Coxsackievirus B4 (CVB4) has one of the highest proportions of fatal outcomes of other enterovirus serotypes. However, the pathogenesis of severe respiratory disease caused by CVB4 infection remains unclear. In this study, 3 of 42 (7.2%, GZ-R6, GZ-R7 and GZ-R8) patients with severe pneumonia tested positive for CVB4 infection in southern China. Three full-length genomes of pneumonia-derived CVB4 were sequenced and annotated for the first time, showing their high nucleotide similarity and clustering within genotype V. To analyze the pathogenic damage caused by CVB4 in the lungs, a well-differentiated human airway epithelium (HAE) was established and infected with the pneumonia-derived CVB4 isolate GZ-R6. The outcome was compared with that of a severe hand-foot-mouth disease (HFMD)-derived CVB4 strain GZ-HFM01. Compared with HFMD-derived CVB4, pneumonia-derived CVB4 caused more intense and rapid disruption of HAE polarity, leading to tight-junction barrier disruption, loss of cilia, and airway epithelial cell hypertrophy. More pneumonia-derived CVB4 were released from the basolateral side of the HAE than HFMD-derived CVB4. Of the 18 cytokines tested, only IL-6 and IL-1b secretion significantly increased on bilateral sides of HAE during the early stage of pneumonia-derived CVB4 infection, while multiple cytokine secretions significantly increased in HFMD-derived CVB4-infected HAE. HFMD-derived CVB4 exhibited stronger neurovirulence in the human neuroblastoma cells SH-SY5Y than pneumonia-derived CVB4, which is consistent with the clinical manifestations of patients infected with these two viruses. This study has increased the depth of our knowledge of severe pneumonia infection caused by CVB4 and will benefit its prevention and treatment.

The transcription factor p63 is a member of the p53 gene family that plays a complex role in cancer due to its involvement in epithelial differentiation, cell cycle arrest and apoptosis. MicroRNAs are a class of small, non-coding RNAs with an important regulatory role in various cellular processes, as well as in the development and progression of cancer. A number of microRNAs have been shown to function as transcriptional targets of p63. Conversely, microRNAs also can modulate the expression and activity of p63. However, the p63-microRNA regulatory circuit has not been addressed in depth so far. Here, computational genomic analysis was performed using miRtarBase, Targetscan, microRNA.ORG, DIANA-MICROT, RNA22-HSA and miRDB to analyze miRNA binding to the 3'UTR of p63. JASPAR (profile score threshold 80%) and TFSEARCH datasets were used to search transcriptional start sites for p53/p63 response elements. Remarkably, these data revealed 63 microRNAs that targeted p63. Furthermore, there were 39 microRNAs targeting p63 that were predicted to be regulated by p63. These analyses suggest a crosstalk between p63 and microRNAs. Here, we discuss the crosstalk between p63 and the microRNA network, and the role of their interactions in cancer.

Background: Seed-based studies on resting-state functional connectivity (rsFC) in schizophrenia have shown disrupted connectivity involving a number of brain networks; however, the results have been controversial. Methods: We conducted a meta-analysis based on independent component analysis (ICA) brain templates to evaluate dysconnectivity within resting-state brain networks in patients with schizophrenia. Seventy-six rsFC studies from 70 publications with 2,588 schizophrenia patients and 2,567 healthy controls (HCs) were included in the present meta-analysis. The locations and activation effects of significant intergroup comparisons were extracted and classified based on the ICA templates. Then, multilevel kernel density analysis was used to integrate the results and control bias. Results: Compared with HCs, significant hypoconnectivities were observed between the seed regions and the areas in the auditory network (left insula), core network (right superior temporal cortex), default mode network (right medial prefrontal cortex, and left precuneus and anterior cingulate cortices), self-referential network (right superior temporal cortex), and somatomotor network (right precentral gyrus) in schizophrenia patients. No hyperconnectivity between the seed regions and any other areas within the networks was detected in patients, compared with the connectivity in HCs. Conclusions: Decreased rsFC within the self-referential network and default mode network might play fundamental roles in the malfunction of information processing, while the core network might act as a dysfunctional hub of regulation. Our meta-analysis is consistent with diffuse hypoconnectivities as a dysregulated brain network model of schizophrenia.

