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Dairy mastitis is one of the most common diseases in dairy farming, and the formation of pathogenic bacteria biofilms may be an important reason why traditional antibiotic therapy fails to resolve some cases of dairy mastitis. We isolated and identified three strains of A. lwoffii were with strong biofilm forming ability from dairy cow mastitis samples from Chongqing dairy farms in China. In order to investigate the effect of novel anti-biofilm peptide CRAMP-34 on A.lwoffii biofilms, the anti-biofilm effect was evaluated by crystal violet staining, biofilms viable bacteria counting and confocal laser scanning microscopy (CLSM). In addition, transcriptome sequencing analysis, qRT-PCR and phenotypic verification were used to explore the mechanism of its action. The results showed that CRAMP-34 had a dose-dependent eradicating effect on A. lwoffii biofilms. Transcriptome sequencing analysis showed that 36 differentially expressed genes (11 up-regulated and 25 down-regulated) were detected after the intervention with the sub-inhibitory concentration of CRAMP-34. These differentially expressed genes may be related to enzyme synthesis, fimbriae, iron uptake system, capsular polysaccharide and other virulence factors through the functional analysis of differential genes. The results of subsequent bacterial motility and adhesion tests showed that the motility of A.lwoffii were enhanced after the intervention of CRAMP-34, but there was no significant change in adhesion. It was speculated that CRAMP-34 may promote the dispersion of biofilm bacteria by enhancing the motility of biofilm bacteria, thereby achieving the effect of eradicating biofilms. Therefore, these results, along with our other previous findings, suggest that CRAMP-34 holds promise as a new biofilm eradicator and deserves further research and development.

Biofilm is a structured community of bacteria encased within a self-produced extracellular matrix. When bacteria form biofilms, they undergo a phenotypic shift that enhances their resistance to antimicrobial agents. Consequently, inducing the transition of biofilm bacteria to the planktonic state may offer a viable approach for addressing infections associated with biofilms. Our previous study has shown that the mouse antimicrobial peptide CRAMP-34 can disperse Pseudomonas aeruginosa (P. aeruginosa) biofilm, and the potential mechanism of CRAMP-34 eradicate P. aeruginosa biofilms was also investigated by combined omics. However, changes in bacterial extracellular metabolism have not been identified. To further explore the mechanism by which CRAMP-34 disperses biofilm, this study analyzed its effects on the extracellular metabolites of biofilm cells via metabolomics. The results demonstrated that a total of 258 significantly different metabolites were detected in the untargeted metabolomics, of which 73 were downregulated and 185 were upregulated. Pathway enrichment analysis of differential metabolites revealed that metabolic pathways are mainly related to the biosynthesis and metabolism of amino acids, and it also suggested that CRAMP-34 may alter the sensitivity of biofilm bacteria to antibiotics. Subsequently, it was confirmed that the combination of CRAMP-34 with vancomycin and colistin had a synergistic effect on dispersed cells. These results, along with our previous findings, suggest that CRAMP-34 may promote the transition of PAO1 bacteria from the biofilm state to the planktonic state by upregulating the extracellular glutamate and succinate metabolism and eventually leading to the dispersal of biofilm. In addition, increased extracellular metabolites of myoinositol, palmitic acid and oleic acid may enhance the susceptibility of the dispersed bacteria to the antibiotics colistin and vancomycin. CRAMP-34 also delayed the development of bacterial resistance to colistin and ciprofloxacin. These results suggest the promising development of CRAMP-34 in combination with antibiotics as a potential candidate to provide a novel therapeutic approach for the prevention and treatment of biofilm-associated infections.

IntroductionCocaine is a highly addictive drug that is abused due to its excitatory effect on the central nervous system. It is critical to reveal the mechanisms of cocaine addiction and identify key genes that play an important role in addiction.MethodsIn this study, we proposed a centrality algorithm integration strategy to identify key genes in a protein–protein interaction (PPI) network constructed by deferential genes from cocaine addiction-related datasets. In order to investigate potential therapeutic drugs for cocaine addiction, a network of targeted relationships between nervous system drugs and key genes was established.ResultsFour key genes (JUN, FOS, EGR1, and IL6) were identified and well validated using CTD database correlation analysis, text mining, independent dataset analysis, and enrichment analysis methods, and they might serve as biomarkers of cocaine addiction. A total of seventeen drugs have been identified from the network of targeted relationships between nervous system drugs and key genes, of which five (disulfiram, cannabidiol, dextroamphetamine, diazepam, and melatonin) have been shown in the literature to play a role in the treatment of cocaine addiction.DiscussionThis study identified key genes and potential therapeutic drugs for cocaine addiction, which provided new ideas for the research of the mechanism of cocaine addiction.

Mungbean is a warm-season annual food legume and plays important role in supplying food and nutritional security in many tropical countries. However, the genetic basis of its agronomic traits remains poorly understood. Therefore, we resequenced 558 Chinese mungbean landraces and produced a comprehensive map of mungbean genomic variation. We phenotyped all landraces in six different environments. Genome-wide association studies (GWAS) produced 110 signals significantly associated with nine agronomic traits, for which several candidate genes were identified. Overall, this study provides new insight into the genetic architecture of mungbean agronomic traits. Moreover, the genome-wide variations identified here should be valuable resources for future breeding studies of this important food legume.

