Bacterial nanocellulose membrane with opposite surface charges for large-scale and large-area osmotic energy harvesting and ion transport.

How to optimize ion-exchange membrane materials has been the key for researchers recently working on the use of reverse electrodialysis to harvest osmotic energy. Based on the considerations of improving membrane performance and conversion to large-area industrial production, this work first proposes an easy-industrialized strategy to treat bacterial cellulose membranes by hot pressing and hot pressing with etherification modification, and then to obtain anion-selective and cation-selective membrane pairs (PBC-M and NBC-M) with opposite charges. The PBC-M obtained by multi-step treatment has excellent hydrophobicity, good surface charge density, and more favorable nanochannel size for the functioning of double layer. The maximum output power density of 44.1 mW m-2 was obtained in artificial river water and seawater simulated salinity gradient power generation. Applied to a larger test area, the power output of the system where a single membrane is located can reach 2.2 × 10-3 mW, which is ahead of similar experimental products. The two membranes prepared can also be used in combination, which provides a new idea for full cell design. It's important to open up a new route for optimizing nanofluidic channel design, regulating ion flux transport, and advancing the large-scale industrialization of biomass nanofluidic membrane RED system.

Lifestyle patterns influence the composition of the gut microbiome in a healthy Chinese population.

High-throughput sequencing allows for the comprehensive analysis of the human intestinal microbiota. However, extensive association analyses between the microbiome and lifestyle differences in the Chinese population are limited. Here, we carried out an independent cohort study-the Chinese Healthy Gut Project (n = 483)-where correlations between the gut microbiota and dietary and lifestyle variables in a healthy Chinese population are defined. We collected both questionnaire data, including basic information and lifestyle and dietary variables, and fecal stools from the enrolled volunteers. We then performed 16S rRNA sequencing on the microbial DNA isolated from the stools to assess the composition of the intestinal microbiota. We found that Prevotella and Bacteroides were the most abundant genera in the healthy Chinese gut microbiome. Additionally, 9 out of 29 clinical and questionnaire-based phenotype covariates were found to be associated with the variation in the composition of the gut microbiota. Among these lifestyle phenotypes, sleep procrastination, negative mood, and drinking habits had the largest effect size. Additionally, an appreciable effect of urbanization was observed, resulting in decreased intra-individual diversity, increased inter-individual diversity, and an increased abundance of the Bacteroides enterotype. The results of this study provide a foundation for assessing the healthy Chinese gut microbiota community structure at baseline in a healthy Chinese population. Furthermore, this study also provides insights into understanding how distinctive living habits influence the relationships between the Chinese gut microbiome and systemic health state.

Primary pulmonary choriocarcinoma in male: report a case with genetic testing and review of the literature.

Background: Primary pulmonary choriocarcinoma is an extremely rare malignant trophoblastic tumor with a poor prognosis. Most choriocarcinomas originated from gonads, such as the ovaries and testes. Review the previous literature, only 41 cases were reported. Case Description: We reported that a 65-year-old man found shadows in the lungs when undergoing the X-ray examination. Positron emission tomography (PET) was performed to exclude metastatic disease before surgery. The patient underwent three-dimension uniportal thoracoscopic left upper lung resection and lymph node dissection. The operation was uneventful, and he was discharged on the fourth day postoperatively. Postoperative pathology: malignant trophoblastic tumors (choriocarcinoma). After the operation, the patient has genetically tested, the mutations in tumor protein p53 (TP53), NRAS proto-oncogene (NRAS), and fibroblast growth factor receptor 1 (FGFR1) were found. Conclusions: Primary pulmonary choriocarcinoma is an extremely rare and highly malignant tumor difficult to detect in the early stage. By analyzing the previous literature, the patients with active treatment have more extended survival periods than the patients without treatment (P=0.0051). Patients, including surgery, had better survival than patients without surgery (P=0.027) depending on the different treatment regimens. Hence, once the diagnosis was confirmed, the comprehensive treatment of surgical resection combined with chemotherapy and radiotherapy is of great significance to improve the prognosis of patients.

Establishment and validation of a novel immune-related prognostic signature in malignant pleural mesothelioma.