Despite the P300 event-related potential (ERP) differences between distinct stimulus sequences, the effect of stimulus sequence on the brain network is still left unveiled. To uncover the corresponding effect of stimulus sequence, we thus investigated the differences of functional brain networks, when a target (T) or standard (S) stimulus was presented preceding another T as background context. Results of this study demonstrated that, when an S was first presented preceding a T (i.e., ST sequence), the P300 experiencing large amplitude was evoked by the T, along with strong network architecture. In contrast, if a T was presented in advance [i.e., target-to-target (TT) sequence], decreased P300 amplitude and attenuated network efficiency were demonstrated. Additionally, decreased activations in regions, such as inferior frontal gyrus and superior frontal gyrus were also revealed in TT sequence. Particularly, the effect of stimulus sequence on P300 network could be quantitatively measured by brain network properties, the increase in network efficiency corresponded to large P300 amplitude evoked in P300 task.

Drug-eluting balloon (DEB) has become an alternative option to drug-eluting stent (DES) for the treatment of in-stent restenosis (ISR). However, the effect of drug-eluting balloon with regular bare-mental stent (BMS) in de novo coronary artery disease (CAD) is unclear. This meta-analysis aimed to evaluate the efficacy of DEB with regular BMS compared to BMS or DES in de novo CAD.

Cervical cancer is the second most common malignancy in women worldwide and always has recurrence owing to radioresistance. MicroRNA (miRNA or miR) has been identified to relate to the sensitivity of cancer radiotherapy. Here, we investigated the potential of miRNA-320 as a biomarker for radiosensitivity by targeting β-catenin in cervical cancer. A radioresistant cervical cancer cell line, C33AR, was established, and the radioresistance of C33AR cells was confirmed by a colony-formation assay. The expression of miRNA-320 was detected by reverse transcription-quantitative polymerase chain reaction, and compared between C33A and C33AR. β-catenin, the target of miRNA-320, was determined at the protein level by western blotting after transfecting the inhibitor of miRNA-320. The expression of miRNA-320 was markedly decreased in C33AR cells, which appeared to be more radioresistant, compared with its parental cell line C33A. Target prediction suggested that miRNA-320 negatively regulated the expression of β-catenin. Knockdown of β-catenin increased C33AR radiosensitivity, which revealed that the inhibition of β-catenin could rescue the miRNA-320-mediated cell radioresistance. On the other hand, overexpressing miRNA-320 increased C33AR radiosensitivity. In conclusion, miRNA-320 regulated the radiosensitivity of C33AR cells by targeting β-catenin. This finding provides evidence that miRNA-320 may be a potential biomarker of radiosensitivity in cervical cancer.

The aim of this study was to investigate the protective effects of sulfur dioxide (SO2) on the endothelial function of the aorta in D-galactose (D-gal)-induced aging rats. Sprague Dawley rats were randomized into a D-gal group, a D-gal + SO2 group and a control group, then injected with D-gal, D-gal + SO2 donor or equivalent volumes of saline, respectively, for 8 consecutive weeks. After 8 weeks, the mean arterial pressure was significantly increased in the D-gal group, but was lowered by SO2. SO2 significantly ameliorated the endothelial dysfunction induced by D-gal treatment. The vasorelaxant effect of SO2 was associated with the elevated nitric oxide levels and upregulated phosphorylation of endothelial nitric oxide synthase. In the D-gal group, the concentration of angiotensin II in the plasma was significantly increased, but was decreased by SO2. Moreover, levels of vascular tissue hydrogen peroxide (H2O2) and malondialdehyde were significantly lower in SO2-treated groups than those in the D-gal group. Western blot analysis showed that the expressions of oxidative stress-related proteins (the angiotensin II type 1 receptor (AT1R), and nicotinamide adenine dinucleotide phosphate oxidase subunits) were increased in the D-gal group, while they were decreased after treatment with SO2. In conclusion, SO2 attenuated endothelial dysfunction in association with the inhibition of oxidative stress injury and the downregulation of the angiotensin II/AT1R pathway in D-gal-induced aging rats.

Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. B cell translocation gene 4 (BTG4) is a key adaptor of the CCR4-NOT deadenylase complex, which is involved in maternal mRNA decay in mice, but no human diseases caused by mutations in BTG4 have previously been reported. Here, we identified four homozygous mutations in BTG4 (GenBank: NM_017589.4) that are responsible for the phenotype of ZCF, and we found they followed a recessive inheritance pattern. Three of them-c.73C>T (p.Gln25Ter), c.1A>G (p.?), and c.475_478del (p.Ile159LeufsTer15)-resulted in complete loss of full-length BTG4 protein. For c.166G>A (p.Ala56Thr), although the protein level and distribution of mutant BTG4 was not altered in zygotes from affected individuals or in HeLa cells, the interaction between BTG4 and CNOT7 was abolished. In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF. Thus, we provide evidence that ZCF is a Mendelian phenotype resulting from mutations in BTG4. These findings contribute to our understanding of the role of BTG4 in human early embryonic development and provide a genetic marker for female infertility.

Chinese adolescents encounter a lot of stressors, such as academic burden and parental pressure. However, little is known about their perception of stress. The 10-item Perceived Stress Scale (PSS-10) is a widely used instrument to measure individuals' appraisal of global stress in academic research and clinical practice. The current study aimed to evaluate the best-fit factor structure model of the PSS-10 and the measurement invariance across genders in Chinese adolescents.

To evaluate the efficacy and safety of caudal dexmedetomidine in pediatric caudal anesthesia (CA).

Single-nucleotide polymorphism (SNP) and Alternative splicing (AS) were found to be implicated in certain diseases, nevertheless, the contributions of mRNA SNPs and AS to pathogenesis in developing rat brains with hypoxic-ischemic encephalopathy (HIE) remained largely vague. Additionally, the disease associated with Tacr3 was normosmic congenital hypogonadotropic hypogonadism, while the relationship between HIE and Tacr3 remained largely elusive. The current study was designed to investigate the differentially expressed mRNAs and related SNPs as well as AS in neonatal rats subjected to HIE to identify if the exhibition of AS was associated with SNPs under pathological condition. Firstly, we used postnatal day 7 Sprague-Dawley rats to construct neonatal HIE model, and analyzed the expression profiles of SNP mRNA in hypoxic-ischemic (HI) and sham brains by using RNA sequencing. Then four genes, including Mdfic, Lpp, Bag3 and Tacr3, connecting with HIE and exhibiting SNPs and AS were identified by bioinformatics analysis. Moreover, combined with exonic splicing enhancer (ESE) and alternative splice site predictor (ASSP) analysis, we found that Tacr3 is associated specifically with HIE through 258547789 G > A SNP in inside the Alt First Exon and 258548573 G > A SNP in outside the Alt First Exon. Taken together, our study provides new evidence to understand the role of Tacr3 in HIE and it is possibly a potential target for the treatment of HIE in future clinic trial.

Total fertilization failure (TFF) can occur during in vitro fertilization (IVF) treatments, even following intracytoplasmic sperm injection (ICSI). Various male or female factors could contribute to TFF. Increasing evidence suggested that genetic variations in PLCZ1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCζ), is involved in oocyte activation and is a key male factor in TFF. In the present study, we explored the genetic variants in male individuals that led to TFF. A total of 54 couples with TFF or poor fertilization (fertilization rate < 20%) were screened, and 21 couples were determined to have a male infertility factor by the mouse oocyte activation test. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 (actin like 9) in three individuals. ACTL9 variations led to abnormal ultrastructure of the perinuclear theca (PT), and PLCζ was absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in an Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. These findings identified the role of ACTL9 in the PT structure and the correct localization of PLCζ. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.