Stomach, liver, and colon cancers are the most common digestive system cancers leading to mortality. Cancer leader genes were identified in the current study as the genes that contribute to tumor initiation and could shed light on the molecular mechanisms in tumorigenesis. An integrated procedure was proposed to identify cancer leader genes based on subcellular location information and cancer-related characteristics considering the effects of nodes on their neighbors in human protein–protein interaction networks. A total of 69, 43, and 64 leader genes were identified for stomach, liver, and colon cancers, respectively. Furthermore, literature reviews and experimental data including protein expression levels and independent datasets from other databases all verified their association with corresponding cancer types. These final leader genes were expected to be used as diagnostic biomarkers and targets for new treatment strategies. The procedure for identifying cancer leader genes could be expanded to open up a window into the mechanisms, early diagnosis, and treatment of other cancer types.

The development of a colorectal adenoma (CA) into carcinoma (CRC) is a long and stealthy process. There remains a lack of reliable biomarkers to distinguish CA from CRC. To effectively explore underlying molecular mechanisms and identify novel lipid biomarkers promising for early diagnosis of CRC, an ultrahigh-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS) method was employed to comprehensively measure lipid species in human serum samples of patients with CA and CRC. Results showed significant differences in serum lipid profiles between CA and CRC groups, and 85 differential lipid species (P < 0.05 and fold change > 1.50 or < 0.67) were discovered. These significantly altered lipid species were mainly involved in fatty acid (FA), phosphatidylcholine (PC), and triacylglycerol (TAG) metabolism with the constituent ratio > 63.50%. After performance evaluation by the receiver operating characteristic (ROC) curve analysis, seven lipid species were ultimately proposed as potential biomarkers with the area under the curve (AUC) > 0.800. Of particular value, a lipid panel containing docosanamide, SM d36:0, PC 36:1e, and triheptanoin was selected as a composite candidate biomarker with excellent performance (AUC = 0.971), and the highest selected frequency to distinguish patients with CA from patients with CRC based on the support vector machine (SVM) classification model. To our knowledge, this study was the first to undertake a lipidomics profile using serum intended to identify screening lipid biomarkers to discriminate between CA and CRC. The lipid panel could potentially serve as a composite biomarker aiding the early diagnosis of CRC. Metabolic dysregulation of FAs, PCs, and TAGs seems likely involved in malignant transformation of CA, which hopefully will provide new clues to understand its underlying mechanism.

With the increasing bacterial resistance to traditional antibiotics, there is an urgent need for the development of alternative drugs or adjuvants of antibiotics to enhance antibacterial efficiency. The combination of antimicrobial peptides (AMPs) and traditional antibiotics is a potential alternative to enhance antibacterial efficiency. In this study, we investigated the synergistic bactericidal effect of AMPs, including chicken (CATH-1,−2,−3, and -B1), mice (CRAMP), and porcine (PMAP-36 and PR-39) in combination with conventional antibiotics containing ampicillin, tetracycline, gentamicin, and erythromycin against Staphylococcus aureus, Salmonella enteritidis, and Escherichia coli. The results showed that the minimum bactericidal concentration (MBC) of CATH-1,−3 and PMAP-36 was lower than 10 μM, indicating that these three AMPs had good bacterial activity against S. aureus, S. enteritidis, and E. coli. Then, the synergistic antibacterial activity of AMPs and antibiotics combination was determined by the fractional bactericidal concentration index (FBCI). The results showed that the FBCI of AMPs (CATH-1,−3 and PMAP-36) and erythromycin was lower than 0.5 against bacterial pathogens, demonstrating that they had a synergistic bactericidal effect. Furthermore, the time-killing kinetics of AMPs (CATH-1,−3 and PMAP-36) in combination with erythromycin showed that they had a continuous killing effect on bacteria within 3 h. Notably, the combination showed lower hemolytic activity and cytotoxicity to mammal cells compared to erythromycin and peptide alone treatment. In addition, the antibacterial mechanism of CATH-1 and erythromycin combination against E. coli was studied. The results of the scanning electron microscope showed that CATH-1 enhanced the antibacterial activity of erythromycin by increasing the permeability of bacterial cell membrane. Moreover, the results of bacterial migration movement showed that the combination of CATH-1 and erythromycin significantly inhibits the migration of E. coli. Finally, drug resistance analysis was performed and the results showed that CATH-1 delayed the emergence of E. coli resistance to erythromycin. In conclusion, the combination of CATH-1 and erythromycin has synergistic antibacterial activity and reduces the emergence of bacterial drug resistance. Our study provides valuable information to develop AMPs as potential substitutes or adjuvants for traditional antibiotics.

The chromosomal homologies of human (Homo sapiens—HSA) and Trachypithecus phayrei (TPH—Phayre’s leaf-monkey, family Cercopithecidae) have previously been studied by using classical chromosome staining/banding and fluorescence in situ hybridization (FISH) from the 1970s to 1990s. In this study, we carried out molecular cytogenetics applying human multicolor banding (MCB), locus-specific, and human heterochromatin-specific probes to establish the first detailed chromosomal map of TPH, which was not available until now. Accordingly, it was possible to precisely determine evolutionary-conserved breakpoints (ECBs) and the orientation of evolutionary-conserved segments compared to HSA. It could be shown that five chromosomes remained completely unchanged between these two species, and 16 chromosomes underwent only intrachromosomal changes. In addition, 50 ECBs that failed to be resolved in previous reports were exactly identified and characterized in this study. It could also be shown that 43.5% of TPH centromere positions were conserved and 56.5% were altered compared to HSA. Interestingly, 82% ECBs in TPH corresponded to human fragile sites. Overall, this study is an essential contribution to future studies and reviews on chromosomal evolution in Cercopithecidae.

