Search

The study aimed to investigate whether serum sFlt-1 (soluble fms-like tyrosine kinase-1) at 11-13 weeks’ gestation in pregnancies that subsequently developed preeclampsia was different from those without preeclampsia and compare screening performance of the International Prediction of Pregnancy Complications (IPPIC) reported models, which include various combinations of maternal factors, systolic blood pressure, diastolic blood pressure, PlGF (placental growth factor) and sFlt-1 and the competing risk (CR) models, which include various combinations of maternal factors, mean arterial pressure (MAP) and PlGF for predicting any-onset, early-onset, and late-onset preeclampsia. This was a prospective multicenter study in 7877 singleton pregnancies. The differences of the predictive performance between the IPPIC and CR models were compared. There were 141 women (1.79%) who developed preeclampsia, including 13 cases (0.17%) of early-onset preeclampsia and 128 cases (1.62%) of late-onset preeclampsia. In pregnancies that developed preeclampsia compared to unaffected pregnancies, median serum sFlt-1 levels and its MoMs were not significantly different ( p >0.05). There was no significant association between gestational age at delivery and log 10 sFlt-1 and log 10 sFlt-1 MoM ( p >0.05). The areas under the curve of CR models were significantly higher than the IPPIC models for the prediction of any-onset and late-onset preeclampsia but not for early-onset preeclampsia. In conclusion, there are no significant differences in the maternal serum sFlt-1 levels at 11-13 weeks’ gestation between women who subsequently develop preeclampsia and those who do not. Moreover, the CR models for the prediction of any-onset and late-onset preeclampsia perform better than the IPPIC reported model.

Objective: This study aims to identify key genes and pathways associated with the molecular biological mechanisms of major depressive disorder through bioinformatics analysis in the Gene Expression Omnibus (GEO) public database of the National Center for Biotechnology Information (NCBI) website. Methods: The whole-transcriptome brain expression profile dataset (GSE101521) was obtained from the GEO database. Differentially-expressed genes (DEGs) in normal group (non-psychiatric human) and MDD group (depressive patients) were identified applying Networkanalyst online database. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to function annotation and enrichment analysis. After that, STRING online database was conducted to protein–protein interaction (PPI) network, and Cytoscape.3.7.2 software was performed to module analysis. Results: Out of the 41 DEGs identified from normal tissue samples and MDD, 39 were upregulated and 2 were downregulated. GO enrichment analysis discovered that DEGs were primarily involved in inflammatory response, and KEGG pathway analysis suggested that the most chiefly pathway related to MDD were IL-17 signaling pathway, TNF signaling pathway and NOD-like receptor signaling pathway. Six hub genes (IL6, CXCL8, IL1B, FOS, CCL2 and CXCL2) were identified by PPI network and module analysis. Conclusion: Our current study detected novel markers and targets involved immune system, which are involved in pivotal biological mechanisms related to the pathogenesis of major depression. Looking forward, these findings still need to be validated in future experimental studies.

Purpose To evaluate the contralateral lymph node recurrence rate (clLNRR) of stage IVA to IVB well-lateralized oral cavity cancer. To evaluate the risk factors of clLNRR. Materials and methods Pathologic stage IVA-B squamous cell carcinoma of oral cavity, originating from buccal mucosa, gingiva, or retromolar trigone were retrospectively recruited. Those who did not receive definitive surgery, with previous cancer history, or with contralateral nodal metastasis at diagnosis were excluded. Results From 2010 to 2017, 120 cases were enrolled, including 103 pT4 and 38 pN2. Thirty-one patients underwent contralateral neck dissection, and 18 had contralateral elective nodal irradiation. After median follow up of 35.1 months, the 3-year clLNRR was 15.7% (95% CI: 8.8 - 22.6%) as first event and was 17.1% (95% CI: 9.8 - 24.4%) for overall recurrences. The 3-year disease-free survival and overall survival were 52.8% and 63.1%, respectively. In multivariate analysis, positive nodal metastasis, gingival origin, and perineural invasion were associated with significantly higher clLNRR. Nodal metastasis was the strongest prognostic factor for clLNRR (pN1, HR: 17.1, p = 0.010; pN2, HR: 16.7, p = 0.004, comparing to pN0). The 3-year clLNRR were 2.9% for pN0 (n = 71, 95% CI: 0 - 6.8%), 37.7% for pN1 (n = 11, 95% CI: 8.3 - 67.1%), and 38.4% for pN2 (n = 38, 95% CI: 19.2 - 57.6%). Advanced T classification, elective contralateral neck dissection, and contralateral nodal irradiation did not have significant impact on clLNRR. Conclusions Positive homolateral nodal metastasis, gingival origin, and perineural invasion were risk factors correlated with significantly higher clLNRR. For patient without nodal metastasis, the clLNRR was low and elective contralateral neck management might be safely omitted. For patients with homolateral nodal disease, the contralateral nodal recurrence was not unusual. The optimal treatment for these high risk patients warrant further research.

