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Changes of intestinal microbiota have been shown to be involved in the development of gestational diabetes mellitus (GDM). We performed a meta-analysis to systematically evaluate the potential role of probiotics for the prevention of GDM. Systematic literature search was performed in electronic databases including PubMed, Cochrane library, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) to obtain relevant randomized controlled studies. A random-effects model was used to pool the results by incorporating the impact of the potential heterogeneity. Meta-regression and subgroup analyses were conducted to evaluate the source of heterogeneity. Fourteen studies involving 3527 pregnant women were included. Results showed that probiotics significantly reduced the incidence of GDM as compared to control (risk ratio [RR]: 0.71, 95% confidence interval [CI]: 0.52–0.96, P = 0.03) with significant heterogeneity (I2 = 73%). The meta-regression showed that body mass index (BMI) of females was positively associated with the RR for the effect of probiotics on GDM (coefficient = 0.084, P = 0.01). The results of subgroup analyses also suggested that probiotics significantly reduced the risk of GDM in women with BMI < 26 kg/m2, but not in those with BMI ≥ 26 kg/m2 (P for subgroup difference = 0.001). In addition, the preventative efficacy of probiotics on GDM was remarkable in women < 30 years, but not in those ≥ 30 years (P for subgroup difference < 0.001). In conclusion, probiotics may be effective in reducing the risk of GDM, particularly for females with lower BMI and younger age.

Antipsychotic drug treatment for schizophrenia (SZ) can alter brain structure and function, but it is unclear if specific regional changes are associated with treatment outcome. Therefore, we examined the effects of antipsychotic drug treatment on regional grey matter (GM) density, white matter (WM) density, and functional connectivity (FC) as well as associations between regional changes and treatment efficacy. SZ patients (n = 163) and health controls (HCs) (n = 131) were examined by structural magnetic resonance imaging (sMRI) at baseline, and a subset of SZ patients (n = 77) were re-examined after 8 weeks of second-generation antipsychotic treatment to assess changes in regional GM and WM density. In addition, 88 SZ patients and 81 HCs were examined by resting-state functional MRI (rs-fMRI) at baseline and the patients were re-examined post-treatment to examine FC changes. The Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB) were applied to measure psychiatric symptoms and cognitive impairments in SZ. SZ patients were then stratified into response and non-response groups according to PANSS score change (≥50 % decrease or

ObjectivesThis study aimed to analyze the predictive value of umbilical cord blood Interleukin-6 (UCB IL-6) for the severity-graded BPD and to establish machine learning (ML) predictive models in a Chinese population based on the 2019 NRN evidence-based guidelines.MethodsIn this retrospective analysis, we included infants born with gestational age

ABSTRACT Porcine deltacoronavirus (PDCoV) is a newly emerged enteric pathogen that causes diarrhea, dehydration, vomiting, and in suckling piglets, a high rate of death. Here, we used endocytosis inhibitors, dominant-negative mutants, and small interfering RNA (siRNA) interference to investigate PDCoV entry into swine testicle (ST) cells. Results showed that chlorpromazine, dynasore, and methyl-β-cyclodextrin (MβCD) inhibited PDCoV internalization; immunofluorescence assay (IFA) of dominant-negative (DN) mutants and siRNA interference further demonstrated these results, indicating that PDCoV utilizes clathrin-mediated endocytosis and requires dynamin and cholesterol to enter ST cells. The role of endosomes in PDCoV infection was also investigated and we found that PDCoV does not require Rab5, Rab7, or Rab11 for productive infection, indicating that the transport of PDCoV in ST cells does not require the participation of the endosomal system. Our findings will provide additional understanding of the entry mechanisms of PDCoV and possible antiviral targets. IMPORTANCE Porcine deltacoronavirus (PDCoV) is a newly emerged enteric virus threatening pig industries worldwide. Our previous work showed that PDCoV enters porcine kidney (PK-15) cells through a caveolae-dependent pathway, but the entry mechanism for PDCoV into swine testicle (ST) cells remains unclear. Mechanisms of virus entry can be different with different virus isolates and cell types. Here, we determined that PDCoV enters ST cells via clathrin-mediated endocytosis. Additionally, we found that PDCoV entry does not require Rab5, Rab7, or Rab11. These findings provide additional understanding of the entry mechanisms of PDCoV and possible antiviral targets.

