsanin A and TKIs enhanced the activation of the Raf/MEK/ERK cascade. Together, this is the first study to evaluate the synergy of vibsanin A and TKIs in AML cell differentiation. Our study lays the foundation in assessing new opportunities for the combination of vibsanin A and TKIs as a promising approach for future differentiation therapy.

Severe fever with thrombocytopenia syndrome virus (SFTSV) infection typically causes acute fever, thrombocytopenia and leucopenia, presenting with a high case fatality rate. The pathogenesis of SFTSV infection, however, is not well described. It was hypothesized that endothelial dysfunction might play part in the disease process. In current study, we retrospectively analyzed the clinical manifestations among a large group of confirmed SFTS cases and found evidence of plasma leakage and vascular endothelial injury. Then we established a SFTSV infection cell model and determined the infectivity and stimulation of SFTSV on vascular endothelial cells in vitro. The hyperpermeability of endothelial cells directly induced by SFTSV was confirmed by electrical resistance and dextran diffusion assay. The virus induced alterations of cell junctions and cytoskeleton was also revealed. It's suggested that vascular endothelial cell injury and barrier function damage were induced after SFTSV infection, which is a vital but neglected pathogenesis of SFTS.

Ethnopharmacological relevance Diabetic nephropathy (DN) is a major complication of diabetes. The kidney disease develops in nearly 20%–40% of type 2 diabetes (T2D) patients. Ginseng is the root of Panax ginseng C. A. Meyer and has been used in prevention and treatment of diseases for more than 2000 years as a traditional oriental medicine. The 20(R)-ginsenoside Rg3, an active saponin isolated from ginseng, can prevent and treat many diseases. The object of this research was to explore the alleviative effects of 20(R)-Rg3 on DN in mice. Materials and methods The T2D animal model was induced by continuous access to a high fat diet (HFD) combined with a single injection of 100 mg/kg streptozotocin (STZ) in C57BL/6 mice. The mice were treated by oral gavage of the 20(R)-Rg3 (10, 20 mg/kg) for 8 weeks. Functional and histopathological analyses of the kidneys were then performed. Protein expression levels of MAPKs and NF-κB signal pathways in the kidney were evaluated by western blotting. The expressions of HO-1 and NF-κB in the kidney were measured by fluorescent labeling staining. Other assessments including fasting blood glucose (FBG) levels, blood lipids, oxidative indicators, and inflammatory factors were all performed. Results Abnormally elevated FBG levels were observed in HFD/STZ mice, contributing significantly to the occurrence of DN. Simultaneously, HFD/STZ mice showed the rise of serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels, and the decrease in high density lipoprotein cholesterol (HDL-C). DN was evidenced by the overproduction of malondialdehyde (MDA), decreased levels of superoxide dismutase (SOD) and catalase (CAT) enzymatic activities, high levels of serum blood urea nitrogen (BUN) and creatinine (Cr). Simultaneously, the results of the immunofluorescence assay showed an increased expression level in NF-κB p65 while a decrease in antioxidant enzyme HO-1 was observed. Herein, 20(R)-Rg3 treatment for 8 weeks not only attenuated FBG levels and advanced glycation end products (AGEs) levels but also improved insulin (INS) level, blood lipids, oxidative stress, and renal function by regulating MAPKs and NF-κB signal pathways in DN mice. Conclusion Taken together, the findings from the present study explicitly confirmed that 20(R)-Rg3 exerted ameliorative effects on DN mice via improving anti-oxidative activity and reducing renal inflammation.

Objectives To study the role of the neutrophil-to-lymphocyte ratio in predicting survival outcomes for patients with advanced bladder cancer. Methods We retrospectively reviewed 150 patients diagnosed with advanced or metastatic bladder cancer between January 2004 and June 2014. The neutrophil-to-lymphocyte ratio was computed on diagnosis and after the first cycle of chemotherapy. A neutrophil-to-lymphocyte ratio cut-off of 3.0 was determined, with a concordance index of 0.89. Kaplan–Meier curves, log–rank tests, Cox proportional hazards and logistic regression models were used to predict the association of the neutrophil-to-lymphocyte ratio with survival outcomes. Results Just five patients were alive at the end of the study; the rest died from metastatic bladder cancer. On multivariate analysis, higher Eastern Cooperative Oncology Group status, lymphadenopathy, visceral metastases and neutrophil-to-lymphocyte ratio ≥3.0 were associated with poorer overall survival (hazard ratio 1.67, P = 0.03; hazard ratio 1.97, P =