Great progress has been made over the past decade in understanding the structural, functional, and pharmacological diversity of lipid GPCRs. From the first determination of the crystal structure of bovine rhodopsin in 2000, much progress has been made in the field of GPCR structural biology. The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened our comprehension of the structural and functional facets of the receptor family members and has helped usher in a modern age of structure-based drug design and development. First, we provide a primer on lipid mediators and lipid GPCRs and their role in physiology and diseases as well as their value as drug targets. Second, we summarize the current advancements in the understanding of structural features of lipid GPCRs, such as the structural variation of their extracellular domains, diversity of their orthosteric and allosteric ligand binding sites, and molecular mechanisms of ligand binding. Third, we close by collating the emerging paradigms and opportunities in targeting lipid GPCRs, including a brief discussion on current strategies, challenges, and the future outlook.

BACKGROUND The ATP6AP1 gene coding for the accessory protein Ac45 of the vacuolar-type adenosine triphosphatases (V-ATPase) is located on chromosome Xq28. Defects in certain subunits or accessory subunits of the V-ATPase can lead to congenital disorders of glycosylation (CDG). CDG is a group of metabolic disorders in which defective protein and lipid glycosylation processes affect multiple tissues and organs. Therefore, the clinical presentation of patients with ATP6AP1-CDG varies widely. In this report, we present a case of ATP6AP1-CDG in a Chinese infant, with clinical features and genotype. CASE SUMMARY An 8-mo-old boy was admitted to our hospital because unexplained hepatosplenomegaly and elevated transaminases that had been noted while he was being treated for a cough at a local hospital. A post-admission examination at our hospital revealed abnormalities in the infant’s liver, brain, and immune system. Trio-based whole exome gene analysis identified a hemizygous pathogenic mutation c.1036G>A (p.E346K) in exon 9 of the ATP6AP1 gene. This variant of the ATP6AP1 gene has not been reported in East Asian countries until now. CONCLUSION Based on the infant’s clinical manifestations and the results of genetic detection, he was clearly diagnosed with ATP6AP1-CDG. The clinical manifestations of children with CDG vary widely. Genetic testing analysis helps in the clinical diagnosis of children with CDG.

Background Robot-assisted gait training (RAGT) is a practical treatment that can complement conventional rehabilitation by providing high-intensity repetitive training for patients with stroke. RAGT systems are usually either of the end-effector or exoskeleton types. We developed a novel hybrid RAGT system that leverages the advantages of both types. Objective This single-blind randomized controlled trial evaluated the beneficial effects of the novel RAGT system both immediately after the intervention and at the 3-month follow-up in nonambulatory patients with subacute stroke. Methods We recruited 40 patients with subacute stroke who were equally randomized to receive conventional rehabilitation either alone or with the addition of 15 RAGT sessions. We assessed lower-extremity motor function, balance, and gait performance by using the following tools: active range of motion (AROM), manual muscle test (MMT), the Fugl–Meyer Assessment (FMA) lower-extremity subscale (FMA-LE) and total (FMA-total), Postural Assessment Scale for Stroke (PASS), Berg Balance Scale (BBS), Tinetti Performance-Oriented Mobility Assessment (POMA) balance and gait subscores, and the 3-m and 6-m walking speed and Timed Up and Go (TUG) tests. These measurements were performed before and after the intervention and at the 3-month follow-up. Results Both groups demonstrated significant within-group changes in the AROM, MMT, FMA-LE, FMA-total, PASS, BBS, POMA, TUG, and 3-m and 6-m walking speed tests before and after intervention and at the 3-month follow-up (p p = 0.014) and total (p = 0.002) assessments. Conclusion Although the novel hybrid RAGT is effective, strong evidence supporting its clinical effectiveness relative to controls in those with substantial leg dysfunction after stroke remains elusive. Trial registration The study was registered with an International Standard Randomized Controlled Trial Number, ISRCTN, ISRCTN15088682. Registered retrospectively on September 16, 2016, at https://www.isrctn.com/ISRCTN15088682

It is of great clinical importance to explore more efficacious treatments for OCD. Recently, cognitive-coping therapy (CCT), mainly focusing on recognizing and coping with a fear of negative events, has been reported as an efficacious psychotherapy. However, the underlying neurophysiological mechanism remains unknown. This study of 79 OCD patients collected Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and resting-state functional magnetic resonance imaging (rs-fMRI) scans before and after four weeks of CCT, pharmacotherapy plus CCT (pCCT), or pharmacotherapy. Amygdala seed-based functional connectivity (FC) analysis was performed. Compared post- to pretreatment, pCCT-treated patients showed decreased left amygdala (LA) FC with the right anterior cingulate gyrus (cluster 1) and with the left paracentral lobule/the parietal lobe (cluster 2), while CCT-treated patients showed decreased LA-FC with the left middle occipital gyrus/the left superior parietal/left inferior parietal (cluster 3). The z-values of LA-FC with the three clusters were significantly lower after pCCT or CCT than pretreatment in comparisons of covert vs. overt and of non-remission vs. remission patients, except the z-value of cluster 2 in covert OCD. CCT and pCCT significantly reduced the Y-BOCS score. The reduction in the Y-BOCS score was positively correlated with the z-value of cluster 1. Our findings demonstrate that both pCCT and CCT with large effect sizes lowered LA-FC, indicating that FCs were involved in OCD. Additionally, decreased LA-FC with the anterior cingulate cortex (ACC) or paracentral/parietal cortex may be a marker for pCCT response or a marker for distinguishing OCD subtypes. Decreased LA-FC with the parietal region may be a common pathway of pCCT and CCT. Trial registration: ChiCTR-IPC-15005969.