Neuroimaging studies have revealed that insomnia is characterized by aberrant neuronal connectivity in specific brain regions, but the topological disruptions in the white matter (WM) structural connectivity networks remain largely unknown in insomnia. The current study uses diffusion tensor imaging (DTI) tractography to construct the WM structural networks and graph theory analysis to detect alterations of the brain structural networks. The study participants comprised 30 healthy subjects with insomnia symptoms (IS) and 62 healthy subjects without IS. Both the two groups showed small-world properties regarding their WM structural connectivity networks. By contrast, increased local efficiency and decreased global efficiency were identified in the IS group, indicating an insomnia-related shift in topology away from regular networks. In addition, the IS group exhibited disrupted nodal topological characteristics in regions involving the fronto-limbic and the default-mode systems. To our knowledge, this is the first study to explore the topological organization of WM structural network connectivity in insomnia. More importantly, the dysfunctions of large-scale brain systems including the fronto-limbic pathways, salience network and default-mode network in insomnia were identified, which provides new insights into the insomnia connectome. Topology-based brain network analysis thus could be a potential biomarker for IS.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies. A growing number of studies have shown that competitive endogenous RNA (ceRNA) regulatory networks might play important roles during HCC process. The present study aimed to identify a regulatory axis of the ceRNA network associated with the development of HCC. The roles of SNX16 and PAPOLG in HCC were comprehensively analyzed using bioinformatics tools. Subsequently, the "mRNA-miRNA-lncRNA" model was then used to predict the upstream miRNAs and lncRNAs of SNX16 and PAPOLG using the miRNet database, and the miRNAs with low expression and good prognosis in HCC and the lncRNAs with high expression and poor prognosis in HCC were screened by differential expression and survival analysis. Finally, the risk-prognosis models of ceRNA network axes were constructed by univariate and multifactorial Cox proportional risk analysis, and the immune correlations of ceRNA network axes were analyzed using the TIMER and GEPIA database. In this study, the relevant ceRNA network axis GSEC/miR-101-3p/SNX16/PAPOLG with HCC prognosis was constructed, in which GSEC, SNX16, and PAPOLG were highly expressed in HCC with poor prognosis, while miR-101-3p was lowly expressed in HCC with good prognosis. The risk-prognosis model predicted AUC of 0.691, 0.623, and 0.626 for patient survival at 1, 3, and 5 years, respectively. Immuno-infiltration analysis suggested that the GSEC/miR-101-3p/SNX16/PAPOLG axis might affect macrophage polarization. The GSEC/miR-101-3p/SNX16/PAPOLG axis of the ceRNA network axis might be an important factor associated with HCC prognosis and immune infiltration.

Pear fruits have been reported to contain abundant bioactive compounds and exhibit antidiabetic activity. In this study, Pingguoli pear (Pyrus pyrifolia cv.'Pingguoli') fermentation broth was sequentially extracted by five solvents with increasing polarity (petroleum ether, chloroform, ethyl acetate, n-butanol, and water) to evaluate its antioxidant and hypothermic activities, and then the main compounds of the fraction with the highest activity were assessed, which might be responsible for such activities. The results showed that the ethyl acetate fraction (EAF) exhibited the highest antioxidant activity according to DPPH (IC50 = 0.238 mg/mL), ABTS (IC50 = 0.293 mg/mL), and FRAP (IC50 = 0.193 mg/mL) assays. The in vitro hypoglycemic activity assay showed that EAF exhibited the strongest inhibitory effect, with IC50 values of 0.34 and 0.95 mg/mL for α-amylase and α-glucosidase, respectively. The glucose consumption in HepG2 cells treated with EAF was significantly increased to 252%, compare with control group. Liquid chromatography-mass spectrometry analysis implied that the main compounds, 3'-C-glucosylisoliquiritigenin, robustside D, caffeic acid, and chlorogenic acid may be potential candidates for the antioxidant and hypoglycemic activities of the EAF. This study suggested that EAF of Pingguoli pear fermentation broth could be utilized for development of potential functional food and antidiabetic agents.

