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Objective: Understanding the characteristics of alveolar bone resorption in an East Asian population after maxillary incisor extraction and providing a reference for implant treatment plans. Study design: Cone-beam computerized tomography (CBCT) data of 125 East Asian patients with unilateral extraction of maxillary incisors for 3 months were collected. The alveolar bone width and height in the extraction sites were measured and compared with the corresponding contralateral sites. Results: The differences in alveolar bone width between the extraction site and contralateral site were as follows: 4.11 mm, 2.68 mm, and 2.09 mm (3 mm, 5 mm, 7 mm apical from CEJ of the contralateral tooth). Data are expressed as the median. The horizontal resorption ratio of alveolar bone was 49.94 %, 31.5 %, and 24.46 %. The difference in alveolar bone height was 0.78 mm. The vertical resorption ratio was 7.78 %. The resorption did not differ significantly between sexes and was not significantly affected by tooth positions. Conclusions: In the studied East Asian population, significant horizontal and vertical alveolar bone resorption occurs after natural healing of maxillary incisor extraction for 3 months. The closer to the alveolar ridge crest, the more significant the horizontal resorption, resulting in an “inverted triangle” shape residual alveolar bone.

Myofibroblastic sarcoma (MS) is a malignant tumor of soft tissue or bone that can occur in children or adults, with a high rate of recurrence and metastasis. We report a case of low-grade malignant MS of the left shoulder, diagnosed based on pathological examination and immunohistochemical staining. However, the patient had unexplained pleural maculopathy. The patient passed away 6 months after the diagnosis of myofibroblast sarcoma due to multiple metastases throughout the sarcoma. Combined with the patient’s history, ancillary findings, and after MDT discussion, the patient was ultimately considered to have a high probability of myofibroblast sarcoma combined with pleural maculopathy. In conclusion, when a patient is diagnosed with myofibroblast sarcoma in combination with pleural macula, in the absence of other causative factors, a deep tissue biopsy of the pleura should be actively performed to confirm the diagnosis.

Abstract Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA‐induced ALI (SA‐ALI) remains unclear. In this study, serum samples were collected from SA‐sepsis patients, and a SA‐ALI mouse model was established by grouping WT and Nrf2−/− mice after 6 h of intraperitoneal injection. A cell model simulating SA‐ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA‐sepsis patients, negatively correlated with the severity of ALI. In SA‐ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation‐induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA‐ALI. The p‐Nrf2/total‐Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA‐treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual‐luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA‐ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

ObjectiveTo establish a rapid method for simultaneous determination of 27 antibiotics in tap water with ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) combined with automatic solid phase extraction. Methods After added internal standard solutions of 27 antibiotics within 24 hours, the tap water sample (200 mL) was filtered with glass fiber filters and adjusted for pH value of 7.5 – 8.5. The reference antibiotics in the tap water samples were concentrated with extraction column in the automated solid phase extraction instrument and then eluted with methanol solution. The reference antibiotics in the eluate was reconstituted into constant solution with 20% methanol and separated gradiently with T3 chromatography column using 40% acetonitrile methanol and 0.2% formic acid solution as mobile phase; and finally detected with UHPLC-MS/MS and quantified with internal standard method. Thereafter, 70 tap water samples were collected in rural areas of Zhejiang province and 27 antibiotics in the samples were detected simultaneously using the established method. ResultsA good linearity was observed for detections of the 27 antibiotics at the concentration of 1 to 100 ng/mL, with the correlation coefficient ranging from 0.9963 to 1.0000. For the established method, the detection limits were between 0.004 – 0.296 ng/L; the quantification limits were from 0.013 to 0.998 ng/L; and the mean recoveries ranged from 70.0% – 120.8%. For the 70 rural tap water samples, only four macrolide antibiotics were detected, including roxithromycin, clarithromycin, erythromycin, and tilmicosin, with the concentration ranges (ng/L) of 0.162 – 2.858, 0.063 – 0.849, 0.100 – 1.804, and 0.100 – 1.804, respectively．Conclusion The established method is simple to operate, time- and labor-saving; the method is also of high sensitivity, accuracy and reliability; and the method could be applied to rapid determination of 27 antibiotics in tap water．

Abstract Background Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MECP2), is one of the most prevalent neurodevelopmental disorders in girls. However, the underlying mechanism of MECP2 remains largely unknown and currently there is no effective treatment available for RTT. Methods We generated MECP2-KO human embryonic stem cells (hESCs), and differentiated them into neurons and cerebral organoids to investigate phenotypes of MECP2 loss-of-function, potential therapeutic agents, and the underlying mechanism by transcriptome sequencing. Results We found that MECP2 deletion caused reduced number of hESCs-derived neurons and simplified dendritic morphology. Moreover, MECP2-KO cortical organoids exhibited fewer neural progenitor cells and neurons at day 60. Electrophysiological recordings showed that MECP2 deletion altered synaptic activity in organoids. Transcriptome analysis of organoids identified many genes in the PI3K-AKT pathway downregulated following MECP2 deletion. Treatment with either KW-2449 or VPA, small molecules for the activation of PI3K-AKT signaling pathway, alleviated neuronal deficits and transcriptome changes in MECP2-KO human neuronal models. Conclusions These findings suggest that KW-2449 and VPA might be promising drugs for RTT treatment.

Colorectal cancer is a global malignancy with a high incidence and mortality rate. THZ2, a small inhibitor targeted CDK7, could inhibit multiple human tumor growths including small cell lung cancer, triple-negative breast cancer, ovarian cancer. However, the effect of THZ2 on inflammation, especially on colitis-associated colorectal cancer, is still unknown. In this study, we assessed the anti-inflammatory and anti-tumor effect of THZ2 in the mouse models of dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer. We found that THZ2 ameliorated inflammatory symptoms, including bleeding and diarrhea, in mouse models of DSS-induced acute colitis and AOM/DSS-induced colorectal cancer. The results of Western blot and immunohistochemistry showed that THZ2 rescued the up-regulated expression of COX2, IL-6, β-catenin, and snail in the mouse models. Moreover, THZ2 inhibits the development of colorectal cancer in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer. Generally, THZ2 not only can inhibit DSS-induced colitis, but also can hinder AOM/DSS-induced colorectal cancer.