It has been confirmed that the new coronavirus SARS-CoV-2 caused the global pandemic of coronavirus disease 2019 (COVID-19). Studies have found that 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for virus replication, and could be used as a potential target to inhibit SARS-CoV-2. In this work, 3CLpro was used as the target to complete the high-throughput virtual screening of the FDA-approved drugs, and Indinavir and other 10 drugs with high docking scores for 3CLpro were obtained. Studies on the binding pattern of 3CLpro and Indinavir found that Indinavir could form the stable hydrogen bond (H-bond) interactions with the catalytic dyad residues His41-Cys145. Binding free energy study found that Indinavir had high binding affinity with 3CLpro. Subsequently, molecular dynamics simulations were performed on the 3CLpro and 3CLpro-Indinavir systems, respectively. The post-dynamic analyses showed that the conformational state of the 3CLpro-Indinavir system transformed significantly and the system tended to be more stable. Moreover, analyses of the residue interaction network (RIN) and H-bond occupancy revealed that the residue-residue interaction at the catalytic site of 3CLpro was significantly enhanced after binding with Indinavir, which in turn inactivated the protein. In short, through this research, we hope to provide more valuable clues against COVID-19.

To compare the treatment outcome and severe late adverse effects (AEs) between conventional volume and dose (CVD) and simultaneously reduced volume and dose (SRVD) of clinical target volume treatments in patients with nasopharyngeal carcinoma.This retrospective cohort study enrolled patients with nonmetastatic stage II to IV nasopharyngeal cancer from a single institute. Survival endpoints and severe (≥grade 3) late AEs and comorbidity were compared between groups. The correlation of severe late AEs, comorbidity, and overall survival (OS) were evaluated using Kaplan-Meier and Cox regression methods.From January 2012 to June 2017, this study enrolled 178 patients, 64 in the CVD group and 114 in the SRVD group. The 2 groups did not differ significantly in patient characteristics except for mean follow-up time (37.6 vs 48.8 months; P = .01). The SRVD group did not significantly differ from the CVD group in local control survival (82.0% vs 78.4%; P = .85), regional control survival (89.9% vs 86.0%; P = .62), or disease-free survival (76.4% vs 66.9%; P = .67). The SRVD group had significantly better OS (93.9% vs 67.0%; P.001) and salvage survival (79.3% vs 20.7%; P.01) and a significantly lower ratio of severe lung infection (1 of 113 vs 5 of 59; P = .02). The SRVD group had a significantly lower risk of mortality (hazard ratio [HR], 0.3; P = .03). The factors associated with a significantly higher risk of mortality were N3 (regional lymph node stage status of N3) (HR, 3.0; P = .02); comorbidities of diabetes, coronary artery disease, or chronic kidney disease (grades 2-3) (HR, 3.8; P = .009), and severe lung infection (HR, 6.3; P = .007).Simultaneously reduced volume and dose of clinical target volumes did not impair locoregional control or disease-free survival. The benefits of SRVD treatment may include significant reduction in severe late AEs, particularly lung infection, dysphagia, and xerostomia. However, additional studies with longer patient follow-up are required to confirm these benefits.

Background To assess the benefit of postoperative radiotherapy in patients with pT1-2N1M0 oral and oropharyngeal cancer by the quality of neck dissection. Methods In the Surveillance, Epidemiology, and End Results database, pT1-2N1M0 oral and oropharyngeal cancer patients treated by primary tumor resection and neck dissection with or without radiotherapy were included between 2004 and 2015. Univariate and multivariate analysis were used to explore the effect of adjuvant radiotherapy on 5-year overall survival (OS) and disease-specific survival (DSS) among different quality of neck dissection. Results Of the 1765 patients identified, 1108 (62.8%) had oral cancer, 1141 (64.6%) were men, and 1067 (60.5%) underwent adjuvant radiotherapy. After adjusting for confounding factors, postoperative radiotherapy reduced the adjusted hazard ratio (aHR) of 5-year OS to 0.64 (95% confidence interval [CI] 0.49–0.84) in those with Conclusion Radiotherapy was associated with improved survival in pT1-2N1M0 oral and oropharyngeal cancer patients without adequate neck dissection.

Context The traditional drying method, sun drying, for Chrysanthemum morifolium Ramat. cv. Hang-ju (Compositae) (HJ) is widely replaced by sulphur fumigation (SF), which has an unknown effect on its efficacy. Objective To investigate protective effects of nonfumigated HJ (NHJ) and sulphur-fumigated HJ (SHJ) water extracts against oxidative stress and lipid peroxidation. Materials and methods Sprague-Dawley rats were administered high-fat diet to induce hyperlipidaemia and randomly divided into eight groups (n = 6): control, fenofibrate, NHJ and SHJ extracts (1, 2 or 4 g crude drugs/kg/d; intragastric administration for 8 weeks). Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected. Human umbilical vein endothelial cells (HUVECs) were treated with NHJ and SHJ extracts (50, 100 or 200 μg/mL) for 24 h, followed by oxidized low-density lipoprotein (ox-LDL, 20 μg/mL) for 2 h in vitro. Cellular reactive oxygen species (ROS), SOD and MDA levels and apoptosis were evaluated. Results NHJ was more effective than SHJ in decreasing serum TG, TC, LDL-C, LDL/HDL and MDA while increasing serum HDL-C and SOD levels at high doses. SHJ (IC50=19.9 mg/mL) suppressed HUVEC growth stronger than NHJ (IC50=186.7 mg/mL). At 200 μg/mL, NHJ was more effective than SHJ in downregulating ROS and MDA levels, reducing HUVECs apoptosis rate and elevating SOD activity in ox-LDL-treated HUVECs. Conclusions SF causes oxidative damage and attenuates antioxidative activity in ox-LDL-treated HUVECs, which promotes lipid peroxidation. SF is not recommended for processing HJ.