Human mesenchymal stem cells (hMSCs) are effective in treating disorders resulting from an inflammatory or heightened immune response. The hMSCs derived from induced pluripotent stem cells (ihMSCs) share the characteristics of tissue derived hMSCs but lack challenges associated with limited tissue sources and donor variation. To meet the expected future demand for ihMSCs, there is a need to develop scalable methods for their production at clinical yields while retaining immunomodulatory efficacy. Herein, we describe a platform for the scalable expansion and rapid harvest of ihMSCs with robust immunomodulatory activity using degradable gelatin methacryloyl (GelMA) microcarriers. GelMA microcarriers were rapidly and reproducibly fabricated using a custom microfluidic step emulsification device at relatively low cost. Using vertical wheel bioreactors, 8.8 to 16.3-fold expansion of ihMSCs was achieved over 8 days. Complete recovery by 5-minute digestion of the microcarriers with standard cell dissociation reagents resulted in >95% viability. The ihMSCs matched or exceeded immunomodulatory potential in vitro when compared with ihMSCs expanded on monolayers. This is the first description of a robust, scalable, and cost-effective method for generation of immunomodulatory ihMSCs, representing a significant contribution to their translational potential.

Berberine is a promising botanical pesticide against fungal plant pathogens. However, whether berberine inhibits the invasion of fungal pathogen across plant surface remains unclear. Here we demonstrated that the enzyme activities of purified cutinase from fungal pathogen Colletotrichum capsici were partially inhibited in presence of berberine toward different substrates. Molecular dynamics simulation results suggested the rigidity of cutinase was decreased with berberine added into the system. Interestingly, aggregations of berberine to the catalytic center of cutinase were observed, and stronger hydrophobic interactions were detected between key residue His 208 and berberine with concentrations of berberine increased. More importantly, this hydrophobic interaction conferred conformational change of the imidazole ring of His 208, which swung out of the catalytic center to an inactive mode. In summary, we provided the molecular mechanism of the effect of berberine on cutinase from C. capsici.

Despite an increasing focus on transdiagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a transdiagnostic set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder, and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability. A total of 404 patients with a psychiatric diagnosis were recruited (psychosis, n = 129; unipolar depression, n = 92; post-traumatic stress disorder, n = 91; obsessive-compulsive disorder, n = 92) alongside n = 201 healthy controls and n = 20 unaffected first-degree relatives. We collected structural magnetic resonance imaging scans from each participant, and tested for transdiagnostic alterations using Voxel-based morphometry. Inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. The four psychiatric groups relative to healthy controls were all characterized by significantly greater gray matter volume in the putamen (right: z-score: 5.97, p-value < 0.001; left: z-score: 4.97, p-value = 0.001); the volume of this region was positively correlated with severity of symptoms across groups (r = 0.313; p < 0.001). Putamen enlargement was also evident in unaffected relatives compared to healthy controls (right: z-score: 8.13, p-value < 0.001; left: z-score: 9.38, p-value < 0.001). Taken collectively, these findings indicate that increased putamen volume may reflect a transdiagnostic marker of familial vulnerability to psychopathology. This is consistent with emerging conceptualizations of psychiatric illness, in which each disorder is understood as a combination of diagnosis-specific features and a transdiagnostic factor reflecting general psychopathology.

Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. In an implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor 4 (FGF4) enabled the highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24h despite exposure to FGF4. However, hypoxic stress supported differentiation poorly after 4-7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential and maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited optimum differentiation at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5-2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation.

Growing evidence suggests that long non-coding RNAs (lncRNAs) play a key role in tumorigenesis. However, the mechanism remains largely unknown.