Background: Immune-related genes (IRGs) play an important role in the tumor immune microenvironment and affect tumor prognosis. This study aimed to establish a prognostic signature for malignant pleural mesothelioma (MPM) patients. Methods: We obtained the relevant data of MPM patients in The Cancer Genome Atlas (TCGA), and univariate and multivariate Cox regression were used to construct the prediction signature and verify it with the external validation dataset GSE2549. A nomogram was then constructed, and its predictive ability was evaluated and analyzed the level of immune cell infiltration in different groups in the signature. Results: An IRG-related prognostic signature composed of INHBA, CAT, SORT1, TNFSF13B, and BIRC5 was constructed, with patients divided into high-risk and low-risk groups according to the risk score. The survival time of overall survival (OS), progression-free survival (PFS), disease-free interval (DFI), and relapse-free survival (RFS) in low-risk groups was longer than in high-risk groups. Furthermore, the signature had high predictive performance, and the receiver operating characteristic (ROC) of 1, 2, and 3 years could reach 0.853, 0.881, and 0.914, respectively. The predictive accuracy of the signature was verified by using the independent GSE2549 dataset. The levels of activated CD4 T cells, immature dendritic cells, and type 2 T helper cells were higher in high-risk patients. The gene set enrichment analysis (GSEA) analysis showed that a high concentration and P53 signal pathways were found in high-risk groups. Conclusions: This research developed and verified a new type of immune prognostic signature based on five IRGs, which can predict the prognosis of tumor patients and provide new ideas for individualized treatment.

Treatment of Chylothorax complicating pulmonary resection with hypertonic glucose Pleurodesis.

BACKGROUND: To retrospectively assess the efficacy of hypertonic glucose pleurodesis for treatment of chylothorax after pulmonary resection. METHODS: Out of a total of 8252 patients who underwent pulmonary resection (at least lobectomy) at department of thoracic surgery, between June 2008 and December 2015, 58 patients (0.7%) developed postoperative chylothorax. All patients received conservative treatment, including thoracic closed drainage, oral fasting, and total parenteral nutrition. RESULTS: Conservative treatment was successful in 50 (86.2%) patients, while eight patients [mean age: 58.0 years (range, 45-75)] were treated with hypertonic glucose pleurodesis. All eight patients had undergone operation for lung cancer (four squamous cell carcinomas and four adenocarcinomas). The bronchial stump was covered by pleural flap in three patients. After pleurodesis, three patients developed fever but without empyema; thoracentesis was performed in two patients. The mean time interval between pleurodesis and operation was 4.3 days (range,3-5) days. The average length of stay was 23.1 days (range, 18-31). No recurrent pleural effusion was observed over a mean follow-up duration of 28 months. CONCLUSION: Hypertonic glucose pleurodesis performed via the chest drainage tube is a viable treatment option for chylothorax after lung resection, prior to resorting to a thoracoscopic or thoracotomic ductus thoracicus ligation of the thoracic duct leak. It is a simple, safe and efficient modality associated with rapid recovery and less pain.

Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms.

BACKGROUND & AIMS: The etiology of cholestasis remains unknown in many children. We surveyed the genome of children with chronic cholestasis for variants in genes not previously associated with liver disease and validated their biological relevance in zebrafish and murine models. METHOD: Whole-exome (n = 4) and candidate gene sequencing (n = 89) was completed on 93 children with cholestasis and normal serum γ-glutamyl transferase (GGT) levels without pathogenic variants in genes known to cause low GGT cholestasis such as ABCB11 or ATP8B1. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing was used to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice. RESULTS: In a 1-year-old female patient with normal GGT cholestasis and bile duct paucity, we identified a homozygous truncating pathogenic variant (c.198delA, p.Gly67Alafs∗6) in the ABCC12 gene (NM_033226). Five additional rare ABCC12 variants, including a pathogenic one, were detected in our cohort. ABCC12 encodes multidrug resistance-associated protein 9 (MRP9) that belongs to the adenosine 5'-triphosphate-binding cassette transporter C family with unknown function and no previous implication in liver disease. Immunohistochemistry and Western blotting revealed conserved MRP9 protein expression in the bile ducts in human, mouse, and zebrafish. Zebrafish abcc12-null mutants were prone to cholangiocyte apoptosis, which caused progressive bile duct loss during the juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared with wild-type mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge. CONCLUSIONS: Our work connects MRP9 with bile duct homeostasis and cholestatic liver disease for the first time. It identifies a potential therapeutic target to attenuate bile acid-induced cholangiocyte injury.

Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders.

This article explores the distribution and mutation spectrum of potential disease-causing genetic variants in hemophagocytic lymphohistiocytosis (HLH)-associated genes observed in a large tertiary clinical referral laboratory. Samples from 1892 patients submitted for HLH genetic analysis were studied between September 2013 and June 2018 using a targeted next-generation sequencing panel approach. Patients ranged in age from 1 day to 78 years. Analysis included 15 genes associated with HLH. A potentially causal genetic finding was observed in 227 (12.0%) samples in this cohort. A total of 197 patients (10.4%) had a definite genetic diagnosis. Patients with pathogenic variants in familial HLH genes tended to be diagnosed significantly younger compared with other genes. Pathogenic or likely pathogenic variants in the PRF1 gene were the most frequent. However, mutations in genes associated with degranulation defects (STXBP2, UNC13D, RAB27A, LYST, and STX11) were more common than previously appreciated and collectively represented >50% of cases. X-linked conditions (XIAP, SH2D1A, and MAGT1) accounted for 17.8% of the 197 cases. Pathogenic variants in the SLC7A7 gene were the least encountered. These results describe the largest cohort of genetic variation associated with suspected HLH in North America. Merely 10.4% of patients were identified with a clearly genetic cause by this diagnostic approach; other possible etiologies of HLH should be investigated. These results suggest that careful thought should be given regarding whether patients have a clinical phenotype most consistent with HLH vs other clinical and disease phenotypes. The gene panel identified known pathogenic and novel variants in 10 HLH-associated genes.

Mouse models of neutropenia reveal progenitor-stage-specific defects.

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.

LINC00210 plays oncogenic roles in non-small cell lung cancer by sponging microRNA-328-5p.

Long noncoding RNA (lncRNA) has an important role in regulating non-small cell lung cancer (NSCLC) progression. The present study aimed to investigate the effect of LINC00210 in NSCLC progression in order to provide a novel treatment target for patients with NSCLC. A total of 39 NSCLC patients were obtained and divided into LINC00210 high expression and low expression groups. Subsequently, the 5-year survival rate from this patient cohort was analyzed. The SK-MES-1 and A549 NSCLC and the human 16-HBE bronchial epithelial cell lines were utilized to investigate expression level of LIN00210. A549 cells were used to investigate cell proliferation, migration and invasive abilities using Cell Counting kit 8, Transwell and Matrigel assays, respectively. In addition, the luciferase reporter gene assay was performed to investigate the potential target of LINC00210. Reverse transcription-quantitative PCR was used to determine LINC00210 and microRNA (miR)-328-5p expression levels in NSCLC tissues and tumor cell lines (SK-MES-1 and A549). The results demonstrated that LINC00210 was upregulated in NSCLC tissues and cell lines compared with that in normal tissues and 16-HBE cells, and that LINC00210 expression was associated with a poor prognosis in patients with NSCLC (P<0.05). Furthermore, A549 cell transfection with small interfering (si)LINC00210#1 and siLINC00210#2 induced a significant decrease in cell proliferation, and migratory and invasive abilities compared with that in the control groups (P<0.05). In addition, miR-328-5p overexpression was stimulated by knockdown of LINC00210. Furthermore, A549 cells transfected with siLINC00210#1 and miR-328-5p inhibitor exhibited a significant increase in cell proliferation, and migratory and invasive ability compared with that in A549 cells transfected with siLINC00210#1. These findings suggest that LINC00210 may serve as an oncogenic role in NSCLC by sponging miR-328-5p.

PAX1 is essential for development and function of the human thymus.

We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development.

Corrigendum: The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

[This corrects the article DOI: 10.3389/fphys.2019.00815.].