Background Antidepressant agents have been shown to be an effective and safe treatment method for patients with globus. However, there are few clinical trials dedicated to studying the effects of antidepressant agents on the natural history and upper oesophageal sphincter (UES) pressure of treated globus patients. Aims To evaluate the effect of paroxetine and amitriptyline to prevent relapses in patients with globus, the simultaneous relationship between changes in UES pressure and improvement of globus symptoms were measured. Methods Globus patients were randomised into amitriptyline, paroxetine and lansoprazole groups for a 6-week treatment period, and follow-up was extended to 12 additional months. Efficacy was evaluated in terms of the Glasgow-Edinburgh Throat Scale (GETS), and UES pressure was measured by standard oesophageal manometry. Results Paroxetine therapy resulted in a higher withdrawal rate due to symptom relapse (15.9% vs 44.1%, P = 0.01; 15.9% vs 64.7, P = 0.001) than amitriptyline and lansoprazole. Furthermore, globus symptoms were alleviated with the decrease of UES pressure after paroxetine and amitriptyline treatment (r = 0.620, P = 0.02; r = 0.575, P = 0.03) Conclusions This follow-up study indicates that paroxetine may alter the natural history of globus and can effectively be used for the long-term management of patients with the disease. Apart from the clinical benefits, paroxetine and amitriptyline can potentially decrease UES pressure.

Objectives: Based on previous reports that ginsenosides have been shown to exert better preventive effects on cisplatin‐induced kidney injury, the present work aims to evaluate the protective effects of ginsenoside Rb3 (G‐Rb3) on cisplatin‐induced renal damage and underlying mechanisms in vivo and in vitro. Materials and methods: The protective effect of G‐Rb3 on cisplatin‐induced acute renal failure in ICR mouse model and HEK293 cell model was investigated, and the underlying possible mechanisms were also explored. For animal experiment, renal function, kidney histology, inflammation, oxidative stress, relative protein molecules involved in apoptosis and autophagy signalling pathways were assessed. In addition, rapamycin (a specific inhibitor of mTOR), compound C (a specific inhibitor of AMPK) and acetylcysteine (NAC, a specific ROS scavenger) were employed to testify the effects of AMPK/mTOR signal pathway on the protective effects of G‐Rb3 in HEK293 cells. Results: Pre‐treatment with G‐Rb3 at doses of 10 and 20 mg/kg for ten days significantly reversed the increases in serum creatinine (CRE), blood urea nitrogen (BUN) and malondialdehyde (MDA), and decrease in glutathione (GSH) content and superoxide dismutase (SOD) activity. Histopathological examination further revealed that G‐Rb3 inhibited cisplatin‐induced nephrotoxicity. G‐Rb3 diminished cisplatin‐induced increase in protein expression levels of p62, Atg3, Atg5 and Atg7, and decrease in protein expression level of p‐mTOR and the ratio of LC3‐I/LC3‐II, indicating that G‐Rb3 suppressed cisplatin‐induced activation of autophagy. Inhibition of autophagy induced inactivation of apoptosis, which suggested that autophagy played an adverse effect on cisplatin‐evoked renal damage. Further, we found that G‐Rb3 might potentially modulate the expressions of AMPK‐related signal pathways. Conclusions: These findings clearly suggested that G‐Rb3‐mediated alleviation of cisplatin‐induced nephrotoxicity was in part due to regulation of AMPK‐/mTOR‐mediated autophagy and inhibition of apoptosis in vitro and in vivo.

