Search

Abstract Background The clinical presentation of extrapulmonary tuberculosis (EPTB) is atypical and it is easily confused with other diseases such as common infections, making prompt diagnosis a great challenge. This study aimed to evaluate the accuracy of targeted nanopore sequencing (TNS) in the diagnosis of EPTB. The diagnostic accuracy of TNS using different types of extrapulmonary specimens was also evaluated. Methods We reviewed the clinical data of patients with suspected EPTB for whom TNS was conducted and who were hospitalized at our center. The true positive, false positive, false negative, and true negative values were determined. Indices of diagnostic accuracy were computed, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) for TNS and acid-fast bacilli (AFB) culture, and compared with those from clinical diagnosis. Results 149 patients were included in the analysis. The overall sensitivity, specificity, PPV, NPV, and AUC of TNS for the diagnosis of EPTB were 86.4%, 87.5%, 97.3%, 55.3%, and 0.87, respectively. For diagnosis by AFB culture, these values were 25.6%, 100.0%, 100.0%, 20.5%, and 0.63, respectively. The most common specimens used were lymph node tissue, cerebrospinal fluid, pleural effusion, and pleural tissue. The diagnostic accuracy of TNS using all types of extrapulmonary specimens was good. Conclusions TNS demonstrates good diagnostic accuracy in the rapid diagnosis of EPTB and this was true across different types of extrapulmonary specimens.

Objectives: To investigate the role of the intestinal flora and metabolites in the development of hyperuricemic renal injury in chronic kidney disease (CKD).Methods: Unilaterally nephrectomized mice were fed with adenine and potassium oxonate for 9 weeks. HE staining combined with plasma biochemical indicators was used to evaluate renal pathological and functional changes. We conducted 16S rRNA sequencing and untargeted metabolomics on feces and plasma samples to reveale changes in intestinal microbiota and metabolites.Result: Our analysis revealed significant differences in 15 bacterial genera, with 7 being upregulated and 8 being downregulated. Furthermore, metabolomic analysis revealed changes in the distribution of amino acid and biotin metabolites in basic metabolic pathways in both feces and serum. Specifically, differentially abundant metabolites in feces were associated primarily with histidine metabolism; the biosynthesis of phenylalanine, tyrosine, and tryptophan; and tyrosine metabolism. In plasma, the differentially abundant metabolites were involved in multiple metabolic pathways, including aminoacyl-tRNA biosynthesis; glycine, serine, and threonine amino acid metabolism; valine, leucine, and isoleucine biosynthesis; tyrosine biosynthesis and metabolism; biotin metabolism; and taurine and hypotaurine metabolism. Furthermore, correlation analysis revealed that Akkermansia, UCG-005, Lachnospiraceae_NK4A136_group, Lactococcus, and Butymonas were associated with various differentially abundant metabolites as well as renal function, oxidative stress, and mitophagy. The changes in the intestinal flora observed in hyperuricemia may lead to imbalances in amino acid and biotin metabolism in both the intestine and host, ultimately affecting oxidative stress and mitophagy in mice and accelerating the progression of CKD.Conclusion: Our findings provide insights into a potential pathogenic mechanism by which hyperuricemia exacerbates renal injury in mice with renal insufficiency. Understanding these pathways may offer new therapeutic strategies for managing hyperuricemic renal injury in CKD patients.

Cyanobacteria have great potential in CO2-based bio-manufacturing and synthetic biological studies. The filamentous cyanobacterium, Leptolyngbya sp. strain BL0902, is comparable to Arthrospira (Spirulina) platensis in commercial-scale cultivation while proving to be more genetically tractable. Here, we report the analyses of the whole genome sequence, gene inactivation/overexpression in the chromosome and deletion of non-essential chromosomal regions in this strain. The genetic manipulations were performed via homologous double recombination using either an antibiotic resistance marker or the CRISPR/Cpf1 editing system for positive selection. A desD-overexpressing strain produced γ-linolenic acid in an open raceway photobioreactor with the productivity of 0.36 g·m−2·d−1. Deletion mutants of predicted patX and hetR, two genes with opposite effects on cell differentiation in heterocyst-forming species, were used to demonstrate an analysis of the relationship between regulatory genes in the non-heterocystous species. Furthermore, a 50.8-kb chromosomal region was successfully deleted in BL0902 with the Cpf1 system. These results supported that BL0902 can be developed into a stable photosynthetic cell factory for synthesizing high value-added products, or used as a model strain for investigating the functions of genes that are unique to filamentous cyanobacteria, and could be systematically modified into a genome-streamlined chassis for synthetic biological purposes.