ObjectiveTo analyze epidemiological characteristic and transmission process of a local coronavirus disease 2019 (COVID-19) outbreak induced by imported cases from other provinces in Henan province. MethodsThe data on all local COVID-19 cases in Xiuwu county, Henan province reported during March 18 – 28, 2022 were extracted from National Notifiable Disease Report System. The results of field investigations on the cases were also collected simultaneously. Descriptive statistics was performed on the data collected with SPSS 22.0. ResultsTotally 45 cases (16 males and 29 females, 14 minor or common patients and 31 asymptomatic infections) were reported during the 11-day outbreak period. The median age (25th percentile [P25], 75 percentile [P75]) of the cases was 23.02 (18.57, 28.64) years. The median (P25, P75) of cycle threshold (Ct) value for Orf1ab gene and N gene for positive cases in primary screening were 23.02 (18.57, 28.64) and 23.10 (18.63, 28.03), respectively. A case clustering involving 18 cases was identified in a local textile factory, with an incidence rate of 6.6%; seven family clusters were also identified, with a family secondary attack rate of 20.78% and a secondary attack rate of 3.79% among close contacts. Of all the cases, 12.5% could attributed the infection to the exposure to the asymptomatic infections being negative for nucleic acid test at that time. The results of genome second generation sequencing for the isolates from 29 infections indicated that the pathogen of the outbreak was severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron (BA.2.2) and the local transmission of the virus variant was traced back to the 2 first generation cases returning home from other epidemic area. The median (P25, P75) of incubation period was 3 (2, 4.25) days and that of generation interval was 3 (2, 3) days. Five generations of transmission were identified for the outbreak . The estimated basic reproductive number (R0) of this epidemic was 6.14, and the effective reproduction number (Rt) decreased 2 days after the control measures were taken and declined to less than 1 in 8 days after the implementa-tion of control measures. ConclusionThe reported COVID-19 outbreak in Henan province was caused by imported cases from other epidemic area and spread mainly in factories, families and schools. The control measures on the outbreak were effective and subsequent transmission was prevented.

Text classification is a common task in natural language processing,in which there are a lot of research and progress based on machine learning and deep learning.However,these traditional methods can only process Euclidean spatial data,and cannot express the semantic information of the document effectively.To break the traditional learning mode,many recent studies start to use graphs to represent complicated relationships among entities in the document,and explore graph convolutional neural network for text representation.This paper reviews the text classification methods based on graph convolutional network.Firstly,the background and principle of graph convolutional network are summarized.Then,text classification methods based on graph convolutional network are described in detail according to different types of graph-based networks.Meanwhile,it analyzes the limi-tation of graph convolutional network in the depth of networks,and introduces the latest developments of deep networks in text classification.Finally,the classification performance of models involved in this paper is compared through some experiments,and the challenges and future research direction in this field are discussed.

Abstract Pleural mesothelioma (PM) with pericardial involvement is extremely rare. We now report a rare case of malignant PM with constrictive pericarditis as the first presentation. A 59‐year‐old male diagnosed with constrictive pericarditis underwent pericardiectomy and pericardial pathology revealed mesothelial hyperplasia. Eight months after surgery, the patient was admitted to the hospital with chest tightness and wheezing for 5 days. Computed tomography scan of the chest showed a left lung expansion insufficiency, limited bilateral pleural thickening, pericardial thickening with a small amount of pericardial effusion, and multiple enlarged lymph nodes in the mediastinum, bilateral supraclavicular fossa, bilateral cervical roots, and right axilla. The pleural malignancy should be possibly considered. Pathology after pleural puncture showed malignant PM. Pathology after left supraclavicular lymph node puncture biopsy showed metastatic malignant mesothelioma. The diagnosis of this patient was clear. Although malignant PM rarely involves the pericardial constriction, we cannot ignore the fact that malignant PM involves the pericardium. The patient has been diagnosed with constrictive pericarditis, accompanied by pleural thickening and pleural effusion. Without other pathogenic factors, pleural biopsy should be aggressively performed in patients with constrictive pericarditis to determine the cause.

Abstract Introduction Regulation of brain‐derived neurotrophic factor (BDNF) in the basal forebrain ameliorates sleep deprivation‐induced fear memory impairments in rodents. Antisense oligonucleotides (ASOs) targeting ATXN2 was a potential therapy for spinocerebellar ataxia, whose pathogenic mechanism associates with reduced BDNF expression. We tested the hypothesis that ASO7 targeting ATXN2 could affect BDNF levels in mouse basal forebrain and ameliorate sleep deprivation‐induced fear memory impairments. Methods Adult male C57BL/6 mice were used to evaluate the effects of ASO7 targeting ATXN2 microinjected into the bilateral basal forebrain (1 μg, 0.5 μL, each side) on spatial memory, fear memory and sleep deprivation‐induced fear memory impairments. Spatial memory and fear memory were detected by the Morris water maze and step‐down inhibitory avoidance test, respectively. Immunohistochemistry, RT‐PCR, and Western blot were used to evaluate the changes of levels of BDNF, ATXN2, and postsynaptic density 95 (PSD95) protein as well as ATXN2 mRNA. The morphological changes in neurons in the hippocampal CA1 region were detected by HE staining and Nissl staining. Results ASO7 targeting ATXN2 microinjected into the basal forebrain could suppress ATXN2 mRNA and protein expression for more than 1 month and enhance spatial memory but not fear memory in mice. BDNF mRNA and protein expression in basal forebrain and hippocampus was increased by ASO7. Moreover, PSD95 expression and synapse formation were increased in the hippocampus. Furthermore, ASO7 microinjected into the basal forebrain increased BDNF and PSD95 protein expression in the basal forebrain of sleep‐deprived mice and counteracted sleep deprivation‐induced fear memory impairments. Conclusion ASOs targeting ATXN2 may provide effective interventions for sleep deprivation‐induced cognitive impairments.

Nbr1 recognizes cargos in selective autophagy. Here, authors show filamentous yeast Nbr1 binds Ams1 via an FW domain, and the cryo-EM structure reveals that Nbr1 recognizes the N-terminal di-glycine and tetrameric assembly of Ams1.

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer’s disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood–brain barrier, and we introduce potential pathways by which TREM2 affects the blood–brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.

Colorectal cancer is a common malignant tumor. A major factor in the high mortality rate of colorectal cancer is the emergence of multidrug resistance (MDR). Overexpression of the ABCG2 gene in cancer cells directly leads to MDR. Finding new inhibitors of ABCG2 may be an effective way to overcome drug resistance. We found that the compound GSK2606414 enhanced the sensitivity of the ABCG2 substrate to the chemotherapeutic drugs mitoxantrone and doxorubicin in ABCG2-overexpressing multidrug-resistant colorectal cancer cells by increasing their intracellular accumulation without affecting the protein expression of ABCG2. Molecular docking experiments predicted that GSK2606414 could stably bind in the drug-binding pocket of ABCG2. In conclusion, GSK2606414 can sensitize ABCG2-overexpressed multidrug-resistant colorectal cancer cells to chemotherapy drugs and can be used as a potential inhibitor of ABCG2.