Abstract Little is known about the association between surface water quality and cancer incidence, especially in China. Drinking water quality has been linked to the incidence of several cancers in individual-level studies. However, few studies have attempted to examine multiple pollutants and multiple cancers at population level. This study used water monitoring and population-level cancer data from across China to examine spatial associations between water pollutants and types of cancer. We found a “dose–response” relationship between the number of pollutants present at high levels and cancer incidence. These results provide evidence of a nationwide spatial association between water quality and cancer in China. The precise relationship varies with cancers and pollutants. However, the overall consistency of the “dose–response” relationship suggests that surface water quality is an important factor in cancer incidence. Our findings highlight new issues such as the changing effects when different pollutants co-exist and an increasing number of new cancer cases partially attributable to poor water quality. Our work also points to some ways to deal with these challenges.

Surface water pollution and digestive cancers are concerning environmental health issues. Multiple pollutants of surface water coexist within unique geospatial heterogeneous contexts of surface water flow, which can lead to complex patterns of impact on cancer incidence. This complexity has posed challenges to comprehensive assessment. In this study, we integrated nationwide surface water data of 21 pollutants collected from 3632 sections of nine large river basins and cancer incidence data for six digestive cancers covering 381.6 million people in China. Local Moran's I method was used to assess the patterns of spatial aggregation of each surface water pollutant separately to observe the local spatial nonstationarity and heterogeneity of the pollutant concentrations in different spatial areas. A geographically weighted random forest (GWRF) model, a spatial machine learning approach, was applied to address the spatial heterogeneity of the pollutants and assess their association with cancer incidence. Goodness-of-fit and overall performance of the GWRF model were assessed by the local statistics in the out-of-bag set, such as the mean local pseudo-R2, increase in mean squared error, and local residuals in each local model. Compared with the aspatial random forest model, the GWRF model had better performance (mean local pseudo-R2 ranged from 0.16 (gallbladder cancer) to 0.60 (pancreatic cancer)). Surface water pollution was associated with digestive cancer incidence mainly in the Songhua and Liaohe, Haihe, and Huaihe River Basins. By focusing on these areas, we identified key pollutants specific to different cancer types. Incidence of oesophageal, stomach, colorectal, gallbladder, and pancreatic cancer was associated with common pollutants such as fluoride and arsenic. Our assessment provides targets for the government and environmental health specialists to take tailored actions to control pollution and effectively prevent cancer incidence.

Enterovirus G belongs to the family Picornaviridae and are associated with a variety of animal diseases. We isolated and characterized a novel EV-G2 strain, CHN-SCMY2021, the first genotype 2 strain isolated in China. CHN-SCMY2021 is about 25 nm diameter with morphology typical of picornaviruses and its genome is 7341 nucleotides. Sequence alignment and phylogenetic analysis based on VP1 indicated that this isolate is a genotype 2 strain. The whole genome similarity between CHN-SCMY2021 and other EV-G genotype 2 strains is 78.3–86.4%, the greatest similarity is to EVG/Porcine/JPN/Iba26–506/2014/G2 (LC316792.1). Recombination analysis indicated that CHN-SCMY2021 resulted from recombination between 714,171/CaoLanh_VN (KT265894.2) and LP 54 (AF363455.1). Except for ST cells, CHN-SCMY2021 has a broad spectrum of cellular adaptations, which are susceptible to BHK-21, PK-15, IPEC-J2, LLC-PK and Vero cells. In piglets, CHN-SCMY2021 causes mild diarrhea and thinning of the intestinal wall. The virus was mainly distributed to intestinal tissue but was also found in heart, liver, spleen, lung, kidney, brain, and spinal cord. CHN-SCMY2021 is the first systematically characterized EV-G genotype 2 strain from China, our results enrich the information on the epidemiology, molecular evolution and pathogenicity associated with EV-G.