Abstract The Myoviridae cyanophage A-1(L) specifically infects the model cyanobacteria Anabaena sp. PCC 7120. Following our recent report on the capsid structure of A-1(L), here we present the high-resolution cryo-EM structure of its intact tail machine including the neck, tail and attached fibers. Besides the dodecameric portal, the neck contains a canonical hexamer connected to a unique pentadecamer that anchors five extended bead-chain-like neck fibers. The 1045-Å-long contractile tail is composed of a helical bundle of tape measure proteins surrounded by a layer of tube proteins and a layer of sheath proteins, ended with a five-component baseplate. The six long and six short tail fibers are folded back pairwise, each with one end anchoring to the baseplate and the distal end pointing to the capsid. Structural analysis combined with biochemical assays further enable us to identify the dual hydrolytic activities of the baseplate hub, in addition to two host receptor binding domains in the tail fibers. Moreover, the structure of the intact A-1(L) also helps us to reannotate its genome. These findings will facilitate the application of A-1(L) as a chassis cyanophage in synthetic biology.

Due to channel noise and random atmospheric turbulence, retrieved satellite images are always distorted and degraded and so require further restoration before use in various applications. The latest quaternion-based weighted nuclear norm minimization (QWNNM) model, which utilizes the idea of low-rank matrix approximation and the quaternion representation of multi-channel satellite images, can achieve image restoration and enhancement. However, the QWNNM model ignores the impact of noise on similarity measurement, lacks the utilization of residual image information, and fixes the number of iterations. In order to address these drawbacks, we propose three adaptive strategies: adaptive noise-resilient block matching, adaptive feedback of residual image, and adaptive iteration stopping criterion in a new adaptive QWNNM model. Both simulation experiments with known noise/blurring and real environment experiments with unknown noise/blurring demonstrated that the effectiveness of adaptive QWNNM models outperformed the original QWNNM model and other state-of-the-art satellite image restoration models in very different technique approaches.

Conventional oxidation processes for alkyl aromatics to ketones employ oxidants that tend to generate harmful byproducts and cause severe equipment corrosion, ultimately creating critical environmental problems. Thus, in this study, a practical, efficient, and green method was developed for the synthesis of aromatic ketones by applying a bis(2-butoxyethyl) ether/O2 system under external catalyst-, additive-, and base-free conditions. This O2-mediated oxidation system can tolerate various functional groups and is suitable for large-scale synthesis. Diverse target ketones were prepared under clean conditions in moderate-to-high yields. The late-stage functionalization of drug derivatives with the corresponding ketones and one-pot sequential chemical conversions to ketone downstream products further broaden the application prospects of this approach.

Background Non-small cell lung cancer (NSCLC) has a poor prognosis. Transvascular intervention is an important approach for treating NSCLC. Drug-eluting bead bronchial artery chemoembolisation (DEB-BACE) is a technique of using DEBs loaded with chemotherapeutic drugs for BACE. This study aims to conduct a meta-analysis to comprehensively assess the effectiveness and safety of DEB-BACE in treating NSCLC and investigate a novel therapeutic strategy for NSCLC.Methods and analysis Wanfang, China National Knowledge Infrastructure, Medline (via PubMed), Cochrane Library, Scopus and Embase databases will be searched in November 2024. A meta-analysis will be conducted to assess the effectiveness and safety of DEB-BACE in the treatment of NSCLC. The following keywords will be applied: “Carcinoma, Non-Small-Cell Lung”, “Non-Small Cell Lung Cancer”, “Drug-Eluting Bead Bronchial Arterial Chemoembolization” and “drug-eluting beads”. Reports in Chinese or English comparing the efficacy of DEB-BACE with other NSCLC treatment options will be included. Case reports, single-arm studies, conference papers, abstracts without full text and reports published in languages other than English and Chinese will not be considered. The Cochrane Handbook for Systematic Reviews of Interventions will be used to independently assess the risk of bias for each included study. In case of significant heterogeneity between studies, possible sources of heterogeneity will be explored through subgroup and sensitivity analysis. For the statistical analysis of the data, RevMan V.5.3 will be used.Ethics and dissemination This meta-analysis will seek publication in a peer-reviewed journal on completion. Ethical approval is not required for this study as it is a database-based study.PROSPERO registration number CRD42023411392.