Traditional Chinese Medicine for Coronary Heart Disease: Clinical Evidence and Possible Mechanisms.

Coronary heart disease (CHD) remains a major cause of mortality with a huge economic burden on healthcare worldwide. Here, we conducted a systematic review to investigate the efficacy and safety of Chinese herbal medicine (CHM) for CHD based on high-quality randomized controlled trials (RCTs) and summarized its possible mechanisms according to animal-based researches. 27 eligible studies were identified in eight database searches from inception to June 2018. The methodological quality was assessed using seven-item checklist recommended by Cochrane Collaboration. All the data were analyzed using Rev-Man 5.3 software. As a result, the score of study quality ranged from 4 to 7 points. Meta-analyses showed CHM can significantly reduce the incidence of myocardial infarction and percutaneous coronary intervention, and cardiovascular mortality (P < 0.05), and increase systolic function of heart, the ST-segment depression, and clinical efficacy (P < 0.05). Adverse events were reported in 11 studies, and CHMs were well tolerated in patients with CHD. In addition, CHM exerted cardioprotection for CHD, possibly altering multiple signal pathways through anti-inflammatory, anti-oxidation, anti-apoptosis, improving the circulation, and regulating energy metabolism. In conclusion, the evidence available from present study revealed that CHMs are beneficial for CHD and are generally safe.

The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin (ANK1), band 3 (SLC4A1), protein 4.2 (EPB42), and α (SPTA1) or ß-spectrin (SPTB). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1-associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1-associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients' reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression αLEPRA allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis, either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1-associated HS and guide toward appropriate management.

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.

PURPOSE: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. METHODS: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. RESULTS: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. CONCLUSION: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.

Variations in early gut microbiome are associated with childhood eczema.

We assessed the relationship between gut microbiome profile and childhood eczema in 172 subjects (age < 3 years, healthy group N = 123, eczema group N = 49) utilizing 16S rRNA gene sequencing. Lower relative abundance of Bifidobacterium was shown to be associated with childhood eczema. Considering that developmental and environmental factors could modify the state of children's gut microbiome, we divided the samples into four age groups: 0-0.5 years, 0.5-1 years, 1-2 years and 2-3 years for farther analyses. Data revealed significant inter-group differences between healthy and eczema samples in all age groups, and decreased microbial diversity was most significantly found in children with eczema of age 2-3 years old. Decreased abundance of Bifidobacterium was a major finding in eczema groups from 0.5-3 years compared to the age matched healthy controls, but not significant in children younger than 6 month old. Of note, Bifidobacterium operational taxonomic units were identified by Random Forest with highly predictive power of 0.83 (AUC = 0.83) in ROC analysis, which also confirmed its role as a key genus that is associated with eczema. To verify the sequencing results, we performed quantitative polymerase chain reaction of Bifidobacterium and Bacteroides in the same cohort, and in a new eczema cohort (N = 57) for validation. Significantly, lower Bifidobacterium quantities were found in both eczema groups with an age range of 0.5-3 years. These results suggest variations in early gut microbiome are associated with childhood eczema.

Novel phenotype-disease matching tool for rare genetic diseases.

PURPOSE: To improve the accuracy of matching rare genetic diseases based on patient's phenotypes. METHODS: We introduce new methods to prioritize diagnosis of genetic diseases based on integrated semantic similarity (method 1) and ontological overlap (method 2) between the phenotypes expressed by a patient and phenotypes annotated to known diseases. RESULTS: We evaluated the performance of our methods by two sets of simulated data and one set of patient's data derived from electronic health records. We demonstrated that the two methods achieved significantly improved performance compared with previous methods in correctly prioritizing candidate diseases in all of the three sets. Our methods are freely available as a web application ( https://gddp. RESEARCH: cchmc.org/ ) to aid diagnosis of genetic diseases. CONCLUSION: Our methods can capture the diagnostic information embedded in the phenotype ontology, consider all phenotypes exhibited by a patient, and are more robust than the existing methods when phenotypes are incorrectly or imprecisely specified. These methods can assist the diagnosis of rare genetic diseases and help the interpretation of the results of DNA tests.