We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.

Glioma is a primary, malignant, and aggressive brain tumor in adults. To develop new therapeutic strategies for glioma, we must determine its underlying mechanisms. In the present study, we aimed to investigate the potential role of miR-1272-ADAM9-CDCP1 signaling in the progression of glioma. We found that ectopic expression of miR-1272 produced significant inhibitory effects on cell proliferation and migration and was associated with cell cycle G0/G1 arrest in A172 and SHG44 glioma cells. Using the luciferase reporter assay, we identified ADAM9 as a target of miR-1272. The expression of ADAM9 was markedly decreased or increased after overexpression or inhibition, respectively, of miR-1272 in glioma cells. Moreover, overexpression of ADAM9 reversed the inhibitory effects of miR-1272 on glioma cell progression. Furthermore, CDCP1 served as a potential downstream molecule of miR-1272/ADAM9 signaling in glioma and promoted the proliferation and migration of glioma. Results derived from clinical samples and online databases confirmed correlations between the expression of ADAM9 and CDCP1 and both the severity and prognosis of glioma. In conclusion, these results suggest that miR-1272 and CDCP1 may act as novel regulators in glioma. The miR-1272/ADAM9/CDCP1 pathway may serve as a potential candidate pathway for the prevention of glioma.

Background: The increasing rates of Caesarean section (CS) beyond the WHO standards (10–15%) pose a significant global health concern.Objective: Systematic review and meta-analysis to identify an association between CS history and maternal adverse outcomes for the subsequent pregnancy and delivery among women classified in Robson classification (RC).Search Strategy: PubMed/Medline, EbscoHost, ProQuest, Embase, Web of Science, BIOSIS, MEDLINE, and Russian Science Citation Index databases were searched from 2008 to 2018.Selection Criteria: Based on Robson classification, studies reporting one or more of the 14 adverse maternal outcomes were considered eligible for this review.Data Collection: Study design data, interventions used, CS history, and adverse maternal outcomes were extracted.Main Results: From 4,084 studies, 28 (n = 1,524,695 women) met the inclusion criteria. RC group 5 showed the highest proportion among deliveries followed by RC10, RC7, and RC8 (67.71, 32.27, 0.02, and 0.001%). Among adverse maternal outcomes, hysterectomy had the highest association after preterm delivery OR = 3.39 (95% CI 1.56–7.36), followed by Severe Maternal Outcomes OR = 2.95 (95% CI 1.00–8.67). We identified over one and a half million pregnant women, of whom the majority were found to belong to RC group 5.Conclusions: Previous CS was observed to be associated with adverse maternal outcomes for the subsequent pregnancies. CS rates need to be monitored given the prospective risks which may occur for maternal and child health in subsequent births.

The WHO declared the coronavirus disease 2019 (COVID-19) a global pandemic on 11 March 2020. Lessons from SARS epidemic led Singapore to develop stringent infection control protocols in preparation for future pandemics. However, unlike SARS, COVID-19 appears to be more transmissible and is predicted to continue for longer. As of 14 June 2020, there have been 40,197 positive cases with 26 deaths in Singapore, and KK Women’s and Children’s Hospital (KKH) has managed a total of 73 cases. Obstetrics ultrasound is an indispensable medical service and must continue to operate during a pandemic. A key balance must be struck between keeping patients and healthcare workers safe while being able to provide quality and prompt obstetric care. Our Antenatal Diagnostic Centre (ADC) in KKH developed new strategies to adapt to the pandemic when the national Disease Outbreak Response System Condition (DORSCON) was raised from yellow to orange on 7 February 2020. In this paper, we discuss our clinical workflow to reduce the risk of transmission amongst patients and staff while minimising disruption to our services.

Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology that affects infants and young children. Considerable evidence supports the hypothesis that there is a genetic basis for KD susceptibility. Genome-wide association studies (GWAS) have identified several genetic variants associated with KD. This study aims to replicate three novel KD-associated single nucleotide polymorphisms (SNPs), identified by GWAS in Japanese, in a Taiwanese population. Associations between these SNPs and development of coronary artery lesions (CALs) were also investigated. The rs2254546 A/G, rs2857151 A/G, and rs4813003 C/T SNPs were genotyped in 681 children with KD and 563 ethnically-matched healthy controls using TaqMan Assay or DNA sequencing. We found rs2254546 and rs4813003 SNPs were significantly associated with KD (G allele, odds ratio [OR] = 1.54, P = 1.0 × 10–5; C allele, OR = 1.32, P = 8.1 × 10–4). However, no evidence for associations with CAL development was observed. Our study successfully validates associations of the rs2254546 and rs4813003 SNPs with KD in a Taiwanese population. Further functional studies of the SNPs are important in understanding the pathogenesis of KD.