Chinese herbs are a huge treasure trove of natural products and an important source of many active molecules. The theory of traditional Chinese medicine compatibility (TCMC) is widely applied in clinical practice, but its mechanism is still ambiguous. This study aims to open a new window for this predicament by studying the interaction between the main active ingredients from a drug pair. Carrier-free assembly of natural products improves the shortcomings of traditional nanodelivery systems and opens a new path for the development of new nanomaterials. The drug pair “Pueraria and Hedyotis diffusa” has been commonly used in clinical practice, with a predominant therapeutic effect. This study is devoted to the study of the binary small molecule co-assembly of the main active molecules from the drug pair. In this study, we introduce a carrier-free composite gel, formed by the co-assembly of puerarin (PUE) and deacetylasperulosidic acid (DAA) via non-covalent bonds including π–π packing, intermolecular hydrogen bonding, and C=O π interactions. With a strain point 7-fold higher than that of P gel, the P − D gel exhibited favorable rheological properties. The survival rate of SW1990 cells in the P − D group was only 21.39% when the concentration of administration reached 200 μM. It thus demonstrated activity in inhibiting SW1990 cells’ survival, suggesting potential in combating pancreatic cancer. Furthermore, this research offers a valuable concept for enhancing the mechanical properties and bioactivity of hydrogel materials through the utilization of a multi-component natural small molecule co-assembly approach. More importantly, this provides new ideas and methods for the treatment of pancreatic cancer and the analysis of traditional Chinese medicine compatibility theory.

Background: This prespecified subgroup analysis of the FIDELIO-DKD trial aimed to evaluate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in China. Methods: 372 participants were recruited from 67 centers in China and randomized 1:1 to oral finerenone or placebo with standard therapy for T2DM. The primary composite outcome included kidney failure, sustained decrease of estimated glomerular filtration rate ≥40% from baseline over at least 4 weeks, or renal death. The key secondary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Results: After a median follow-up of 30 months, the finerenone group showed a relative risk reduction (RRR) of 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI], 0.39–0.88; p = 0.009) for the primary composite outcome compared with placebo, consistent across its components with treatment benefits with finerenone. Based on an absolute between-group difference of 12.2% after 30 months, the number of patients who needed to be treated with finerenone to prevent one primary outcome event was eight (95% CI: 4–84). For the key secondary composite outcome, the finerenone group showed a RRR of 25% (HR = 0.75, 95% CI, 0.38–1.48; p = 0.408). Adverse events were similar between the two groups. The effects of finerenone on blood pressure were modest. No gynecomastia events were reported in the study. Hyperkalemia leading to discontinuation occurred in eight (4.3%) and two (1.1%) participants in the finerenone and control groups, respectively. The incidence of acute kidney injury was comparable between the two groups (1.6% vs. 1.6%). Conclusions: Finerenone resulted in lower risks of CKD progression than placebo and a balanced safety profile in Chinese patients with CKD and T2DM.

The intestinal microbiota comprises approximately 1013–1014 species of bacteria and plays a crucial role in host metabolism by facilitating various chemical reactions. Secondary bile acids (BAs) are key metabolites produced by gut microbiota.Initially synthesized by the liver, BA undergoes structural modifications through the activity of various intestinal microbiota enzymes, including eukaryotic, bacterial, and archaeal enzymes. These modified BA then activate specific receptors that regulate multiple metabolic pathways in the host, such as lipid and glucose metabolism, energy balance, inflammatory response, and cell proliferation and death. Recent attention has been given to intestinal flora disorders in diabetic kidney disease (DKD), where activation of BA receptors has shown promise in alleviating diabetic kidney damage by modulating renal lipid metabolism and mitochondrial production. Imbalances in the intestinal flora can influence the progression of DKD through the regulation of bile acid and its receptor pathways. This review aims to propose a mechanism involving the gut-BA-diabetes and nephropathy axes with the goal of optimizing new strategies for treating DKD.