ObjectiveTo investigative the diagnostic performance of the morphological model, radiomics model, and combined model in differentiating invasive adenocarcinomas (IACs) from minimally invasive adenocarcinomas (MIAs).MethodsThis study retrospectively involved 307 patients who underwent chest computed tomography (CT) examination and presented as subsolid pulmonary nodules whose pathological findings were MIAs or IACs from January 2010 to May 2018. These patients were randomly assigned to training and validation groups in a ratio of 4:1 for 10 times. Eighteen categories of morphological features of pulmonary nodules including internal and surrounding structure were labeled. The following radiomics features are extracted: first-order features, shape-based features, gray-level co-occurrence matrix (GLCM) features, gray-level size zone matrix (GLSZM) features, gray-level run length matrix (GLRLM) features, and gray-level dependence matrix (GLDM) features. The chi-square test and F1 test selected morphology features, and LASSO selected radiomics features. Logistic regression was used to establish models. Receiver operating characteristic (ROC) curves evaluated the effectiveness, and Delong analysis compared ROC statistic difference among three models.ResultsIn validation cohorts, areas under the curve (AUC) of the morphological model, radiomics model, and combined model of distinguishing MIAs from IACs were 0.88, 0.87, and 0.89; the sensitivity (SE) was 0.68, 0.81, and 0.83; and the specificity (SP) was 0.93, 0.79, and 0.87. There was no statistically significant difference in AUC between three models (p > 0.05).ConclusionThe morphological model, radiomics model, and combined model all have a high efficiency in the differentiation between MIAs and IACs and have potential to provide non-invasive assistant information for clinical decision-making.

Botanical products have been increasingly popular in topical therapies for melasma, as presumed safer and milder than fully synthetic products. Although the efficacy of different topical botanicals has recently been substantiated through randomized controlled trials (RCTs), there is a lack of sufficiently pooled evidence on their efficacy and safety for the treatment of melasma. Herein, a systematic review and meta-analysis was conducted on the efficacy and safety of topical botanical products for the treatment of melasma, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All RCTs on the use of topical botanical products for the treatment of melasma in humans were included, except for trials enrolling pregnant patients. The primary outcome was Melasma Area and Severity Index (MASI) or its variation. The secondary outcomes included Mexameter® reading, melasma improvement evaluated by participants, and any reported adverse events (AEs). As a result, twelve eligible trials comprising 695 patients with melasma from 6 different countries were included. The topical botanical products contained active ingredients which varied among trials as follows: herb-derived molecule, extracts of a single herb, and extracts of compound herbs. Topical therapy with botanical products significantly improved melasma with a large effect on MASI reduction (SMD −0.79, 95% CI −1.14 to −0.44, p < 0.00001), and a moderate effect on Mexameter® reading reduction (SMD −0.52, 95% CI −0.81 to 0.23, p = 0.0005), when compared with placebo. It also showed a similar improvement of melasma with a better safety profile (RR 0.37, 95% CI 0.15–0.88, p = 0.02), when compared with active-comparators. Botanical products were well-tolerated across studies, with no serious AEs reported. Despite the limitations such as small sample size, short duration of follow up and varied botanical products, this work still represents the best level of evidence currently available on topical use of botanical products on melasma. Moreover, it should be noted that more well-designed studies are needed before recommending topical botanical products as a viable treatment option for melasma.Systematic Review RegistrationPROSPERO, identifier: CRD42021256328.

Objectives: The aim of this study was to present our experience with the management of isolated left vertebral artery (ILVA) during complex thoracic aortic pathology treated with the hybrid thoracic endovascular aortic repair.Methods: This is a single-center, respective cohort study. Between June 2016 and June 2020, 13 patients (12 men; median age 60 years old, range 42–72 years old) who underwent hybrid procedures were identified with ILVA in our center. Demographics, imaging features, operation details, and follow-up in these patients were collected and analyzed.Results: In this study, all patients received the hybrid procedure, and the primary technical success rate was 100%. There were no in-hospital deaths. Complication occurred in two (15.4%) patients. One patient suffered from contrast-induced acute kidney injury (CI-AKI) and recovered before discharge. Another patient required reintervention for acute left-lower-limb ischemia, which was successfully treated using Fogarty catheter embolectomy. Immediate vagus/recurrent laryngeal never palsy, lymphocele, and chylothorax were not observed. The median duration of follow-up was 22 months (range, 13–29 months). No neurologic deficits, bypass occlusion, or ILVA occlusion or stenosis were observed during the follow-up. No aortic rupture, cerebrovascular accident, or spinal cord ischemia was observed during the follow-up period.Conclusions: Our limited experience reveals that hybrid procedures [thoracic endovascular aortic repair (TEVAR), ILVA transposition, and left common carotid artery-left subclavian artery (LCCA-LSA) bypass] are relatively safe, feasible, and durable for the treatment of thoracic aortic pathology with ILVA. However, further technique durability and larger studies with long-term follow-up periods are warranted.

Precision interventional brachytherapy is a radiotherapy technique that combines radiation therapy medicine with computer network technology, physics, etc. It can solve the limitations of conventional brachytherapy. Radioactive drugs and their carriers change with each passing day, and major research institutions and enterprises worldwide have conducted extensive research on them. In addition, the capabilities of interventional robotic systems are also rapidly developing to meet clinical needs for the precise delivery of radiopharmaceuticals in interventional radiotherapy. This study reviews the main radiopharmaceuticals, drug carriers, dispensing and fixation technologies, and interventional robotic precision delivery systems used in precision brachytherapy of malignant tumors. We then discuss the current needs in the field and future development prospects in high-precision interventional brachytherapy.