BackgroundBacterium/fungus-associated pneumonia (BAP/FAP) is the prominent cause of high mortality and morbidity with important clinical impacts globally. Effective diagnostic methods and proper specimen types hopefully facilitate early diagnosis of pneumonia and prevent spread of drug-resistant bacteria/fungi among critically ill patients.MethodsIn the present study, 342 bronchoalveolar lavage fluid (BALF) samples were collected from critically ill patients with pulmonary infections between November 2020 and March 2021. The BALF materials were comparatively employed to screen BAP/FAP through microscopy, culture, antigenic marker and PCR-based methods. The limit of detection (LOD) of cultures and PCR for bacteria/fungi was determined by serial dilution assays. Specimen slides were prepared with Gram staining for microscopic examinations. Microbial cultures and identifications underwent routine clinical protocols with the aid of mass spectrometry. (1,3)-β-D-glucan and galactomannan tests with BALF were carried out accordingly. Direct detection of pathogens in BALF was achieved through PCR, followed by sequencing and BLAST in GenBank database for pathogenic identification. The subjects’ demographic and clinical characteristics were well evaluated.ResultsBAP/FAP was identified in approximately 47% of the subjects by the BALF-based PCR. The PCR-based diagnostic methods showed improved detection performance for fungi with good LOD, but performed similarly for bacteria, when compared to the cultures. There was poor agreement among traditional microscopy, culture and PCR assays for bacterial detections (kappa value, 0.184 to 0.277). For overall bacterial/fungal detections, the microscopy showed the lowest detecting rate, followed by the cultures, which displayed a slightly higher sensitivity than the microscopy did. The sensitivity of PCR was much higher than that of the other means of interest. However, the traditional cultures rather than antigenic marker-based approaches were moderately consistent with the PCR-based methods in fungal species identification, particularly for Candida and Aspergillus spp. Our findings further revealed that the age, length of hospital stay, invasive procedures and cerebral diseases were likely considered as main risk factors for BAP/FAP.ConclusionScreening for BALF in critically ill patients with suspected pneumonia pertaining high risk factors using combined PCR-based molecular detection strategies would hopefully contribute to early diagnosis of BAP/FAP and improved prognosis of the patients.

Abstract Background Islet transplantation is an excellent method for the treatment of type I diabetes mellitus. However, due to the limited number of donors, cumbersome isolation and purification procedures, and immune rejection, the clinical application is greatly limited. The development of a simple and efficient new method to obtain islet β-cells is a key problem that urgently requires a solution for the treatment of type I diabetes mellitus. Methods In this study, Pbx1, Rfx3, Pdx1, Ngn3, Pax4 and MafA were used to form a six-gene combination to efficiently reprogram aMSCs (adipose mesenchymal stem cells) into ra-βCs (reprogrammed aMSCs-derived islet β-cells), and the characteristics and immunogenicity of ra-βCs were detected. Feasibility of ra-βCs transplantation for the treatment of diabetes mellitus in model dogs and clinical dogs was detected. Results In this study, aMSCs were efficiently reprogrammed into ra-βCs using a six-gene combination. The ra-βCs showed islet β-cell characteristics. The immunogenicity of ra-βCs was detected and remained low in vitro and increased after transplantation. The cotransplantation of ra-βCs and aMSCs in the treatment of a model and clinical cases of canine diabetes mellitus achieved ideal therapeutic effects. Conclusions The aMSCs were efficiently reprogrammed into ra-βCs using a six-gene combination. The cotransplantation of ra-βCs and aMSCs as a treatment for canine diabetes is feasible, which provides a theoretical basis and therapeutic method for the treatment of canine diabetes.