Abstract Background As the second most abundant polysaccharide in nature, hemicellulose can be degraded to xylose as the feedstock for bioconversion to fuels and chemicals. To enhance xylose conversion, the engineered Saccharomyces cerevisiae with xylose metabolic pathway is usually adapted with xylose as the carbon source in the laboratory. However, the mechanism under the adaptation phenomena of the engineered strain is still unclear. Results In this study, xylose-utilizing S. cerevisiae was constructed and used for the adaptation study. It was found that xylose consumption rate increased 1.24-fold in the second incubation of the yYST12 strain in synthetic complete-xylose medium compared with the first incubation. The study figured out that it was observed at the single-cell level that the stagnation time for xylose utilization was reduced after adaptation with xylose medium in the microfluidic device. Such transient memory of xylose metabolism after adaptation with xylose medium, named “xylose consumption memory”, was observed in the strains with both xylose isomerase pathway and xylose reductase and xylitol dehydrogenase pathways. In further, the proteomic acetylation of the strains before and after adaptation was investigated, and it was revealed that H4K5 was one of the most differential acetylation sites related to xylose consumption memory of engineered S. cerevisiae. We tested 8 genes encoding acetylase or deacetylase, and it was found that the knockout of the GCN5 and HPA2 encoding acetylases enhanced the xylose consumption memory. Conclusions The behavior of xylose consumption memory in engineered S. cerevisiae can be successfully induced with xylose in the adaptation. H4K5Ac and two genes of GCN5 and HPA2 are related to xylose consumption memory of engineered S. cerevisiae during adaptation. This study provides valuable insights into the xylose adaptation of engineered S. cerevisiae.

Abstract In this research, series of PVDF microporous films with various polymer concentrations and thickness were prepared through thermally‐induced phase separation in air condition with diphenyl carbonate as the diluent. Effects of polymer concentration and film thickness on the formation kinetics of microporous structure of PVDF thin films were in situ investigated via TII technique. The instantaneous heat conduction inside the films during film formation was also evaluated. Two types of parameter models were adopted in order to disclose the time and location dependence of TIPS film solidification kinetics, respectively. Hierarchical microstructures, crystallization behavior and thermal properties of the TIPS films were also characterized by SEM, DSC, and TGA, respectively. The current study could supply an insight into the fabrication of PVDF microporous films with target microstructure and desirable performance.

Background and PurposeAn inguinal hernia is a common surgical disease. Once incarcerated or strangulated, it may endanger the life of the patient. Therefore, it is essential to study the risk factors of incarcerated inguinal hernia (IIH) and strangulated inguinal hernia (SIH). One of the serious complications of IIH and SIH is intestinal necrosis, which occurs owing to blood supply disorder. The study explores the risk factors of intestinal resection and establishes a simple model to assess the incidence of intestinal resection to provide significant assistance and limited guidance for clinical work.Patients and MethodsOur research team collected and retrospectively analysed the clinical data of 338 patients with IIH who were hospitalized in the First Affiliated Hospital of Wenzhou Medical University between September 2008 and December 2016. According to the surgical plan, we divided the included cases into two groups, non-intestinal and intestinal resection groups, and the clinical case characteristics of these groups were statistically analysed.ResultsBased on multivariable logistic regression analysis, we found that increased risk of bowel resection was highly correlated among the elderly (≥70 years), and for people with high temperature (≥37.3°C), high systemic immune-inflammation index(SII) values (≥1230.13), presence of bowel obstruction, and signs of peritonitis. Further, we processed the five independent risk factors using special software to obtain a simple model called a nomogram. To verify the nomogram’s accuracy and predictive ability, we calculate the C-index: 0.806 and use the calibration curve to evaluate its stability and predictive performance. We constructed the ROC curve nomogram and other sub-variables, and calculated the area under the curve (AUC) corresponding to the nomogram (AUC = 0.808, 95% CI = 0.762 to 0.848), SII (AUC = 0.752, 95% CI = 0.703 to 0.797), age (AUC = 0.641, 95% CI = 0.587 to 0.692), temperature (AUC = 0.579, 95% CI = 0.524 to 0.632), bowel obstruction (AUC = 0.685, 95% CI = 0.633 to 0.734), and signs of peritonitis (AUC = 0.580, 95% CI = 0.525 to 0.633).ConclusionIt can be said that we found for the first time that clinical variables such as SII are independent risk factors for enterectomy for IIH. The nomogram based on SII and other variables can accurately and easily predict the probability of IIH requiring bowel resection.

Objective To analyze the differential expressions of miRNA in monocyte derived dendritic cells (moDCs) from systemic lupus erythematosus (SLE) patients and healthy people by bioinformatic analysis. Methods The GSE79240 dataset was downloaded from the gene expression omnibus (GEO) database, differential miRNAs were screened by R language. Funrich software was used to analyze the gene ontology (GO) enrichment, Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment and transcription factors. MiRTarBase database was used to predict target genes. Results A total of 19 differential miRNAs were screened out,of which 11 were up-regulated and 8 were down-regulated.Biological process of GO enrichment was enriched in signal transduction and cell communication; cellular component of GO enrichment was enriched in nucleus and cytoplasm; molecular function of GO enrichment was expressed in transcription factor activity, ubiquitin-specific protease activity and receptor signalling complex scaffold activity. KEGG pathway was shown mainly in glypican signalling pathway, TRAIL signalling pathway and S1P signalling pathway. The transcription factors related to miRNA mainly included: SP1, SP4, EGR1 and POU2F1. Forteen miRNAs have been experimentally verified to have target genes. Conclusions The differential miRNAs in moDCs of SLE patients may play an important role in the pathogenesis of SLE and provide new clue for the diagnosis of SLE.