Orthosiphon stamineus Benth. (OSB) is a well-known herbal medicine exerting various pharmacological effects and medicinal potentials. Owing to its complex of phytochemical constituents, as well as the ambiguous relationship between phytochemical constituents and varied bioactivities, it is a great challenge to explore which constituents make a core contribution to the efficacy of OSB, making it difficult to determine the efficacy makers underlying the varied efficacies of OSB. In our work, a new strategy was exploited and applied for investigating efficacy markers of OSB consisting of phytochemical analysis, in vivo absorption analysis, bioactive compound screening, and bioactive compound quantification. Using liquid chromatography coupled with mass spectrometry, a total of 34 phytochemical components were detected in the OSB extract. Subsequently, based on in vivo absorption analysis, 14 phytochemical constituents in the form of prototypes were retained as potential bioactive compounds. Ten diseases were selected as the potential indications of OSB based on previous reports, and then the overall interaction between compounds, action targets, action pathways, and diseases was revealed based on bioinformatic analysis. After refining key pathways and targets, the interaction reversing from pathways, targets to constituents was deduced, and the core constituents, including tanshinone IIA, sinensetin, salvianolic acid B, rosmarinic acid, and salvigenin, were screened out as the efficacy markers of OSB. Finally, the contents of these five constituents were quantified in three different batches of OSB extracts. Among them, the content of salvianolic acid B was the highest while the content of tanshinone IIA was the lowest. Our work could provide a promising direction for future research on the quality control and pharmacological mechanism of OSB.

The role of the gut microbiome has been a hot topic in recent years. One aim of this review is to shed light on the crosstalk between sex hormones and the gut microbiome. Researchers have observed a sex bias of the composition of the gut microbiome in mice and have proved that sex differences influence the composition of the gut microbiome, although the influence is usually obscured by genetic variations. Via cell studies, animal studies and some observational studies in humans, researchers have confirmed that the gut microbiome can be shaped by the hormonal environment. On other hand, some theories suggest that the gut microbiota regulates the levels of sex hormones via interactions among its metabolites, the immune system, chronic inflammation and some nerve-endocrine axes, such as the gut-brain axis. In addition, bidirectional interactions between the microbiome and the hormonal system have also been observed, and the mechanisms of these interactions are being explored. We further describe the role of the gut microbiome in sex hormone-related diseases, such as ovarian cancer, postmenopausal osteoporosis (PMOP), polycystic ovary syndrome and type 1 diabetes. Among these diseases, PMOP is described in detail. Finally, we discuss the treatments of these diseases and the application prospects of microbial intervention.

Microplastics (MPs) are ubiquitous in the aquatic environment and can be frequently ingested by zooplankton, leading to various effects. Brine shrimp (Artemia parthenogenetica) has an important role in the energy flow through trophic levels in different seawater systems. In this work, the influence of polyethylene (PE) and polystyrene (PS) MPs on the growth of brine shrimp and corresponding changes of gut microbiota were investigated. Our results showed that the MPs remarkably reduced the growth rate of brine shrimp, and the two types of MPs have different impacts. The average body length of brine shrimps was reduced by 17.92 and 14.95% in the PE group and PS group, respectively. MPs are mainly found in the intestine, and their exposure evidently affects the gut microbiota. By using 16S rRNA gene high-throughput sequencing, 32 phyla of bacteria were detected in the intestine, and the microbiome consisted mainly of Proteobacteria, Firmicutes, and Actinobacteria. MPs’ exposure significantly increased the gut microbial diversity. For the PE group, the proportion of Actinobacteria and Bacteroidetes increased by 45.26 and 2.73%, respectively. For the PS group, it was 54.95 and 1.27%, respectively. According to the analysis on genus level, the proportions of Ponticoccus, Seohaeicola, Polycyclovorans, and Methylophaga decreased by 46.38, 1.24, 1.07, and 2.66%, respectively, for the PE group and 57.87, 1.43, 0.88, and 2.24%, respectively, for the PS group. In contrast, the proportions of Stappia, Microbacterium, and Dietzia increased by 1.12, 23.27, and 11.59%, respectively, for the PE group, and 1.09, 3.79, and 42.96%, respectively, for the PS group. These experimental results demonstrated that the ingestion of MPs by brine shrimp can alter the composition of the gut microbiota and lead to a slow growth rate. This study provides preliminary data support for understanding the biotoxicity of MPs to invertebrate zooplankton and is conducive to the further risk assessment of MP exposure.

Objective: To investigate the genetic characteristics and transcriptional regulation of the SCN5A gene of Brugada syndrome (BrS) patients in China.Methods: Using PubMed, Medline, China National Knowledge Internet (CNKI), and Wanfang Database, Chinese patients with BrS who underwent SCN5A gene testing were studied.Results: A total of 27 suitable studies involving Chinese BrS patients who underwent the SCN5A gene test were included. A total of 55 SCN5A gene mutations/variations were reported in Chinese BrS patients, including 10 from southern China and 45 from northern China. Mutations/variations of BrS patients from southern China mostly occurred in the regions of the α-subunit of Nav1.5, including DIII (Domain III), DIV, DIII-DIV, C-terminus regions, and the 3'UTR region. Furthermore, we analyzed the post-transcriptional modifications (PTMs) throughout the Nav1.5 protein encoded by SCN5A and found that the PTM changes happened in 72.7% of BrS patients from southern China and 26.7% from northern China.Conclusions: SCN5A mutations/variations of BrS patients in southern China mostly occurred in the DIII-DIV to C-terminus region and the 3'-UTR region of the SCN5A gene, different from northern China. PTM changes were consistent with the mutation/variation distribution of SCN5A, which might be involved in the regulation of the pathogenesis of BrS patients.