Abstract Background Pediatric leukemia is the most prevalent childhood cancer in China and incurs heavy economic burden to patients without sufficient insurance protection. Although all Chinese children are obliged to enroll in the national insurance scheme, “Resident Basic Medical Insurance (RBMI)”, the protection may vary among patient subgroups. This study is designed to measure the disparities in economic burden for patients with leukemia under RBMI protection and explore the influencing factors. Methods The included patients were aged ≤ 15 and diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML, with/without transplantation). They all completed treatment course consecutively in Nanfang Hospital and Zhujiang Hospital from Jan.1, 2015, to Dec.30, 2019, in Guangzhou, China. Their inpatient treatment and insurance settlement data were drawn from the Hospital Information System (HIS) and Insurance Settlement System (ISS). A total of 765 consecutive patients and 14,477 inpatient medical records were included and analyzed. Their insurance status (6 subtypes), economic burden [total cost, out-of-pocket cost (OOP), reimbursement, reimbursement rate (RR)], and cost structures (operation/procedure, blood products, drug, simple treatment) were calculated respectively. Non-normally distributed costs were reported as the median and interquartile range (IQR). Wilcoxon test was used for univariate tests and generalized linear model with log link was used to explore the influencing factors. Results The insured patients who were treated in the location of insurance with instant reimbursement reported the highest total cost and reimbursement, while those who seek medical care cross-province with no instant reimbursement reported the lowest total cost and highest OOP payment. In terms of annual change, the total cost of children with leukemia decreased from 2015–2019 with stably increasing reimbursement rate. Blood products and drugs were the major components of total cost, but they decreased annually. Patients who received transplantation and treated across provinces were with a higher economic burden. Conclusion The economic burden for children with leukemia decreased overtime under the protection of RBMI, but disparities exist among subtypes. The payer-provider contract on instant reimbursement and drug cost control are effective measures for insurance administrators to curb the economic burdens of pediatric leukemia treatment.

Abstract Background Lymphomas usually present with different occurrence patterns across different geographical locations, but their epidemiology in Zambia is yet to be extensively explored. Objectives To study the spectrum of lymphoma subtypes prevalent within the Zambian population. Methods Histopathological records with suspected lymphoma at the University Teaching Hospital (UTH) in Lusaka from the year 2014 to 2016, diagnosed based on the 2008 World Health Organization (WHO) criteria were reviewed. The analysis was done in terms of type, sex, age, and site of biopsy; and Fisher’s exact test was used for significance testing. Results During the study period (2014-2016), there were more B cell neoplasms {222 (92.5%)} than T cell neoplasms {18 (7.5%)}. Non-Hodgkin’s lymphoma (NHL) was seen in 191 (79.6%) whereas classic Hodgkin’s lymphoma (CHL) was seen in 39 (16.3%). Burkitt’s lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) showed equal proportions {17.5% of all lymphoma cases (42/240) each}, as the most prevalent subtypes of NHL whereas marginal zone B cell lymphoma was the rarest subtype with 1.4% (4/240). For CHL, mixed cellularity and lymphocyte rich subtypes (4.6% of all lymphoma cases) were the most common subtypes. There was a statistically significant difference in the occurrences of lymphoma subtypes across different age categories (p = 0.002). Conclusion Zambia has a diverse lymphoma subtypes population, affecting a relatively young population. The data from this study will serve as a baseline for improved health care provision and more robust future studies.

Acute lung injury (ALI) is significantly associated with morbidity and mortality in patients with critical diseases. In recent years, studies have identified that mesenchymal stem/stromal cells (MSCs) ameliorate ALI and pulmonary fibrosis. However, the mechanism underlying this outcome in ALI has not yet been investigated. In this study, RNA sequencing technology was used to analyze the gene expression profile of lung tissue in lipopolysaccharide (LPS)-induced ALI rats following treatment with human umbilical cord MSC (HUCMSC). Differential expression analyses, gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes enrichment, protein–protein interaction network identification, and hub gene analysis were also performed. HUCMSC treatment decreased inflammatory factor production and alveolar exudates, and attenuated lung damage in LPS-induced ALI rats. The RNA-Seq data indicated that HUCMSC treatment activated the IL-17, JAK-STAT, NF-κB, and TNF-α signaling pathways, increased oxygen transport, and decreased extracellular matrix organization. HUCMSC exert beneficial effects on ALI via these signaling pathways by reducing inflammation, inhibiting pulmonary fibrosis, and improving lung ventilation. Moreover, our study further revealed the hub genes (Tbx2, Nkx2-1, and Atf5) and signaling pathways involved in HUCMSC treatment, thus providing novel perspectives for future research into the molecular mechanisms underlying cell treatment of ALI. HUCMSC can regulate multiple genes and signaling pathways, which can prevent LPS-induced lung damage in an ALI rat model.