Perioperative antibiotic therapy is recommended to reduce the incidence of infection after caesarean section. However, the optimal timing of prophylactic antibiotic administration in such cases remains controversial. With this meta-analysis, we aimed to evaluate the safety and efficacy of prophylactic antibiotic therapy before skin incision versus after umbilical cord clamping in patients undergoing elective caesarean section. We searched the PubMed, EMBASE, Cochrane Library and Web of Science databases for randomised controlled trials (RCTs) published between January 1, 2000 and July 1, 2020. The 1101 initially identified references were narrowed to 10 RCTs involving 5020 women for the final analysis. Briefly, we determined that prophylactic antibiotic therapy before skin incision not only reduced the incidence of postpartum endometritis (relative risk (RR), 0.56; 95% confidence interval (CI), 0.34-0.92; P = 0.02), but also decreased the rate of total infectious morbidity (RR, 0.79; 95% CI, 0.64-0.98; P = 0.03) when compared to antibiotic therapy after umbilical cord clipping. However, the two timings of antibiotic administration did not lead to significant differences in the incidence of wound infection (RR, 0.73; 95% CI, 0.54-1.00; P = 0.05), maternal febrile morbidity (RR, 1.20; 95% CI, 0.67-2.14; P = 0.54), neonatal sepsis (RR = 0.65; 95% CI, 0.37-1.13; P = 0.13), septic workup (RR, 0.89; 95% CI, 0.67-1.18; P = 1.00) or neonatal intensive care unit admission (RR, 0.87; 95% CI, 0.69-1.09; P = 0.23). In conclusion, the prophylactic administration of antibiotics before a skin incision is made for an elective caesarean section can significantly decrease the incidence of total infectious morbidity and postpartum endometritis.

Cadmium (Cd) is a dispensable element that can be absorbed by crops, posing a threat to human health through the food chains. Melatonin (MT), as a plant growth regulator, has been used to alleviate Cd toxicity in many plant species; however, the underlying molecular mechanisms responsible for Cd toxicity in wheat are still poorly understood. In this study, the suitable exogenous MT concentration (50 μM) was screened to mitigate Cd toxicity of wheat plants by increasing the plant height, root length, fresh or dry weight and chlorophyll content, or decreasing the malondialdehyde (MDA) content. In addition, MT application significantly increased ascorbic acid (ASA) and glutathione (GSH) content by reducing ROS production, especially in roots, further decreasing Cd content in fraction of organelles. Moreover, the expression levels of ASA-GSH synthesis genes, APX, GR, and GST were significantly increased by 171.5%, 465.2%, and 256.8% in roots, respectively, whereas GSH, DHAR, or MDHAR were significantly decreased by 48.5%, 54.3%, or 60.0% in roots under MT + Cd stress. However, the expression levels of Cd-induced metal transporter genes TaNramp1, TaNramp5, TaHMA2, TaHMA3, and TaLCT1 were significantly decreased by 53.7%, 50.1%, 86.5%, 87.2%, and 94.5% in roots under MT + Cd stress compared with alone Cd treatment, respectively. In conclusion, our results suggesting that MT alleviate Cd toxicity in wheat by enhancing ASA-GSH metabolism, suppressing Cd transporter gene expression, and regulating Cd uptake and translocation in wheat plants.

Soil microorganisms play a key role in soil fertility. Exploring the microbial community composition and diversity in response to cover crops is important for improving soil fertility in orchards. This study investigated how cover cropping can improve soil fertility by altering microbial community composition and the interrelations among soil microorganisms. Soil physicochemical and biological indicators and microbial community composition were evaluated after a 6-years application of cover cropping in an apple (Malus pumila cv. Fuji) orchard located on the Loess Plateau, China. Three treatments were applied: Trifolium repens treatment (TR), Lolium perenne treatment (LP), clear tillage treatment (CT). The soil of the cover crop treatments had a more complex microbial co-occurrence network than that of the clear tillage treatment; in particular, the correlations among fungi were significantly increased. Cover cropping increased the levels of soil organic matter (SOM), microbial biomass carbon (MBC), and total nitrogen (TN) in orchard soil. Changes in the fungal community were more related to microbial biomass nitrogen (MBN), TN, and carbon-nitrogen ratio (C:N). This indicates that cover cropping not only increases the diversity of soil microorganisms but also increases the interrelations between microbial groups, thereby improving the soil fertility of apple orchards on the Loess Plateau.

Fungal α‐mannosidase Ams1 and its mammalian homolog MAN2C1 hydrolyze terminal α‐linked mannoses in free oligosaccharides released from misfolded glycoproteins or lipid‐linked oligosaccharide donors. Ams1 is transported by selective autophagy into vacuoles. Here, we determine the tetrameric structure of Ams1 from the fission yeast Schizosaccharomyces pombe at 3.2 Å resolution by cryo‐electron microscopy. Distinct from a low resolution structure of S. cerevisiae Ams1, S. pombe Ams1 has a prominent N‐terminal tail that mediates tetramerization and an extra β‐sheet domain. Ams1 shares a conserved active site with other enzymes in glycoside hydrolase family 38, to which Ams1 belongs, but contains extra N‐terminal domains involved in tetramerization. The atomic structure of Ams1 reported here will aid understanding of its enzymatic activity and transport mechanism.

Abstract. More evidences show that microRNAs play an important role in the pathogenesis of inflammation and autoimmune diseases including Lichen planus, and are an attractive therapeutic target. MicroRNA family plays an important role in the regulation of gene expression, which involves cell proliferation, apoptosis, growth, differentiation and metabolism, vascularization, immune response and other biological processes. The changes of expression profile and expression level are closely related to the occurrence and development of many diseases, such as tumor, inflammatory disease and autoimmune disease relevant. However, there are few reports on microRNA in the pathogenesis of LP. This review summarizes the research advance of microRNAs (microRNAs -137, microRNAs -125b, microRNAs -138, microRNAs -27b, microRNAs -203) and their downstream proteins in LP.

Abstract Background Herpes simplex virus (HSV) can cause encephalitis. Its infected cell polypeptide 47 (ICP47), encoded by immediate-early gene US12, promotes immune escape. ICP47 was modified in the clinically approved oncolytic HSV (oHSV) T-Vec. However, transcription regulatory sequence (TRS) and transcription regulatory factor (TRF) of HSV US12 are seldom reported. Methods Previously, our laboratory isolated a new HSV strain named HSV-1-LXMW from a male patient with oral herpes in Beijing, China. Firstly, the genetic tree was used to analyze its genetic relationship. The US12 TRS and TRF in HSV-1-LXMW were found by using predictive software. Secondly, the further verification by the multi-sequence comparative analysis shown that the upstream DNA sequence of HSV US12 gene contained the conserved region. Finally, the results of literature search shown that the expression of transcription factors was related to the tissue affinity of HSV-1 and HSV-2, so as to increase the new understanding of the transcriptional regulation of HSV biology and oncolytic virus (OVs) therapy. Results Here we reported the transcriptional regulation region sequence of our new HSV-1-LXMW, and its close relationship with HSV-1-CR38 and HSV-1-17. Importantly we identified eight different kinds of novel TRSs and TRFs of HSV US12 for the first time, and found they are conserved among HSV-1 (c-Rel, Elk-1, Pax-4), HSV-2 (Oct-1, CF2-II, E74A, StuAp) or both HSVs (HNF-4). The TRFs c-Rel and Oct-1 are biologically functional respectively in immune escape and viral replication during HSV infection. Conclusions Our findings have important implication to HSV biology, infection, immunity and oHSVs.