Human adenoviruses (HAdVs) type 7 can cause severe respiratory disease. During the period between December 2018 and August 2019, HAdV-7 infection was identified in 129 patients in Wuhan Children’s Hospital, Hubei Province, China. Samples were collected from hospitalized children and metagenomic sequencing was applied to detect the HAdV infections. Hemophagocytic lymphohistiocystosis (HLH) related to HAdV infections was observed in some patients clinically and patients were divided into two groups based on this to test the differences among clinical indicators. Genome variation, in silico restriction endonuclease analysis (REA), and phylogenetic analyses were carried out to show the genome characterization of HAdV-7 in this study. It was found that many indicators, such as all blood routine indicators, in patients of the HLH group showed significant levels. In this study, REA revealed that HAdV-7 might belong to genome 7d and genome variation analysis displayed the stable genome of HAdV. HAdV-7 is an ongoing threat to the public, and global surveillance should be established.

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

The clathrin-associated protein adaptin-2 (AP2) is a distinctive member of the hetero-tetrameric clathrin adaptor complex family. It plays a crucial role in many intracellular vesicle transport pathways. The hydroxyapatite (HAp) nanoparticles can enter cells through clathrin-dependent endocytosis, induce apoptosis, and ultimately inhibit tumor metastasis. Exploring the micro process of the binding of AP2 and HAp is of great significance for understanding the molecular mechanism of HAp’s anti-cancer ability. In this work, we used molecular modeling to study the binding of spherical, rod-shaped, and needle-shaped HAps toward AP2 protein at the atomic level and found that different nanoparticles’ morphology can determine their binding specificity through electrostatic interactions. Our results show that globular HAp significantly changes AP2 protein conformation, while needle-shaped HAP has more substantial binding energy with AP2. Therefore, this work offers a microscopic picture for cargo recognition in clathrin-mediated endocytosis, clarifies the design principles and possible mechanisms of high-efficiency nano-biomaterials, and provides a basis for their potential anti-tumor therapeutic effects.

Emerging evidence supports that oral microbiota are associated with health and diseases of the esophagus. How oral microbiota change in Chinese patients with esophageal cancer (EC) is unknown, neither is their biomarker role. For an objective to understand alterations of oral microbiota in Chinese EC patients, we conducted a case-control study including saliva samples from 39 EC patients and 51 healthy volunteers. 16S rDNA genes of V3-V4 variable regions were sequenced to identify taxon. Relationship between oral flora and disease was analyzed according to alpha diversity and beta diversity. Resultantly, the Shannon index (p = 0.2) and the Simpson diversity index (p = 0.071) were not significant between the two groups. Yet we still found several species different in abundance between the two groups. For the EC group, the most significantly increased taxa were Firmicutes, Negativicutes, Selenomonadales, Prevotellaceae, Prevotella, and Veillonellaceae, while the most significantly decreased taxa were Proteobacteria, Betaproteobacteria, Neisseriales, Neisseriaceae, and Neisseria. In conclusion, there are significant alterations in abundance of some oral microbiomes between the EC patients and the healthy controls in the studied Chinese participants, which may be meaningful for predicting the development of EC, and the potential roles of these species in EC development deserve further studies.

The full-length single-molecular sequencing and short reads Illumina sequencing were combined to generate the transcripts of adzuki bean with high-quality. A total of 17,636 loci and 60,454 transcripts were detected in this study. To characterize the drought-responsive genes during seed germination in adzuki bean, two varieties, i.e., tolerant and sensitive to drought stress, were selected to conduct analysis of alternative splicing dynamics (AS) and differentially expressed genes (DEGs) by combining the newly assembled draft genome and public adzuki bean reference genome. AS analysis indicated that both the two varieties underwent a little more AS events under control conditions than under drought stress. Among the AS events, IR (intron retention) predominately accounted for 34.3%, whereas AD (alternative donor site) was the least frequent with 15.8%. Meanwhile, 562 long non-coding RNAs, 409 fusion genes and 1208 transcription factors were identified. Moreover, a total of 5,337 DEGs were identified in comparison of the two varieties with drought or control treatments. Notably, 82 DEGs were discovered in the two varieties under drought stress, which might be the candidate in regulation of seed germination to answer for different drought tolerance. The DEGs encoded proteins involved in primary or second metabolism, plant hormone signal transduction, transcript or translation processes, ubiquitin proteasome system, transcription factor, transporters, and so on. The results facilitate to increase the knowledge about the mechanism of drought tolerance during crop seed germination, and provide reference for the breeding of drought-tolerant adzuki bean.