Alcoholic liver disease (ALD) is the major cause of chronic liver disease and a global health concern. ALD pathogenesis is initiated with liver steatosis, and ALD can progress to steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Salvianic acid A (SAA) is a phenolic acid component of Danshen, a Chinese herbal medicine with possible hepatoprotective properties. The purpose of this study was to investigate the effect of SAA on chronic alcoholic liver injury and its molecular mechanism. We found that SAA significantly inhibited alcohol‐induced liver injury and ameliorated ethanol‐induced hepatic inflammation. These protective effects of SAA were likely carried out through its suppression of the BRD4/HMGB1 signalling pathway, because SAA treatment largely diminished alcohol‐induced BRD4 expression and HMGB1 nuclear translocation and release. Importantly, BRD4 knockdown prevented ethanol‐induced HMGB1 release and inflammatory cytokine production in AML‐12 cells. Similarly, alcohol‐induced pro‐inflammatory cytokines were blocked by HMGB1 siRNA. Collectively, our results reveal that activation of the BRD4/HMGB1 pathway is involved in ALD pathogenesis. Therefore, manipulation of the BRD4/HMGB1 pathway through strategies such as SAA treatment holds great therapeutic potential for chronic alcoholic liver disease therapy.

Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 are genetic risk factors for Type 1 Diabetes Mellitus (T1DM) and Celiac disease (CD) in Caucasians, but their association with Taiwanese Han population is unknown. We screened 532 Taiwanese T1DM patients for CD biomarkers including anti-tissue transglutaminase (TGM2), anti-gliadin and anti-neoepitope antibodies (Abs), sequencing DQB1 genotypes, and characterized the TGM2 Abs. We report that 3.76% of Taiwanese patients had TGM2-Abs and all had no CD's symptoms. In contrast to Caucasian's CD patients, DQ2/DQ8 only constituted ~4/5 of TGM2-Abs positive patients, while the other ~1/5 patients belonged to different HLA genotypes. Either anti-gliadin or anti-neoepitope Abs coexisted with ~3/4 of TGM2-Abs positive patients that were likely due to gluten-ingestion, while the cause of TGM2-Abs production for other ~1/4 of patients was unknown. Purified anti-TGM2 IgA (TGA) and anti-TGM2 IgG (TGG) could bind on endothelial cells surface, recognized native better than denatured forms of TGM2, and TGA inhibited TGM2's transamidation activity by up to 80% but TGG had no effects. Epitope mapping of all TGM2-Abs positive sera demonstrated that TGM2-Abs had heterogeneity in specificities. This is the first study on the differences between Taiwanese Han group and Caucasian in HLA genotypes and properties of TGM2-Abs.

Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barre syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 μM and displayed EC50 values of 1.52 μM and 1.91 μM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.

Incorporation of water has been revealed to successfully facilitate visible-light photoredox catalysis of indole leading to increased production of C2-quaternary indolinone. The water-promoted photoreaction of indole under catalyst-free conditions by a household compact fluorescence light was also demonstrated. The antiproliferative activity of the synthesized indolinones was evaluated against three human cancer cell lines.

Background/Aim: Whole-body positron-emission tomography/computed tomography with the glucose analog 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG-PET/CT) has been used to screen examinees for underlying malignancy in many countries. The aim of this study was to compare the potential value of FDG-PET/CT application in asymptomatic individuals with those with suspected malignancy. Patients and Methods: A total of 9,408 examinees underwent whole-body FDG-PET/CT at our hospital from July 2006 to August 2013. Three thousand and seven hundred asymptomatic individuals and 848 individuals with laboratory and clinical/radiologicaI suspicion of malignancy who had undergone FDG-PET/CT for cancer screening were recruited. The final confirmation of cancer and outcomes were based on a pathological report and continuous follow-up. Results: Forty-five out of 3,700 asymptomatic individuals (1.2%) had proven malignancy, and 42 of them (93.3%) were found by FDG-PET/CT. Two hundred and twelve out of 848 with suspected malignancy (25%) had proven malignancy, and 196 of them (92.5%) were detected by FDG-PET/CT. Most of these cancers in asymptomatic individuals were clinically at an early stage. The discovery rate in asymptomatic individuals and those with suspected malignancy was 1.1% and 23.1%, respectively. The overall survival of patients with cancer diagnosed with PET/CT was higher than those with suspected malignancy (78.6% vs. 48.5%, p

Purpose This study aims to report the clinical features of an infant with CGL in a Chinese Zhuang ethnic family, whose family members were discovered to carry new pathogenic mutations in the BSCL2. Patients and methods In this study, we report clinical and molecular investigations of CGL disease in a family of 4 members (parents and two sons). We used whole exome sequencing (WES) in the family to examine the genetic cause of the disease. Results The proband presented with skin pigmentation, hypertriglyceridemia and diabetes. WES identified a previously unreported compound heterozygous mutation in the BSCL2 (c.545_546insCCG heterozygous mutation and exon 3 heterozygous deletion) in the proband. His mother is a heterozygous carrier of the c.545_546insCCG mutation and his father and brother are carriers of the exon 3 heterozygous deletion. Conclusion Compound heterozygous mutation of the BSCL2 (new c.545_546insCCG heterozygous mutation and new exon 3 heterozygous deletion) was detected in the proband with characteristic clinical manifestations of CGL2.