Abstract Background Problematic mobile phone use (PMPU) has become a public health issue in China, particularly in adolescents and young adults. The Problematic Mobile Phone Use Questionnaire-Short Version (PMPUQ-SV) is a validated instrument that measures multiple aspects of PMPU. The current study aimed to test the psychometric characteristics of a Chinese adaption of the PMPUQ-SV and examine its measurement invariance across gender. Methods A total of 2086 participants were recruited form nine schools (six undergraduate colleges and three vocational colleges) through an online platform. Measures included socio-demographic variables, patterns of mobile phone use, the Chinese version of the PMPUQ-SV (C-PMPUQ-SV), the Chinese version of the Smartphone Addiction Proneness Scale (C-SAPS), and the Depression Anxiety Stress Scales (DASS-21). Results Exploratory and confirmatory factor analyses conducted in two independent subsamples confirmed that the postulated dimensions fit the data well. Four items, judged as either outdated or not adapted to the Chinese context, performed poorly and were removed, resulting in a shorter 11-item scale. Convergent validity was established through correlations between emotional symptoms and the C-PMPUQ-SV and addictive smartphone use. Additional measurement invariance analyses showed that the scale performed largely similarly in male and female participants. Conclusions The present study demonstrated that the C-PMPUQ-SV is an adequate instrument to study various types of PMPU in Chinese adolescents and young adults. The updated 11-item scale shortens the evaluation time and is adapted to assess contemporary smartphone use.

Background: Cardiovascular diseases (CVD) are the leading cause of death globally. Electrocardiogram (ECG) analysis can provide thoroughly assessment for different CVDs efficiently. We propose a multi-task group bidirectional long short-term memory (MTGBi-LSTM) framework to intelligent recognize multiple CVDs based on multi-lead ECG signals. Methods: This model employs a Group Bi-LSTM (GBi-LSTM) and Residual Group Convolutional Neural Network (Res-GCNN) to learn the dual feature representation of ECG space and time series. GBi-LSTM is divided into Global Bi-LSTM and Intra-Group Bi-LSTM, which can learn the features of each ECG lead and the relationship between leads. Then, through attention mechanism, the different lead information of ECG is integrated to make the model to possess the powerful feature discriminability. Through multi-task learning, the model can fully mine the association information between diseases and obtain more accurate diagnostic results. In addition, we propose a dynamic weighted loss function to better quantify the loss to overcome the imbalance between classes. Results: Based on more than 170,000 clinical 12-lead ECG analysis, the MTGBi-LSTM method achieved accuracy, precision, recall and F1 of 88.86%, 90.67%, 94.19% and 92.39%, respectively. The experimental results show that the proposed MTGBi-LSTM method can reliably realize ECG analysis and provide an effective tool for computer-aided diagnosis of CVD.

The purpose of this study was to reveal the patterns of reorganization of rich club organization in brain functional networks in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). The study found that the rich club node shifts from sensory/somatomotor network to fronto-parietal network in DLB. For AD, the rich club nodes switch between the temporal lobe with obvious structural atrophy and the frontal lobe, parietal lobe and cerebellum with relatively preserved structure and function. In addition, compared with healthy controls, rich club connectivity was enhanced in the DLB and AD groups. The connection strength of DLB patients was related to cognitive assessment. In conclusion, we revealed the different functional reorganization patterns of DLB and AD. The conversion and redistribution of rich club members may play a causal role in disease-specific outcomes. It may be used as a potential biomarker to provide more accurate prevention and treatment strategies.

BackgroundAortic aneurysm/dissection (AAD) is now encountered more often because of the increasing prevalence of atherosclerosis and hypertension in the population. Despite many therapeutic improvements, in particular timely and successful surgery, in-hospital mortality rates are still higher. Timely identification of patients at high risk will help improve the overall prognosis of AAD. Since early clinical and radiological signs are nonspecific, there is an urgent need for accurate biomarkers. Smooth muscle 22α (SM22α) is a potential marker for AAD because of its abundant expression in vascular smooth muscle, which is involved in development of AAD.MethodsWe prepared three different mouse models, including abdominal aortic aneurysm, neointimal hyperplasia and atherosclerosis. SM22α levels were assessed in serum and vascular tissue of the mice. Next, the relationships between serum SM22α level and vascular lesion were studied in mice. Finally, serum from 41 patients with AAD, 107 carotid artery stenosis (CAS) patients and 40 healthy volunteers were tested for SM22α. Serum levels of SM22α were measured using an enzyme-linked immunosorbent assay (ELISA).ResultsCompared with the controls, serum SM22α levels were reduced in the models of aortic aneurysm, neointimal formation and atherosclerosis, and elevated in mice with ruptured aneurysm. Serum SM22α level was negatively correlated with apoptosis rate of vascular smooth muscle cells (VSMC), ratio of intima/ media (I/M) area and plaque size. Patients with AAD had significantly higher serum SM22α levels than patients with only CAS, or normal controls.ConclusionSerum SM22α could be a potential predictive marker for AAD, and regulation of VSMC is a possible mechanism for the effects of SM22α.

Traumatic brain injury usually results in neuronal loss and cognitive deficits. Promoting endogenous neurogenesis has been considered as a viable treatment option to improve functional recovery after TBI. However, neural stem/progenitor cells (NSPCs) in neurogenic regions are often unable to migrate and differentiate into mature neurons at the injury site. Transglutaminase 2 (TGM2) has been identified as a crucial component of neurogenic niche, and significantly dysregulated after TBI. Therefore, we speculate that TGM2 may play an important role in neurogenesis after TBI, and strategies targeting TGM2 to promote endogenous neural regeneration may be applied in TBI therapy. Using a tamoxifen-induced Tgm2 conditional knockout mouse line and a mouse model of stab wound injury, we investigated the role and mechanism of TGM2 in regulating hippocampal neurogenesis after TBI. We found that Tgm2 was highly expressed in adult NSPCs and up-regulated after TBI. Conditional deletion of Tgm2 resulted in the impaired proliferation and differentiation of NSPCs, while Tgm2 overexpression enhanced the abilities of self-renewal, proliferation, differentiation, and migration of NSPCs after TBI. Importantly, injection of lentivirus overexpressing TGM2 significantly promoted hippocampal neurogenesis after TBI. Therefore, TGM2 is a key regulator of hippocampal neurogenesis and a pivotal therapeutic target for intervention following TBI.