Background and AimReflux Esophagitis (RE) is caused by a variety of factors including anatomical and functional alterations involved in the pathogenesis. Oral microbiota is influenced by many factors such as heredity, nutrition, environments and host conditions, but little is known about relationship between oral microbiota and RE. The aim of this study was to explore whether the oral microbiota is changed in patients with RE.MethodsTo clarify this correlation, fresh saliva samples from all subjects were collected and then oral microorganism diversity was analysed in 55 patients with RE and 51 controls via hypervariable tag sequencing and analyzing the V3–V4 region of the 16S rDNA gene.ResultsThere was no difference found in oral microbial diversity between RE patients and healthy controls by Shannon diversity index (p=0.60) and Simpson diversity index (p= 0.38). The abundance of Proteobacteria was lower, but Bacteroidetes was higher in patients with RE at the phylum level. At the genus level the abundances of Prevotella, Veillonella, Megasphaera, Peptostreptococcus, Atopobium, Oribacterium, Eubacterium, and Lachnoanaerobaculum were increased, while Neisseria, Streptococcus, Rothia, Granulicatella, Gemella, Aggregatibacter, Treponema, Campylobacter, Filifactor, Corynebacterium, and Lactivibrio were decreased in RE patients than the controls.ConclusionsOur study suggested oral microbial dysbiosis in patients with RE, and identified bacterial species with potential biomarker significance. Further studies are required to understand role of oral microbial dysbiosis in the pathogenesis of RE.

Stomatal density (D) and size (S) are an important adaptive mechanism for abiotic stress tolerance and photosynthesis capacity in rice. However, the genetic base of rice stomata-related traits still remains unclear. We identified quantitative trait loci (QTLs) associated with D and S on abaxial and adaxial leaf surfaces using genome-wide association analysis with 451 diverse accessions in two environments. D and S showed significant differences between indica (xian) and japonica (geng) accessions and significantly negative phenotypic correlations. A total of 64 QTLs influencing eight stomata-related traits were identified using 2,936,762 high-quality single nucleotide polymorphism markers. Twelve QTLs were consistently detected for the same traits in nine chromosomal regions in both environments. In addition, 12 QTL clusters were simultaneously detected for the same stomata-related traits on abaxial and adaxial leaf surfaces in the same environment, probably explaining the genetic bases of significant correlations of the stomata-related traits. We screened 64 candidate genes for the nine consistent QTL regions using haplotype analysis. Among them, LOC_Os01g66120 for qDada1, OsSPCH2 (LOC_Os02g15760) for qDada2.1 and qDaba2.1, LOC_Os02g34320 for qSada2.2, OsFLP (LOC_Os07g43420) or LOC_Os07g43530 for qSaba7.1, and LOC_Os07g41200 for qWada7 and qWaba7 were considered as the most likely candidate genes based on functional annotations. The results systematically dissected the genetic base of stomata-related traits and provide useful information for improving rice yield potential via increasing abiotic stress tolerance and photosynthesis capacity under stressed and non-stressed conditions through deploying the favorable alleles underlying stomata-related traits by marker-assisted selection.

A healthy gut is very important for young animal development. The rumen of ruminants expands in size with the colonization of microbiota by 2 months of age. This process is promoted by alfalfa intervention. To elucidate the mechanism of this promotion, we performed transcriptomic analyses using a cohort of 23 lambs to evaluate the effects of starter diets plus alfalfa on the development of the rumen wall from the pre- to the postweaning period. The quantitative PCR analyses were used to validate selected genes that were differentially expressed in the transcriptome mapping. We found that several metabolic processes associated with rumen tissue development were affected by solid feed intake, with genes linked to the calcium signaling transduction pathway and the metabolism of pteridine-containing compounds and homocysteine metabolic process being upregulated in the group with alfalfa intervention. The results suggest that the pteridine-containing compounds and calcium signaling are targets for precise regulation of rumen development.

IntroductionPost-neurosurgical bacterial meningitis (PNBM) is a serious complication for patients who receive neurosurgical treatment, but the diagnosis is difficult given the complicated microenvironment orchestrated by sterile brain injury and pathogenic infection. In this study, we explored potential diagnostic biomarkers and immunological features using a proteomics platform.MethodsA total of 31 patients with aneurysmal subarachnoid hemorrhage (aSAH) who received neurosurgical treatment were recruited for this study. Among them, 15 were diagnosed with PNBM. The remaining 16 patients were categorized into the non-PNBM group. Proteomics analysis of the cerebrospinal fluid (CSF) was conducted on the Olink platform, which contained 92 immunity-related molecules.ResultsWe found that the expressions of 27 CSF proteins were significantly different between the PNBM and non-PNBM groups. Of those 27 proteins, 15 proteins were upregulated and 12 were downregulated in the CSF of the PNBM group. The receiver operating characteristic curve analysis indicated that three proteins (pleiotrophin, CD27, and angiopoietin 1) had high diagnostic accuracy for PNBM. Furthermore, we also performed bioinformatics analysis to explore potential pathways and the subcellular localization of the proteins.ConclusionIn summary, we found a cohort of immunity-related molecules that can serve as potential diagnostic biomarkers for PNBM in patients with aSAH. These molecules also provide an immunological profile of PNBM.