BackgroundStroke is a major cause of mortality and long-term physical and cognitive impairment. This study aims to: (1) examine the prevalence of depressive symptoms, disability and pain among Chinese adults with stroke; (2) test the associations of functional limitations and body pain with occurrence of depressive symptoms; (3) investigate gender and urban-rural disparities in these associations.MethodsThis study utilized the data from the China Health and Retirement Longitudinal Study in 2018, involving 969 patients with stroke among 17,970 participants aged ≥ 45 years. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression (CES-D) Scale. We performed multivariable logistic regression models to estimate the associations between activities of daily life (ADL), instrumental activities of daily life (IADL) and pain with depressive symptoms.ResultsDepressive symptoms were found among 40.2% of stroke patients, with a higher prevalence in females (48.2%) than males (32.7%). Prevalence of ADL limitations, IADL limitations and pain among stroke patients were 39.2, 49.8 and 14.0%, respectively. ADL and IADL limitations and pain were more prevalent among females and residents in rural areas. Multivariable regression analyses showed a significant association between ADL limitation (OR = 1.535, 95% CI = 1.168, 2.018), IADL limitation (OR = 1.666, 95% CI = 1.260, 2.203) and pain (OR = 2.122, 95% CI = 1.466, 3.073) with depressive symptoms. Stratified analyses revealed stronger associations among urban residents. Females had a higher association of ADL and IADL with depressive symptoms but similar in that of pain to the males. The impact of ADL and IADL in male patients is higher than in females, but the impact of pain on depressive symptoms is higher in female patients.ConclusionDepressive symptoms are common amongst post-stroke patients in China and are significantly associated with functional disability and physical pain. Our findings have implications for practitioners on the early assessment of pain and depression after stroke. Future research should explore effective intervention measures for physical-mental stroke complications.

Schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BD) are severe psychiatric disorders and share common characteristics not only in clinical symptoms but also in neuroimaging. The purpose of this study was to examine common and specific neuroanatomical features in individuals with these three psychiatric conditions. In this study, 70 patients with SZ, 85 patients with MDD, 42 patients with BD, and 95 healthy controls (HCs) were recruited. Voxel-based morphometry (VBM) analysis was used to explore brain imaging characteristics. Psychopathology was assessed using the Beck Depression Inventory (BDI), the Beck Anxiety Inventory (BAI), the Young Mania Rating Scale (YMRS), and the Positive and Negative Syndrome Scale (PANSS). Cognition was assessed using the digit symbol substitution test (DSST), forward-digital span (DS), backward-DS, and semantic fluency. Common reduced gray matter volume (GMV) in the orbitofrontal cortex (OFC) region was found across the SZ, MDD, and BD. Specific reduced GMV of brain regions was also found. For patients with SZ, we found reduced GMV in the frontal lobe, temporal pole, occipital lobe, thalamus, hippocampus, and cerebellum. For patients with MDD, we found reduced GMV in the frontal and temporal lobes, insular cortex, and occipital regions. Patients with BD had reduced GMV in the medial OFC, inferior temporal and fusiform regions, insular cortex, hippocampus, and cerebellum. Furthermore, the OFC GMV was correlated with processing speed as assessed with the DSST across four groups (r = 0.17, p = 0.004) and correlated with the PANSS positive symptoms sub-score in patients with SZ (r = − 0.27, p = 0.026). In conclusion, common OFC alterations in SZ, MDD, and BD provided evidence that this region dysregulation may play a critical role in the pathophysiology of these three psychiatric disorders.

Abstract Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient‐derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation‐dependent manner. Mechanistic studies identify that AML cell‐derived exosomes play a vital role during the AML cell‐mediated MSCs education/reprogramming process. Pre‐administration of mice BM microenvironment with AML‐derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML‐derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome‐based AML cells‐MSCs communication. Collectively, the data show that AML‐educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.