Phycospheric bacteria may be the key biological factors affecting the growth of algae. However, the studies about interaction between Isochrysis galbana and its phycospheric bacteria are limited. Here, we show that a marine heterotrophic bacterium, Alteromonas macleodii, enhanced the growth of I. galbana, and inhibited non-photochemical quenching (NPQ) and superoxide dismutase (SOD) activities of this microalgae. Further, we explored this phenomenon via examining how the entire transcriptomes of I. galbana changed when it was co-cultured with A. macleodii. Notable increase was observed in transcripts related to photosynthesis, carbon fixation, oxidative phosphorylation, ribosomal proteins, biosynthetic enzymes, and transport processes of I. galbana in the presence of A. macleodii, suggesting the introduction of the bacterium might have introduced increased production and transport of carbon compounds and other types of biomolecules. Besides, the transcriptome changed largely corresponded to reduced stress conditions for I. galbana, as inferred from the depletion of transcripts encoding DNA repair enzymes, superoxide dismutase (SOD) and other stress-response proteins. Taken together, the presence of A. macleodii mainly enhanced photosynthesis and biosynthesis of I. galbana and protected it from stress, especially oxidative stress. Transfer of fixed organic carbon, but perhaps other types of biomolecules, between the autotroph and the heterotroph might happen in I. galbana-A. macleodii co-culture. The present work provides novel insights into the transcriptional consequences of I. galbana of mutualism with its heterotrophic bacterial partner, and mutually beneficial associations existing in I. galbana-A. macleodii might be explored to improve productivity and sustainability of aquaculture algal rearing systems.

Pulmonary endothelial cell dysfunction plays an important role in ionizing radiation (IR)-induced lung injury. Whether pulmonary endothelial cell ferroptosis occurs after IR and what are the underlying mechanisms remain elusive. Here, we demonstrate that 15-Gy IR induced ferroptosis characterized by lethal accumulation of reactive oxygen species (ROS), lipid peroxidation, mitochondria shrinkage, and decreased glutathione peroxidase 4 (GPX4) and SLC7A11 expression in pulmonary endothelial cells. The phenomena could be mimicked by Yoda1, a specific activator of mechanosensitive calcium channel PIEZO1. PIEZO1 protein expression was upregulated by IR in vivo and in vitro. The increased PIEZO1 expression after IR was accompanied with increased calcium influx and increased calpain activity. The effects of radiation on lung endothelial cell ferroptosis was partly reversed by inhibition of PIEZO1 activity using the selective inhibitor GsMTx4 or inhibition of downstreaming Ca2+/calpain signaling using PD151746. Both IR and activation of PIEZO1 led to increased degradation of VE-cadherin, while PD151746 blocked these effects. VE-cadherin knockdown by specific siRNA causes ferroptosis-like phenomena with increased ROS and lipid peroxidation in the lung endothelial cells. Overexpression of VE-cadherin partly recused the ferroptosis caused by IR or PIEZO1 activation as supported by decreased ROS production, lipid peroxidation and mitochondria shrinkage compared to IR or PIEZO1 activation alone. In summary, our study reveals a previously unrecognized role of PIEZO1 in modulating ferroptosis, providing a new target for future mitigation of radiation-induced lung injury.

The dispersive interaction between a qubit and a cavity is ubiquitous in circuit and cavity quantum electrodynamics. It describes the frequency shift of one quantum mode in response to excitations in the other and, in closed systems, is necessarily bidirectional, i.e., reciprocal. Here, we present an experimental study of a nonreciprocal dispersive-type interaction between a transmon qubit and a superconducting cavity, arising from a common coupling to dissipative intermediary modes with broken time reversal symmetry. We characterize the qubit-cavity dynamics, including asymmetric frequency pulls and photon shot noise dephasing, under varying degrees of nonreciprocity by tuning the magnetic field bias of a ferrite component in situ. We introduce a general master equation model for nonreciprocal interactions in the dispersive regime, providing a compact description of the observed qubit-cavity dynamics agnostic to the intermediary system. Our result provides an example of quantum nonreciprocal phenomena beyond the typical paradigms of non-Hermitian Hamiltonians and cascaded systems. [ABSTRACT FROM AUTHOR]

Abstract Objective To investigate the correlation of M-type phospholipase A2 receptor (PLA2R) expression and serum anti-PLA2R antibody with the clinical parameters and prognosis of patients with idiopathic membranous nephropathy (IMN). Methods A literature search for relevant original articles published between January 2009 and October 2019 was conducted on domestic and foreign databases. RevMan 5.3 software was used for meta-analysis. Results Eighteen studies were included in this meta-analysis. There were 1235 anti-PLA2R antibody-positive and PLA2R-positive patients, and 407 serum anti-PLA2R antibody-negative and PLA2R-negative patients. Compared with negative group, patients in the serum PLA2R antibody -positive group had lower serum albumin [SMD = -1.11, 95% CI (− 1.82, − 0.40), P

Summary: EED (embryonic ectoderm development) is a core component of the Polycomb repressive complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27) during the process of self-renewal, proliferation, and differentiation of embryonic stem cells. However, its function in the mammalian nervous system remains unexplored. Here, we report that loss of EED in the brain leads to postnatal lethality, impaired neuronal differentiation, and malformation of the dentate gyrus. Overexpression of Sox11, a downstream target of EED through interaction with H3K27me1, restores the neuronal differentiation capacity of EED-ablated neural stem/progenitor cells (NSPCs). Interestingly, downregulation of Cdkn2a, another downstream target of EED which is regulated in an H3K27me3-dependent manner, reverses the proliferation defect of EED-ablated NSPCs. Taken together, these findings established a critical role of EED in the development of hippocampal dentate gyrus, which might shed new light on the molecular mechanism of intellectual disability in patients with EED mutations. : In this article, Chang-Mei Liu and colleagues show that EED is necessary for neuronal differentiation in the dentate gyrus, by targeting the downstream target Sox11 through interaction with H3K27me1. These data established a critical role of EED in the development of hippocampal dentate gyrus, which might shed new light on understanding molecular mechanism of intellectual disability in patients with EED mutations. Keywords: EED, PRC2, neural stem cells, dentate gyrus

Alkali metal (M = Na, K) salts of the [CB11H12]− anion have attracted increasing attention in many fields such as catalysis and all-solid-state batteries. However, tedious and low-yielding synthetic methods have seriously limited their application in these fields. We developed a facile method for the direct synthesis of the unsolvated potassium and sodium salts of the [CB11H12]− anion in 66% and 68% yields, respectively, by reactions of Na[B11H14] with NaH/NaHMDS (sodium bis(trimethylsilyl)amide), CF3SiMe3 in THF and K[B11H14] with KH, CF3SiMe3 in DME. This method avoids the exchange of cation and significantly simplifies the reaction setup, thus enabling convenient large-scale synthesis. It is believed that this method will support further application of Na[CB11H12] and K[CB11H12] as solid electrolytes for an all-solid-state battery.