Noni fruits have gained considerable popularity as dietary supplements. However, the major constituents, the laxative activity, and the toxicity of Noni fruit remains still unknown. The purpose of the present study was, therefore, to analyze the constituents of methanol extract of Noni fruit by UPLC-MS, and further evaluate laxative activity and safety aspects of this Noni fruit-derived products in mice. UPLC-MS analysis identified eleven major constituents from this Noni fruit extract. Administration of this extract obviously shortened the time of first fecal excrement, significantly increased the total number and the weight of stools, and remarkably restored the intestinal transit to normal level in the constipated mice, with low toxicity to liver and kidney, and meanwhile, the abundance, composition, and function of gut microbiota remained homeostasis. These results revealed the laxative activity of the methanol extract of Noni fruit with low toxicity and no influence on gut microbiota.

Abstract Early diagnosis of gastrointestinal malignancies in patients with acute coronary syndrome (ACS) is often delayed. The present study aims to demonstrate the value of [68Ga]Ga‐FAPI‐04 PET imaging in ACS with suspected gastrointestinal malignancies. Twelve ACS patients with suspected gastrointestinal malignancies were enrolled, including ST‐elevation myocardial infarction (STEMI) (n = 5), non‐ST‐elevation myocardial infarction (NSTEMI) (n = 5), and unstable angina (UA) (n = 2). All patients underwent coronary angiography (CAG) and [68Ga]Ga‐FAPI‐04 PET/MR or PET/CT within 1 week. All five STEMI and five NSTEMI patients had high [68Ga]Ga‐FAPI‐04 uptake in the injured myocardium compared to remote area (TBR: 2.10 ± 0.72 vs. 0.62 ± 013; p < .001), correlated with peak cTnI level (R = .82, p = .004). No [68Ga]Ga‐FAPI‐04 in the myocardium was found in UA patients. NSTEMI displayed a similar myocardial [68Ga]Ga‐FAPI‐04 intensity as STEMI (p = .42). Compared with STEMI, NSTEMI patients had a significantly delayed door‐to‐balloon time for reperfusion treatment (p = .023). High uptake of [68Ga]Ga‐FAPI‐04 in the gastrointestinal tract was detected in three patients. Because of no myocardial [68Ga]Ga‐FAPI‐04 expression, they discontinued antiplatelet therapy and underwent endoscopy. The rectal, colon, and gastric cancer diagnoses were made by biopsy. The other nine patients showed no accumulation of [68Ga]Ga‐FAPI‐04 beyond the heart, and invasive tumor examinations were delayed. During a median 6‐month follow‐up, no tumor formation was observed. [68Ga]Ga‐FAPI‐04 PET imaging is valuable to assess injured myocardium, detect tumors, and guide invasive examinations in ACS patients with suspected gastrointestinal malignancies.

Postoperative peritoneal adhesion (PPA) is frequent and extremely dangerous complication after surgery. Different tactics have been developed to reduce it. However, creating a postoperative adhesion method that is multifunctional, biodegradable, biocompatible, low-toxic but highly effective, and therapeutically applicable is still a challenge. Herein, we have prepared a degradable spray glycyrrhetinic acid hydrogel (GAG) based on natural glycyrrhetinic acid (GA) by straightforward heating and cooling without the use of any additional chemical cross-linking agents to prevent postoperative adhesion. The resultant hydrogel was demonstrated to possess various superior anti-inflammatory activity, and multiple functions, such as excellent degradability and biocompatibility. Specifically, spraying characteristic and excellent antibacterial activities essentially eliminated secondary infections during the administration of drugs in surgical wounds. In the rat models, the carrier-free spray GAG could not only slow-release GA to inhibit inflammatory response, but also serve as physical anti-adhesion barrier to reduce collagen deposition and fibrosis. The sprayed GAG would shed a new light on the prevention of postoperative adhesion and broaden the application of the hydrogels based on natural products in biomedical fields.