BackgroundThis study aimed to investigate the Aspergillus species distribution, antifungal sensitivities, clinical characteristics, and risk factors of patients with invasive aspergillosis (IA) in a tertiary teaching hospital in Anhui Province.MethodsIn the present study, 156 Aspergillus isolates were collected from patients admitted to a 2,800-bed comprehensive hospital between January 2019 and April 2021. The epidemiology of Aspergillus species was well-examined, and its antifungal susceptibility was specifically measured by the microbroth dilution method. The risk factors of patients with IA were documented and analyzed intensively. In addition, gene sequencing was employed to determine gene mutations of cytochrome P450 14-α sterol demethylase-Aspergillus (cyp51A) associated with azole resistance among Aspergillus fumigatus.ResultsThe Aspergillus species distribution was dominated by A. fumigatus (56.41%), Aspergillus flavus (20.51%), and Aspergillus niger (15.38%) locally. In particular, all Aspergillus species showed very low minimum inhibitory concentrations (MICs, ≤ 0.5 μg/ml) for azoles and echinocandins, slightly high MICs (1.66–2.91 μg/ml) for amphotericin B, and exceptionally high MICs (>64 μg/ml) for flucytosine. Azole-resistant rate of Aspergillus species in this local region reached up to 5.79%. Correlation analyses of multiple antifungals indicate a significant MIC relevance between isavuconazole and voriconazole (Pearson correlation coefficient was 0.81, P < 0.0001). The clinical risk factors for patients with IA were found primarily to be pulmonary diseases (P = 0.007) and patients' age (P < 0.001). Notably, three mutant loci (TR46/Y121F/T289A) of the cyp51A gene were identified in azole-resistant A. fumigatus.ConclusionsThe Aspergillus species emerged increasingly, of which A. fumigatus and A. flavus remained the main pathogens for invasive Aspergillus infections in the local region. The vast majority of Aspergillus species exhibited good susceptibility to all the antifungals, except flucytosine. The local occurrence of azole-resistant Aspergillus species grew gradually and needed monitoring in time. Pulmonary diseases and age were likely considered as highly associated risk factors for IA. To our knowledge, the clinically isolated azole-resistant A. fumigatus with TR46/Y121F/T289A mutations identified here were rarely reported in the area of China.

Functional deficits in schizophrenia (SZ) are observed prior to the onset of psychosis and differ at different stages of SZ. However, there is a paucity of studies focused on adolescent first-episode SZ (AOS), adult first-episode SZ (AFES), and adult chronic SZ (CHSZ). In this study, we investigated regional activity and corresponding functional connectivity alterations that have aimed to compare the three disease stages simultaneously. The subjects comprised 49 patients with AOS, 57 patients with AFES, 51 patients with CHSZ, 41 adolescent healthy controls, and 138 adult healthy controls. We compared regional homogeneity (ReHo) between patients at each disease stage with matched healthy controls. We focused on the shared brain regions that showed significant differences between SZ patients at the three different disease stages and healthy controls. Further analysis was conducted to explore whether the patterns of the whole brain functional connectivity alterations were similar. The putamen and medial frontal gyrus (MFG) showed consistently abnormal patterns in AOS, AFES, and CHSZ. Commonly decreased ReHo values in the MFG and increased ReHo values in the bilateral putamen were found in AOS, AFES, and CHSZ. Functional connectivity of MFG remained common abnormality in different SZ stage. In conclusion, ReHo abnormalities in the MFG and the putamen may be common abnormal patterns of brain function in the three different stages of SZ. The vmPFC-dlPFC FC abnormality common occurs in adolescence and adulthood.. This study may provide a more comprehensive understanding of the neurodevelopmental abnormality across the AOS, AFES, and CHSZ.