In order to discover pesticidal lead compounds with high activity and low toxicity, a series of novel benzamides substituted with pyrazole-linked 1,2,4-oxadiazole were designed via bioisosterism. The chemical structures of the target compounds were confirmed via 1H NMR, 13C NMR and HRMS analysis. The preliminary bioassay showed that most compounds exhibited good lethal activities against Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis and Spodoptera frugiperda at 500 mg/L. Particularly in the case of Mythimna separate, compound 14q (70%) exhibited obvious insecticidal activity. In addition, compound 14h demonstrated good fungicidal activity against Pyricularia oryae with an inhibition rate of 77.8%, and compounds 14e, 14k, 14n and 14r also showed certain antifungal activities (55.6–66.7%). The zebrafish toxicity test showed that the LC50 of compound 14h was 14.01 mg/L, which indicated that it may be used as a potential leading compound for further structural optimization.

This study determined the complete mitochondrial genome of Formosania galericula (Cypriniformes: Gastromyzontidae) from Zhejiang, China, for the first time. The complete mitochondrial genome of F. galericula was sequenced to be 16,555 bp in length. The genome contained 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs, two central non-coding regions (the control region and the origin of light strand replication), identical to most other vertebrates. Phylogenetic analysis highly supported that F. galericula was close to Crossostoma lacustre and the genus Vanmanenia fish. However, F. galericula was not firstly clustered with Formosania chenyiyui but after the genus Vanmanenia fish. These data would explain the evolutionary mechanisms and biogeography of the family Gastromyzontidae and is helpful for the conservation of genetics and stock evaluation for F. galericula.

To develop new compounds with high activity, broad spectrum and low-toxicity, 17 benzamides substituted with quinoline-linked 1,2,4-oxadiazole were designed using the splicing principle of active substructures and were synthesized. The biological activities were evaluated against 10 fungi, indicating that some of the synthetic compounds showed excellent fungicidal activities. For example, at 50 mg/L, the inhibitory activity of 13p (3-Cl-4-Cl substituted, 86.1%) against Sclerotinia sclerotiorum was superior to that of quinoxyfen (77.8%), and the inhibitory activity of 13f (3-CF3 substituted, 77.8%) was comparable to that of quinoxyfen. The fungicidal activities of 13f and 13p to Sclerotinia sclerotiorum were better than that of quinoxyfen (14.19 mg/L), with EC50 of 6.67 mg/L and 5.17 mg/L, respectively. Furthermore, the acute toxicity of 13p was 19.42 mg/L, classifying it as a low-toxic compound.

The vector boson scattering (VBS) processes at the Large Hadron Collider (LHC) are very suitable to probe the anomalous quartic gauge couplings (aQGCs). We study the dimension-8 operators contributing to the anomalous γγWW coupling via the exclusive γγ→W+W− scattering. By analysing the kinematical features of the signals, we propose an event selection strategy to highlight the aQGC contributions. The statistical significances of the signals at 13 and 14 TeV LHC with current luminosity are obtained. The γγ→W+W− scattering is found to be sensitive to OMi operators and can contribute to the combined limits.

Objective: Herpes simplex viruses (HSVs) are widely spread throughout the world, causing infections from oral, and genital mucous membrane ulcerations to severe viral encephalitis. Glycoprotein B (gB) was the first HSV envelope glycoprotein identified to induce cell fusion. This glycoprotein initiates viral entry and thereby determines the infectivity of HSV, as well as oncolytic HSV (oHSV). Clarifying its molecular characterization and enlarging its motif reservoir will help to engineer oHSV and in cancer treatment applications. Only in recent years has the importance of gB been acknowledged in HSV infection and oHSV engineering. Although gB-modified oHSVs have been developed, the detailed molecular biology of gB needs to be illustrated more clearly in order to construct more effective oHSVs.Method: Here, we performed a systematic comparative sequence analysis of gBs from the 9 HSV-1 and 2 HSV-2 strains, including HSV-1-LXMW, which was isolated by our lab. Online software was implemented to predict gB secondary structure and motifs. Based on extensive literature reviews, a functional analysis of the predicted motifs was performed.Results: Here, we reported the DNA and predicted amino acid sequences of our recently isolated HSV-1-LXMW and found that the strain was evolutionarily close to HSV-1 strains F, H129, and SC16 based on gB analysis. The 22 novel motifs of HSV gB were identified for the first time. An amino acid sequence alignment of the 11 HSV strains showed that the gB motifs are conserved among HSV strains, suggesting that they are functional in vivo. Additionally, we found that certain amino acids within the 13 motifs out of the 22 were reported to be functional in vivo. Furthermore, the gB mutants and gB-engineered oHSVs were also summarized.Conclusion: Our identification of the 22 novel motifs shed light on HSV gB biology and provide new options for gB engineering to improve the efficiency and safety of oHSVs.

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor involved in homeostatic regulation of normal cells and carcinogenesis of epithelial malignancies. With rapid development of the precision medicine era, a series of new therapies targeting EGFR are underway. Four EGFR monoclonal antibody drugs (cetuximab, panitumumab, nimotuzumab, and necitumumab) are already on the market, and a dozen other EGFR monoclonal antibodies are in clinical trials. Here, we comprehensively review the newly identified biological properties and anti-tumor mechanisms of EGFR monoclonal antibodies. We summarize recently completed and ongoing clinical trials of the classic and new EGFR monoclonal antibodies. More importantly, according to our new standard, we re-classify the complex evolving tumor cell resistance mechanisms, including those involving exosomes, non-coding RNA and the tumor microenvironment, against EGFR monoclonal antibodies. Finally, we analyzed the limitations of EGFR monoclonal antibody therapy, and discussed the current strategies overcoming EGFR related drug resistance. This review will help us better understand the latest battles between EGFR monoclonal antibodies and resistant tumor cells, and the future directions to develop anti-tumor EGFR monoclonal antibodies with durable effects.