Background:. Facial thread lifting technology has been applied for more than 30 years, with relatively few complications. In 2014, China approved polydioxanone thread (an absorbable barbed thread) for large-scale nonsurgical facial lifting. However, due to surgeons’ lack of overall experience, the complications of polydioxanone thread facelift have been relatively high. Methods:. From April 2014 to January 2020, a total of 190 patients with postoperative complications of facelifts were treated after they underwent thread lifting in other hospitals. Of these, 189 patients were women and one was a man; the age of patients ranged from 28 to 62 years, with an average age of 37.4 years. Results:. Patients were mainly treated in our outpatient clinic for the following complications: skin dimpling (77 cases, 40.5%); contour irregularity (32 cases, 16.8%); visible threads (31 cases, 16.3%); thread extrusion (10 cases, 5.3%); infection (17 cases, 8.9%); swelling (nine cases, 4.7%); incomplete facial paralysis (five cases, 2.6%); hyperpigmentation (four cases, 2.1%); hematoma (four cases, 2.1%); allergy (one case, 0.05%). Follow-up was scheduled 1–24 weeks after treatment. Conclusions:. The most common complications of facial thread lifting are, in the following order, skin dimpling, contour irregularity, visible threads, and thread extrusion. The reasons for complications are mainly unfamiliarity with facial anatomy, unskilled surgical operation, and misunderstanding of the facial aesthetics of Asian women.

Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities.

The effectiveness and safety of electroacupuncture (EA) for depression have been identified by abundant clinical trials and experimental findings. The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway is considered to be involved in the antidepressant mechanism of EA. However, the antidepressant effect of EA via modulating the expression of c-Fos/activator protein-1 (AP-1) under the condition of JNK inhibition remains unexplored. In this study, we investigated the antidepressant effect and possible mechanism of EA in regulating the expression of c-Fos/AP-1 under the condition of JNK inhibition by SP600125 in rats exposed to chronic unpredictable mild stress (CUMS). The depression-like behaviors were evaluated by the body weight, sucrose preference test (SPT), and open field test (OFT). The expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum of CUMS induced rat model of depression were detected by ELISA. The results indicated that treatment with EA and fluoxetine can reverse the CUMS-induced depression-like behaviors in rats and can up-regulate the expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum. Of note, the data demonstrated that SP600125, the inhibitor of JNK signaling pathway, can exert synergistic effect with EA in regulating CUMS-induced abnormal activation of the JNK signaling pathway. The antidepressant effect of EA might be mediated by modulating the expression of c-Fos/AP-1.摘要:目前电针抗抑郁的有效性和安全性得到大量临床研究和实验结果的证实，JNK信号通路被认为是参与了电针抗抑郁的机制过程。然而，电针通过在阻断JNK信号通路条件下调节c-Fos/AP-1表达的抗抑郁机制尚未阐明。在本研究中，我们主要探究电针通过SP600125抑制JNK信号通路条件下调节慢性温和不可预知性应激(CUMS)抑郁模型c-Fos/AP-1表达的抗抑郁效应机制。通过体重监测、糖水偏好实验和旷场实验评价抑郁样行为；采用酶联免疫吸附剂测定技术(ELISA)检测下丘脑c-Jun、垂体c-Fos及血清c-Fos、AP-1水平。结果显示，电针及氟西汀干预显著改善了CUMS诱导的大鼠抑郁样行为，并逆转了CUMS诱导的下丘脑水平c-Jun、垂体c-Fos及血清c-Fos、AP-1上调表达。值得注意的是，研究数据表明JNK信号通路特异性阻断剂SP600125同电针一起在调节CUMS诱导的JNK信号通路异常激活上起到协同作用，电针抗抑郁效应可能是通过调节应激诱导的c-Fos/AP-1表达介导的。.

To develop a noninvasive model to predict significant fibrosis in children with chronic hepatitis B (CHB). A total of 116 CHB pediatric patients who underwent liver biopsy were included in the study. Liver histology, which is the gold standard for assessing fibrosis, was performed. Blood routine examination, coagulation function, liver biochemistry, viral serology, and viral load were analyzed. Receiver operating characteristic curve analysis was used to analyze the sensitivity and specificity of all possible cut-off values. Based on the correlation and difference analyses, 7 available clinical parameters (total bile acid, gamma-glutamyl transpeptidase [GGT], aspartate transaminase, direct bilirubin to total bilirubin ratio, alanine aminotransferase, prealbumin [PA], and cholinesterase) were included in the modeling analysis. A model to predict significant liver fibrosis was derived using the 2 best parameters (PA and GGT). The original model was Y=−1.803 ln PA(mg/L)+0.769lnGGT(U/L)+6.436. After the mathematical calculation, the G index=600 × GGT/PA2 predicted significant fibrosis, with an area under the receiving operating characteristics (AUROC) curve of 0.733, 95% confidence interval (0.643–0.811). The AUROC of the G index (0.733) was higher than that of aminotransferase to platelet ratio index (APRI) (0.680) and Fibrosis index based on 4 factors (FIB-4) (0.601) in predicting significant fibrosis in children with CHB. If the values of the G index were outside the range of 0.28 to 1.16, 52% of children with CHB could avoid liver biopsy, with an overall accuracy of 75%. The G index can predict and exclude significant fibrosis in children with CHB, and it may reduce the need for liver biopsy in children with CHB.