Recently, although ginseng ( Panax ginseng C. A. Meyer) and its main component saponins (ginsenosides) have been reported to exert protective effects on cisplatin (CDDP)-induced acute kidney injury (AKI), the beneficial activities of non-saponin on CDDP-induced AKI is little known. This research was designed to explore the protective effect and underlying mechanism of arginyl-fructosyl-glucose (AFG), a major and representative non-saponin component generated during the process of red ginseng, on CDDP-caused AKI. AFG at doses of 40 and 80 mg/kg remarkably reversed CDDP-induced renal dysfunction, accompanied by the decreased levels of serum creatinine and blood urea nitrogen. Interestingly, all of oxidative stress indices were ameliorated after pretreatment with AFG continuously for 10 days. Importantly, AFG relieved CDDP-induced inflammation and apoptosis in part by mitigating the cascade initiation steps of nuclear factor κB signals and regulating the participation of the phosphatidylinositol 3-kinase/protein kinase B signal pathway. In conclusion, these results clearly provide strong rationale for the development of AFG to prevent CDDP-induced AKI.

Colorectal cancer (CRC) is the third most common type of cancer. In recent decades, genomic analysis has played an increasingly important role in understanding the molecular mechanisms of CRC. However, its pathogenesis has not been fully uncovered. Identification of genes related to CRC as complete as possible is an important way to investigate its pathogenesis. Therefore, we proposed a new computational method for the identification of novel CRC-associated genes. The proposed method is based on existing proven CRC-associated genes, human protein-protein interaction networks, and random walk with restart algorithm. The utility of the method is indicated by comparing it to the methods based on Guilt-by-association or shortest path algorithm. Using the proposed method, we successfully identified 298 novel CRC-associated genes. Previous studies have validated the involvement of the majority of these 298 novel genes in CRC-associated biological processes, thus suggesting the efficacy and accuracy of our method.

An array of novel 7-methoxyl-2,3-disubstituted quinoxaline derivatives was designed, synthesized and their potential antihypertensive activities were examined, in an attempt to discover potent small molecules with vasorelaxant effects. The vasoactivities of these compounds on vascular tone, as well as underlying mechanisms were hereby explored. Results showed that five compounds (7s, 7t, 7v, 7w, 7γ) could induce endothelium-independent relaxation in high extracellular K+- and phenylephrine-precontracted C57 mice aortic rings. These five compounds, unlike other commonly used vasodilators, could slowly but effectively inhibit vasoconstriction.

Neutrophils have been recognized as critical response cells during the pathogenesis of endotoxin-induced uveitis (EIU). Apoptosis of neutrophils induced by roscovitine has previously been demonstrated to ameliorate inflammation in several in vivo models. The present study aimed to assess whether roscovitine ameliorates EIU. EIU was induced in female C57BL/6 mice by a single intravitreal injection of lipopolysaccharide (LPS; 250 ng). The mice were divided into three groups as follows: LPS alone, LPS plus vehicle, LPS plus roscovitine (50 mg/kg). The mice were euthanized 12, 24, 48 and 72 h after LPS-induced uveitis. Accumulation of inflammatory cells in the vitreous body was confirmed by immunohistochemistry, and quantified following hematoxylin and eosin staining. Terminal deoxynucleotidyl transferase dUTP nick-end labeling was performed to detect of apoptotic cells. The mRNA levels of inflammatory cytokines were analyzed by reverse transcription-quantitative polymerase chain reaction and the changes in protein levels were analyzed by western blotting. Inflammatory cells accumulated in the vitreous near the optic nerve head and the quantity peaked at 24 h after LPS injection. Immunohistochemistry revealed that the majority of the inflammatory cells were neutrophils. The number of infiltrating cells was similar in the LPS and LPS plus vehicle groups, while there were significantly less in the roscovitine group at 24 h. Apoptosis of neutrophils was observed between 12 and 48 h after roscovitine injection, while no apoptosis was observed in the other groups. The mRNA expression levels of GMCSF, CINC-1 and ICAM-1 peaked at 12 h after LPS injection, and decreased to normal levels at 72 h. This trend in mRNA expression was similar in the LPS and LPS plus vehicle groups; however, the expression levels decreased more quickly in the roscovitine group at 24 and 48 h. Following roscovitine administration, upregulated cleaved caspase 3 expression levels and downregulated Mcl-1 expression levels were observed. In conclusion, roscovitine ameliorates EIU by effecting neutrophil apoptosis. Timely apoptosis of neutrophils may be an effective process to promote the amelioration of EIU.