Abstract Introduction The mechanisms underlying sleep deprivation‐induced memory impairments and relevant compensatory signaling pathways remain elusive. We tested the hypothesis that increased brain‐derived neurotrophic factor (BDNF) expression in the basal forebrain following acute sleep deprivation was a compensatory mechanism to maintain fear memory performance. Methods Adult male Wistar rats were deprived of 6‐hr total sleep from the beginning of the light cycle. The effects of sleep deprivation on BDNF protein expression and activation of downstream tropomyosin receptor kinase B (TrkB)/phospholipase C‐γ1 (PLCγ1) signaling in the basal forebrain and fear memory consolidation were examined. BDNF or selective downstream TrkB receptor antagonist ANA‐12 was further injected into the basal forebrain bilaterally to observe the changes in fear memory consolidation in response to modulation of the BDNF/TrkB signaling. Results Six hours of sleep deprivation‐induced both short‐ and long‐term fear memory impairments. Increased BDNF protein expression and TrkB and PLCγ1 phosphorylation in the basal forebrain were observed after sleep deprivation. Microinjection of BDNF into the basal forebrain partly reversed fear memory deficits caused by sleep deprivation, which were accompanied by increased BDNF protein levels and TrkB/PLCγ1 activation. After ANA‐12 microinjection, sleep deprivation‐induced activation of the BDNF/TrkB pathway was inhibited and impairments of fear memory consolidation were further aggravated. Conclusions Acute sleep deprivation induces compensatory increase of BDNF expression in the basal forebrain. Microinjection of BDNF into the basal forebrain mitigates the fear memory impairments caused by sleep deprivation by activating TrkB/PLCγ1 signaling.

BACKGROUND:To reach WHO End tuberculosis (TB) targets, countries need a quality-assured laboratory network equipped with rapid diagnostics for tuberculosis diagnosis and drug susceptibility testing. Diagnostic network analysis aims to inform instrument placement, sample referral, staffing, geographical prioritization, integration of testing enabling targeted investments and programming to meet priority needs. METHODS:Supply chain modelling and optimization software was used to map Lesotho's TB diagnostic network using available data sources, including laboratory and programme reports and health and demographic surveys. Various scenarios were analysed, including current network configuration and inclusion of additional GeneXpert and/or point of care instruments. Different levels of estimated demand for testing services were modelled (current [30,000 tests/year], intermediate [41,000 tests/year] and total demand needed to find all TB cases [88,000 tests/year]). RESULTS:Lesotho's GeneXpert capacity is largely well-located but under-utilized (19/24 sites use under 50% capacity). The network has sufficient capacity to meet current and near-future demand and 70% of estimated total demand. Relocation of 13 existing instruments would deliver equivalent access to services, maintain turnaround time and reduce costs compared with planned procurement of 7 more instruments. Gaps exist in linking people with positive symptom screens to testing; closing this gap would require extra 11,000 tests per year and result in 1000 additional TB patients being treated. Closing the gap in linking diagnosed patients to treatment would result in a further 629 patients being treated. Scale up of capacity to meet total demand will be best achieved using a point-of-care platform in addition to the existing GeneXpert footprint. CONCLUSIONS:Analysis of TB diagnostic networks highlighted key gaps and opportunities to optimize services. Network mapping and optimization should be considered an integral part of strategic planning. By building efficient and patient-centred diagnostic networks, countries will be better equipped to meet End TB targets.

Countering the optical network ‘capacity crunch’ requires developments in optical fibres. Here, the authors report a hollow-core fibre with conjoined tubes in the cladding and a negative-curvature core shape. It exhibits a transmission loss of 2 dB/km at 1512 nm and less than 16 dB/km bandwidth in the 1302–1637 nm range.

Abstract Background The key aim of the study is to establish an agreed standardised core outcome set (COS) for use when evaluating non-pharmacological health and social care interventions for people living at home with dementia. Methods/design Drawing on the guidance and approaches of the Core Outcome Measures in Effectiveness Trials (COMET), this study uses a four-phase mixed-methods design:1Focus groups and interviews with key stakeholder groups (people living with dementia, care partners, relevant health and social care professionals, researchers and policymakers) and a review of the literature will be undertaken to build a long list of outcomes.2Two rounds of Delphi surveys will be used with key stakeholder groups. Statements for the Delphi surveys and participation processes will be developed and informed through substantial member involvement with people living with dementia and care partners. A consensus meeting will be convened with key participant groups to discuss the key findings and finalise the COS.3A systematic literature review will be undertaken to assess the properties of tools and instruments to assess components of the COS. Measurement properties, validity and reliability will be assessed using the Consensus-based Standards for the Selection of Health Measurement (COSMIN) and COMET guidance.4A stated preference survey will elicit the preferences of key stakeholders for the outcomes identified as important to measure in the COS. Discussion To the best of our knowledge, this study is the first to use a modified Delphi process to involve people living with dementia as a participant group. Though the study is confined to collecting data in the United Kingdom, use of the COS by researchers will enhance the comparability of studies evaluating non-pharmacological and community-based interventions. Trial registration The study is registered on the COMET initiative, registered in 2014 at comet-initiative.org.

Most of the widely used vaginal lubricants in the U.S. and Europe are strongly hyperosmolal, formulated with high concentrations of glycerol, propylene glycol, polyquaternary compounds or other ingredients that make these lubricants 4 to 30 times the osmolality of healthy vaginal fluid. Hyperosmolal formulations have been shown to cause marked toxicity to human colorectal epithelia in vivo, and significantly increase vaginal transmission of genital herpes infections in the mouse/HSV model. They also cause toxicity to explants of vaginal epithelia, to cultured vaginal epithelial cells, and increase susceptibility to HIV in target cells in cell cultures. Here, we report that the osmolality of healthy vaginal fluid is 370 ± 40 mOsm/Kg in women with Nugent scores 0–3, and that a well-characterized three-dimensional human vaginal epithelium tissue model demonstrated that vaginal lubricants with osmolality greater than 4 times that of vaginal fluid (>1500 mOsm/Kg) markedly reduce epithelial barrier properties and showed damage in tissue structure. Four out of four such lubricants caused disruption in the parabasal and basal layers of cells as observed by histological analysis and reduced barrier integrity as measured by trans-epithelial electrical resistance (TEER). No epithelial damage to these layers was observed for hypo- and iso-osmolal lubricants with osmolality of