Background: Shared psychopathological features and mechanisms have been observed between schizophrenia (SZ) and bipolar disorder (BD), but their common risk genes and full genetic architectures remain to be fully characterized. The genome-wide association study (GWAS) datasets offer the opportunity to explore this scientific question using combined genetic data from enormous samples, ultimately allowing a better understanding of the onset and development of these illnesses.Methods: We have herein performed a genome-wide meta-analysis in two GWAS datasets of SZ and BD respectively (24,600 cases and 40,012 controls in total, discovery sample), followed by replication analyses in an independent sample of 4,918 SZ cases and 5,506 controls of Han Chinese origin (replication sample). The risk SNPs were then explored for their correlations with mRNA expression of nearby genes in multiple expression quantitative trait loci (eQTL) datasets.Results: The single nucleotide polymorphisms (SNPs) rs1637749 and rs3800908 at 7p22.3 region were significant in both discovery and replication samples, and exhibited genome-wide significant associations when combining all East Asian SZ and BD samples (29,518 cases and 45,518 controls). The risk SNPs were also significant in GWAS of SZ and BD among Europeans. Both risk SNPs significantly predicted lower expression of MRM2 in the whole blood and brain samples in multiple datasets, which was consistent with its reduced mRNA level in the brains of SZ patients compared with normal controls. The risk SNPs were also associated with MAD1L1 expression in the whole blood sample.Discussion: We have identified a novel genome-wide risk locus associated with SZ and BD in East Asians, adding further support for the putative common genetic risk of the two illnesses. Our study also highlights the necessity and importance of mining public datasets to explore risk genes for complex psychiatric diseases.

PDCoV is an emerging enteropathogenic coronavirus that mainly causes acute diarrhea in piglets, seriously affecting pig breeding industries worldwide. To date, the molecular mechanisms of PDCoV-induced immune and inflammatory responses or host responses in LLC-PK cells in vitro are not well understood. HSP90 plays important roles in various viral infections. In this study, HSP90AB1 knockout cells (HSP90AB1KO) were constructed and a comparative transcriptomic analysis between PDCoV-infected HSP90AB1WT and HSP90AB1KO cells was conducted using RNA sequencing to explore the effect of HSP90AB1 on PDCoV infection. A total of 1295 and 3746 differentially expressed genes (DEGs) were identified in PDCoV-infected HSP90AB1WT and HSP90AB1KO cells, respectively. Moreover, most of the significantly enriched pathways were related to immune and inflammatory response-associated pathways upon PDCoV infection. The DEGs enriched in NF-κB pathways were specifically detected in HSP90AB1WT cells, and NF-κB inhibitors JSH-23, SC75741 and QNZ treatment reduced PDCoV infection. Further research revealed most cytokines associated with immune and inflammatory responses were upregulated during PDCoV infection. Knockout of HSP90AB1 altered the upregulated levels of some cytokines. Taken together, our findings provide new insights into the host response to PDCoV infection from the transcriptome perspective, which will contribute to illustrating the molecular basis of the interaction between PDCoV and HSP90AB1.

(1) Background: Porcine deltacoronavirus (PDCoV) is a newly emerged enteric virus affecting pig breeding industries worldwide, and its pathogenic mechanism remains unclear. (2) Methods: In this study, we preliminarily identified the endocytic pathway of PDCoV in PK-15 cells, using six chemical inhibitors (targeting clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis pathway and endosomal acidification), overexpression of dominant-negative (DN) mutants to treat PK-15 cells and proteins knockdown. (3) Results: The results revealed that PDCoV entry was not affected after treatment with chlorpromazine (CPZ), 5-(N-ethyl-N-isopropyl) amiloride (EIPA)or ammonium chloride (NH4Cl), indicating that the entry of PDCoV into PK-15 cells were clathrin-, micropinocytosis-, PH-independent endocytosis. Conversely, PDCoV infection was sensitive to nystatin, dynasore and methyl-β-cyclodextrin (MβCD) with reduced PDCoV internalization, indicating that entry of PDCoV into PK-15 cells was caveolae-mediated endocytosis that required dynamin and cholesterol; indirect immunofluorescence and shRNA interference further validated these results. (4) Conclusions: In conclusion, PDCoV entry into PK-15 cells depends on caveolae-mediated endocytosis, which requires cholesterol and dynamin. Our finding is the first initial identification of the endocytic pathway of PDCoV in PK-15 cells, providing a theoretical basis for an in-depth understanding of the pathogenic mechanism of PDCoV and the design of new antiviral targets.