Fatty acids are derived from diet and fermentative processes by the intestinal flora. Two to five carbon chain fatty acids, termed short chain fatty acids (SCFA) are increasingly recognized to play a role in intestinal homeostasis. However, the characteristics of slightly longer 6 to 10 carbon, medium chain fatty acids (MCFA), derived primarily from diet, are less understood. Here, we demonstrated that SCFA and MCFA have divergent immunomodulatory propensities. SCFA down-attenuated host pro-inflammatory IL-1β, IL-6, and TNFα response predominantly through the TLR4 pathway, whereas MCFA augmented inflammation through TLR2. Butyric (C4) and decanoic (C10) acid displayed most potent modulatory effects within the SCFA and MCFA, respectively. Reduction in TRAF3, IRF3 and TRAF6 expression were observed with butyric acid. Decanoic acid induced up-regulation of GPR84 and PPARγ and altered HIF-1α/HIF-2α ratio. These variant immune characteristics of the fatty acids which differ by just several carbon atoms may be attributable to their origins, with SCFA being primarily endogenous and playing a physiological role, and MCFA exogenously from the diet.

Natural products make up a large proportion of medicine available today. Cannabinoids from the plant Cannabis sativa is one unique class of meroterpenoids that have shown a wide range of bioactivities and recently seen significant developments in their status as therapeutic agents for various indications. Their complex chemical structures make it difficult to chemically synthesize them in efficient yields. Synthetic biology has presented a solution to this through metabolic engineering in heterologous hosts. Through genetic manipulation, rare phytocannabinoids that are produced in low yields in the plant can now be synthesized in larger quantities for therapeutic and commercial use. Additionally, an exciting avenue of exploring new chemical spaces is made available as novel derivatized compounds can be produced and investigated for their bioactivities. In this review, we summarized the biosynthetic pathways of phytocannabinoids and synthetic biology efforts in producing them in heterologous hosts. Detailed mechanistic insights are discussed in each part of the pathway in order to explore strategies for creating novel cannabinoids. Lastly, we discussed studies conducted on biological targets such as CB1, CB2 and orphan receptors along with their affinities to these cannabinoid ligands with a view to inform upstream diversification efforts.

Subchondral bone lesions, as the crucial inducement for accelerating cartilage degeneration, have been considered as the initiating factor and the potential therapeutic target of knee osteoarthritis (KOA). Acupotomy, the biomechanical therapy guided by traditional Chinese meridians theory, alleviates cartilage deterioration by correcting abnormal mechanics. Whether this mechanical effect of acupotomy inhibits KOA subchondral bone lesions is indistinct. This study aimed to investigate the effects of acupotomy on inhibiting subchondral bone resorption and to define the possible mechanism in immobilization-induced KOA rabbits. After KOA modeling, 8 groups of rabbits (4w/6w acupotomy, 4w/6w electroacupuncture, 4w/6w model, and 4w/6w control groups) received the indicated intervention for 3 weeks. Histological and bone histomorphometry analyses revealed that acupotomy prevented both cartilage surface erosion and subchondral bone loss. Further, acupotomy suppressed osteoclast activity and enhanced osteoblast activity in KOA subchondral bone, showing a significantly decreased expression of tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinases-9 (MMP-9), and cathepsin K (Ctsk) and a significantly increased expression of osteocalcin (OCN); this regulation may be mediated by blocking the decrease in osteoprotegerin (OPG) and the increase in NF- κ B receptor activated protein ligand (RANKL). These findings indicated that acupotomy inhibited osteoclast activity and promoted osteoblast activity to ameliorate hyperactive subchondral bone resorption and cartilage degeneration in immobilization-induced KOA rabbits, which may be mediated by the OPG/RANKL signaling pathway. Taken together, our results indicate that acupotomy may have therapeutic potential in KOA by restoring the balance between bone formation and bone resorption to attenuate subchondral bone lesions.

SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, such as proliferation, differentiation, adhesion migration and apoptosis. Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer. Hence, SHP2 has become a promising target for cancer immunotherapy. In this paper, we reported the identification of compound 1 as SHP2 inhibitor. Fragment-based ligand design, De novo design, ADMET and Molecular docking were performed to explore potential selective SHP2 allosteric inhibitors based on SHP836. The results of docking studies indicated that the selected compounds had higher selective SHP2 inhibition than existing inhibitors. Compound 1 was found to have a novel selectivity against SHP2 with an in vitro enzyme activity IC50 value of 9.97 μM. Fluorescence titration experiment confirmed that compound 1 directly bound to SHP2. Furthermore, the results of binding free energies demonstrated that electrostatic energy was the primary factor in elucidating the mechanism of SHP2 inhibition. Dynamic cross correlation studies also supported the results of docking and molecular dynamics simulation. This series of analyses provided important structural features for designing new selective SHP2 inhibitors as potential drugs and promising candidates for pre-clinical pharmacological investigations.