The sinoatrial node (SAN) and subsidiary pacemakers in the cardiac conduction system generate spontaneous electrical activity which is indispensable for electrical and therefore contractile function of the heart. The hyperpolarisation-activated cyclic nucleotide-gated channel HCN4 is responsible for genesis of the pacemaker “funny” current during diastolic depolarisation. S-palmitoylation, the reversible conjugation of the fatty acid palmitate to protein cysteine sulfhydryls, regulates the activity of key cardiac Na+ and Ca2+ handling proteins, influencing their membrane microdomain localisation and function. We investigated HCN4 palmitoylation and its functional consequences in engineered human embryonic kidney 293T cells as well as endogenous HCN4 in neonatal rat ventricular myocytes. HCN4 was palmitoylated in all experimental systems investigated. We mapped the HCN4 palmitoylation sites to a pair of cysteines in the HCN4 intracellular amino terminus. A double cysteine-to-alanine mutation CC93A/179AA of full length HCN4 caused a ∼67% reduction in palmitoylation in comparison to wild type HCN4. We used whole-cell patch clamp to evaluate HCN4 current (IHCN4) in stably transfected 293T cells. Removal of the two N-terminal palmitoylation sites did not significantly alter half maximal activation voltage of IHCN4 or the activation slope factor. IHCN4 was significantly larger in cells expressing wild type compared to non-palmitoylated HCN4 across a range of voltages. Phylogenetic analysis revealed that although cysteine 93 is widely conserved across all classes of HCN4 vertebrate orthologs, conservation of cysteine 179 is restricted to placental mammals. Collectively, we provide evidence for functional regulation of HCN4 via palmitoylation of its amino terminus in vertebrates. We suggest that by recruiting the amino terminus to the bilayer, palmitoylation enhances the magnitude of HCN4-mediated currents, but does not significantly affect the kinetics.

The discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. There is a limited access to liver transplantation, as a result, it is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. However, there are still many unknown risks associated with the use of ECD, among which preservation before liver transplantation is important in determining whether patients would experience complications survive after liver transplantation. In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion (NMP) may reduce preservation injury, improve graft viability, and potentially ex vivo assessment of graft viability before transplantation. Data seem to suggest that NMP can enhance the preservation of liver transplantation to some extent and improve the early outcome after transplantation. In this review, we provided an overview of NMP and its application in ex vivo liver preservation and pre-transplantation, and we summarized the data from current clinical trials of normothermic liver perfusion.

Immunoglobulin A (IgA) is the most abundant immunoglobulin synthesized in the human body. It has the highest concentration in the mucosa and is second only to IgG in serum. IgA plays an important role in mucosal immunity, and is the predominant antibody used to protect the mucosal surface from pathogens invasion and to maintain the homeostasis of intestinal flora. Moreover, The binding IgA to the FcαRI (Fc alpha Receptor I) in soluble or aggregated form can mediate anti- or pro- inflammatory responses, respectively. IgA is also known as one of the most heavily glycosylated antibodies among human immunoglobulins. The glycosylation of IgA has been shown to have a significant effect on its immune function. Variation in the glycoform of IgA is often the main characteration of autoimmune diseases such as IgA nephropathy (IgAN), IgA vasculitis (IgAV), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). However, compared with the confirmed glycosylation function of IgG, the pathogenic mechanism of IgA glycosylation involved in related diseases is still unclear. This paper mainly summarizes the recent reports on IgA’s glycan structure, its function, its relationship with the occurrence and development of diseases, and the potential application of glycoengineered IgA in clinical antibody therapeutics, in order to provide a potential reference for future research in this field.

The explosive growth of data centers, cloud computing and various smart devices is limited by the current state of microelectronics, both in terms of speed and heat generation. Benefiting from the large bandwidth, promising low power consumption and passive calculation capability, experts believe that the integrated photonicsbased signal processing and transmission technologies can break the bottleneck of microelectronics technology. In recent years, integrated photonics has become increasingly reliable and access to the advanced fabrication process has been offered by various foundries. In this paper, we review our recent works on the integrated optical signal processing system. We study three different kinds of on-chip signal processors and use these devices to build microsystems for the fields of microwave photonics, optical communications and spectrum sensing. The microwave photonics front receiver was demonstrated with a signal processing range of a full-band (L-band to W-band). A fully integrated microwave photonics transceiver without the on-chip laser was realized on silicon photonics covering the signal frequency of up 10 GHz. An all-optical orthogonal frequency division multiplexing (OFDM) demultiplier was also demonstrated and used for an OFDM communication system with the rate of 64 Gbps. Finally, we show our work on the monolithic integrated spectrometer with a high resolution of about 20 pm at the central wavelength of 1550 nm. These proposed on-chip signal processing systems potential applications in the fields of radar, 5G wireless communication, wearable devices and optical access networks. [ABSTRACT FROM AUTHOR]

Although immunotherapy has paved a new avenue for cancer treatment, inadequate immune response often executes suboptimal therapeutic effects. In general, an effective immune response undergoes presentation of antigen by antigen-presenting cells, proliferation and differentiation of lymphocytes, and attack of cancer cells by cytotoxic T lymphocytes (CTLs). The antigen self-presentation and immunosuppression reversal (ASPIRE) nanovaccine derived from dendritic cells provides a simplified and immune deregulated procedure for immunotherapy profiting from its orientable peculiarity. By integrating major histocompatibility complex class I (MHC-I) molecules into present specific epitopes and co-delivering anti-PD-1 antibody and B7 costimulatory molecules through the programmed biomimetic synthesis, the ASPIRE nanovaccine demonstrates a milestone in personalized cancer immunotherapy.