In this work, a gold biosensor has been constructed and characterised in Escherichia coli ( E. coli ). Though gold biosensors have been previously reported, a NOT gate gold biosensing genetic circuit was constructed using an orthogonal inverter system as an alternative to a circuit where output is contingent solely on input. This enables the detection of changes in gold concentration whereby circuit remains OFF in presence of inducer and ON in absence of inducer. The proposed biosensor is an alternative to conventional forms of gold detection such as Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). The constructed biosensor is a collection of components – golTSB operon (isolated from Salmonella enterica ), mf -Lon protease (isolated from Mesoplasma florum ) and associated ssrA degradation tag with GFP acting as a reporter. The minimum time and concentration required by the biosensor gol- mf lon-GFP (GMG) to achieve the ON output is characterised here using plate reader data derived from a single multi-stage assay.

Background To date, there are just several studies comparing distal locked nails with distal unlocked nails in treating intertrochanteric fractures. We report the first meta-analysis about this issue. Methods Systematic search was conducted for studies in PubMed, Embase and Cochrane Library. Meta-analyses were performed regarding intra operative outcomes, complications and functional outcomes. Results Pooled results showed insignificant difference between distal locking group and distal unlocking group in hip pain (relative risk (RR) 1.14, 95% confidence interval (CI) 0.59-2.19), distal tip fracture (RR 1.08, 95% CI 0.37-3.11), lag screw cut-out (RR 1.60, 95% CI 0.54-4.78), delayed or nonunion (RR 1.32, 95% CI 0.25-7.06), deep vein thrombosis (RR 1.06, 95% CI 0.23-4.84), wound infection (RR 0.58, 95% CI 0.28-1.22), Harris hip score (standard mean deviation (SMD) 0.03, 95% CI -0.15 to 0.21) and walking ability. However, significant difference was detected in operation time (SMD 0.77, 95% CI 0.36-1.17), fluoroscopy exposure time (SMD 1.02, 95% CI 0.52-1.52), blood loss (SMD 0.80, 95% CI 0.62-0.99) and total incision length (SMD 1.16, 95% CI 0.86-1.47). Result of trial sequential analysis indicated conclusive evidence. Conclusion Current evidence indicates that the distal locked intramedullary nails should not be recommended as routine choice for stable intertrochanteric fractures.

Purpose The purpose of this paper is to tackle the problem of technology addiction by investigating the differences between the antecedences of addictive (problematic technology usage) and high-engagement behavior (non-problematic technology usage). The case of social networking site usage (SNS, e.g. Facebook, Instagram or Twitter) is taken as the case out of the reason of prevalent user population. Design/methodology/approach It is revealed that people tend to use SNS not only for building a relationship, but also for communicating. In other words, there are inner needs of adopting the SNS technology. However, no clear definitions can be followed for determining the problematic SNS usage, addictive behavior and the high-engagement behavior. Therefore, this study adopts the notion of uses and gratification theory (U&G theory) for investigating the SNS usage behavior. Also, the social anxiety is also first introduced to integrate into the research for an empirical study. Findings Results reveal that gratification sought and relationship maintenance are associated with the addictive behavior, whereas the relationship maintenance is significantly related to high-engagement behavior. Research limitations/implications First, the selected data represents a sample of SNW users in the Asian Pacific region and mainly from the group of young college users. Therefore, caution must be taken when generalizing the findings to other SNW users or groups. Second, the time aspect related to social media dependence may need to be considered in future studies. Third, the authors found marginal support for the influence of intentions of high engagement¸ and future studies may consider applying other theories that could better explain these types of behavior. Practical implications The results of this study provide strong evidence that inner anxiety perceived by users should not be neglected while tackling the problematic internet use due to SNW addiction because it can strengthen the force for depending on SNW for seeking social support. Apart from the value of perceived enjoyment as asserted in previous studies, this study opens up a new opportunity to tackle SNW dependence. Social implications The key implication of this research is that the impact of the mental health of users on SNW problematic should not be overlooked . The higher the level of anxiety perceived, the more likely is the SNW dependence. Therefore, the online behavior depending on psychological health should be addressed because it may be a critical point for assisting users to adopt SNW wisely. Originality/value This study confirms that social anxiety people experience in real (offline) life has impacts on online behavior of SNS usage (online). It suggests that the difference between users as the perceived level of social anxiety can trigger different levels of SNS usage. Second, U&G theory is proven valid in understanding SNS addiction. Third, relationship maintenance through the use of SNS reveals its dissimilar effects on SNS addiction and high engagement.

Prompt and effective treatment of maternal depression during pregnancy is important as it is an independent predictor of negative maternal and fetal outcomes. Yoga is an increasingly popular non-pharmacological modality. This study thus aimed to undertake a meta-analysis of the efficacy of yoga-based interventions for maternal depression during pregnancy. A total of 8 clinical studies were systematically reviewed, and 6 studies with a total of 405 pregnant mothers were included in the final meta-analysis. Applying per-protocol analysis and a random-effects model, the pooled standardized mean difference (SMD) from baseline depressive score was −0.452 (95% CI: −0.816 to −0.880, P = 0.015), supporting a statistically significant beneficial effect of yoga-based interventions on mood. Overall, yoga-based interventions are a promising non-pharmacological option, however, most trials examined were preliminary, recruited only participants with mild depression, did not blind study participants and had relatively small sample sizes. Larger randomized, controlled trials should be encouraged.