Drug resistance is the most significant causes of cancer chemotherapy failure. Various mechanisms of drug resistance include tumor heterogeneity, tumor microenvironment, changes at cellular levels, genetic factors, and other mechanisms. In recent years, more attention has been paid to tumor resistance mechanisms and countermeasures. Nanomedicine is an emerging treatment platform, focusing on alternative drug delivery and improved therapeutic effectiveness while reducing side effects on normal tissues. Here, we reviewed the principal forms of drug resistance and the new possibilities that nanomaterials offer for overcoming these therapeutic barriers. Novel nanomaterials based on tumor types are an excellent modality to equalize drug resistance that enables gain more rational and flexible drug selectivity for individual patient treatment. With the emergence of advanced designs and alternative drug delivery strategies with different nanomaterials, overcome of multidrug resistance shows promising and opens new horizons for cancer therapy. This review discussed different mechanisms of drug resistance and recent advances in nanotechnology-based therapeutic strategies to improve the sensitivity and effectiveness of chemotherapeutic drugs, aiming to show the advantages of nanomaterials in overcoming of drug resistance for tumor chemotherapy, which could accelerate the development of personalized medicine.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the recent global COVID-19 outbreak, which led to a public health emergency. Entry of SARS-CoV-2 into human cells is dependent on the SARS-CoV receptor, angiotensin converting enzyme 2 (ACE2) receptor, and cathepsin. Cathepsin degrades the spike protein (S protein), which results in the entry of viral nucleic acid into the human host cell.MethodsWe explored the susceptibility of the central nervous system (CNS) to SARS-CoV-2 infection using single-cell transcriptome analysis of glioblastoma.ResultsThe results showed that ACE2 expression is relatively high in endothelial cells (ECs), bone marrow mesenchymal stem cells (BMSCs), and neural precursor cells (NPCs). Cathepsin B (Cat B) and cathepsin (Cat L) were also strongly expressed in various cell clusters within the glioblastoma microenvironment. Immunofluorescence staining of glioma and normal brain tissue chips further confirmed that ACE2 expression co-localized with CD31, CD73, and nestin, which confirmed the susceptibility to SARS-CoV-2 of nervous system cells, including ECs, BMSCs, and NPCs, from clinical specimens.ConclusionsThese findings reveal the mechanism of SARS-CoV-2 neural invasion and suggest that special attention should be paid to SARS-CoV-2–infected patients with neural symptoms, especially those who suffered a glioma.

Statins have been reported to suppress CD40 expression and nuclear factor (NF)-κB activation, which are both up-regulated in the intestines following traumatic brain injury (TBI)-induced intestinal injury. In this study, we aimed to investigate the effects of the statin rosuvastatin on post-TBI jejunal injury in rats, focusing on potential mechanisms involving the CD40/NF-κB signaling pathway. The jejunal CD40 expression was determined by western blotting. The DNA-binding activity of NF-κB was assessed by electrophoretic mobility shift assays (EMSAs). The tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were assessed by enzyme-linked immunosorbent assays (ELISAs). The severity of the jejunal mucosal injury was assessed by hematoxylin and eosin (HE) staining and histopathological evaluation. We found that the post-TBI upregulation of both CD40 expression and NF-κB activity in the jejunal tissues were significantly inhibited by rosuvastatin, while the post-TBI expression of TNF-α and IL-1β was significantly suppressed by rosuvastatin. In addition, rosuvastatin significantly ameliorated TBI-induced effects on the villus height, crypt depth, and villous surface area. Rosuvastatin suppressed TBI-induced intestinal injury in rats, which may be associated with the blockade of the CD40/NF-κB pathway.

Background: Intracranial vertebral artery dissection aneurysms (VADAs) may cause acute ischemia or hemorrhage, in which case urgent endovascular treatment will be needed. Although the majority of patients obtain a good functional outcome after surgery, a surprising finding has been a poor quality of life (QOL) in follow-up. The purpose of this study was to evaluate clinical efficacy in reconstructive endovascular therapy for acute intracranial VADAs and to analyze the factors contributing to subsequent QOL.Methods: In this prospective study, 33 consecutive VADA patients with subarachnoid hemorrhage were recruited for comparison with 37 VADA patients with posterior circulation cerebral ischemia. All VADA patients were treated using a reconstructive strategy. Clinical, radiological, neurological, and cognitive data, as well as QOL, were assessed at admission and 6 months after surgery. Stoke Specific Quality of Life (SS-QOL) was evaluated for patients with good functional outcome [modified Ranking Scale (mRS) scoring 0-2] for subgroup analysis. Predictors for QOL at follow-up were analyzed by regression model.Results: Immediate angiography after surgery showed complete VADA obliteration in 57 (81.4%) patients and partial obliteration in 13 (18.6%) patients. Three (4.3%) cases suffered from perioperative complications, comprising two cases of stent thrombosis in the hemorrhagic group and one case of posterior inferior cerebellar artery occlusion in the ischemic group. Twenty-five (75.8%) patients in the hemorrhagic group and 30 (81.1%) patients in the ischemic group had a favorable outcome (mRS scoring 0-2) at 6-month follow-up. Follow-up angiography displayed that one case of recurrence occurred separately in both groups. Fifteen of the 33 hemorrhagic patients (45.5%) and 19 of the 37 ischemic patients (51.4%) rated QOL at follow-up as bad (SS-QOL score ≤ 3.9) despite a good functional outcome. Severity of neurological disorder and impaired neurocognition at baseline in VADA patients are proved to be independent predictors for the decline of QOL according to regression analysis.Conclusion: Reconstructive endovascular therapy for acute intracranial VADAs is a safe and effective method with a low complication rate. VADAs lead to impaired QOL at 6-month follow-up, which is attributable to multiple factors. This study demonstrated that neurological and cognitive status at baseline is of significant importance for QOL after VADAs.