Object: This study aims to investigate the changes in gut microbiota and metabolism of patients with chronic kidney disease (CKD) stage 1–2, as well as the potential impact of hyperuricemia (HUA) on these factors in CKD stage 1–2 patients. Methods: In this study, fecal samples were collected from CKD stage 1–2 without HUA patients (CKD-N group), CKD stage 1–2 with HUA patients (CKD-H group), and healthy people controls (HCs group). The samples were then subjected to the microbiome (16S rRNA gene sequencing) and metabolome (liquid chromatography-tandem mass spectrometry) analyses. The multi-omics datasets were analyzed individually and integrated for combined analysis using various bioinformatics approaches. Results: Gut microbial dysbiosis was found in CKD-N and CKD-H patients. At the phylum level, compared to HCs group, Bacteroidetes decreased but Proteobacteria increased in CKD-H group significantly. Fusobacteria in CKD-N group was significantly lower than HCs group. At genus level, [Eubacterium]_ventriosum_group, Fusobacterium, Agathobacter, Parabacteroides, and Roseburia significantly changed in CKD groups. [Ruminococcus]_gnavus_group was significantly lower in CKD-H group than CKD-N group. Moreover, the fecal metabolome of CKD-N and CKD-H altered significantly. d-glutamine and d-glutamate metabolism, arginine and proline metabolism, histidine metabolism, and lysine biosynthesis were down-regulated in the CKD-N group. Phenylalanine metabolism, arginine and proline metabolism, purine metabolism, and beta-alanine metabolism were up-regulated in the CKD-H group. There was a significant difference between the two CKD groups in phenylalanine metabolism. The abundance change of [Ruminococcus]_gnavus_group, [Eubacterium]_ventriosum_group, UCG-002, Alistipes, and Bifidobacterium had a close correlation with differential metabolites. Conclusion: The gut microbiota and metabolic status undergo significant changes in CKD patients compared to healthy people. Additionally, HUA has been found to impact the gut microbiota of CKD patients, as well as their metabolism. The close association between gut microbiota and metabolites suggests that the former plays a crucial role in metabolism.

PurposeTo compare the effectiveness and safety of drug-eluting bead bronchial artery chemoembolization (DEB-BACE) with conventional bronchial artery chemoembolization (cBACE) and provide a novel treatment option for advanced non-small cell lung cancer (NSCLC).MethodsPatients with advanced NSCLC underwent DEB-BACE or cBACE and were screened retrospectively. Progression-free survival (PFS) and overall survival (OS) were the primary outcome indicators, while technical success rate, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were the secondary ones.ResultsA total of 41 patients were enrolled in the study, 12 in the DEB-BACE group and 29 in the cBACE group, according to the treatment regimen. No patient achieved complete response. Eighteen patients achieved partial response (9 in each group), 15 patients achieved stable disease (3 in the DEB-BACE group and 12 in the cBACE group), and eight patients achieved progressive disease (all in the cBACE group) when treated for 2 months. The overall ORR and DCR were 43.9% (18/41) and 80.5% (33/41), respectively. ORR and DCR in the DEB-BACE group were 50.0% (9/12) and 100.0% (12/12), respectively, while ORR and DCR in the cBACE group were 31.0% (9/29) and 72.4% (21/29), respectively. Compared to cBACE, the ORR and DCR of DEB-BACE were significantly improved (p

The noise control of flank array sonar is a primary approach to enhance the sonar detection range. During submarine navigation, hydrodynamic noise is the main noise source in the platform region of the flank array sonar, which includes flow noise and flow-induced noise. Therefore, an in-depth investigation of hydrodynamic noise is necessary. In this paper, we firstly take the teardrop submarine as a computational model to validate the computational method. Afterwards, we numerically simulate the flow and flow-induced noise characteristics for the cylindrical shell model, and investigate differences in noise at different detection points along the X, Y, and Z axes. Finally, experiments are conducted to confirm the accuracy of the simulation results. The research findings reveal that, at the same frequency, flow-induced noise exceeds flow noise, and the noise decreases as the distance between the walls of the cylindrical shell increases. The experimental and simulation results are consistent, suggesting that the selected computational method can precisely simulate the submarine’s noise.

Abstract Background and aims Renal fibrosis is the common outcome in all progressive forms of chronic kidney disease. Unfortunately, the pathogenesis of renal fibrosis remains largely unexplored, among which metabolic reprogramming plays an extremely crucial role in the evolution of renal fibrosis. Ceria nanoparticles (CeNP-PEG) with strong ROS scavenging and anti-inflammatory activities have been applied for mitochondrial oxidative stress and inflammatory diseases. The present study aims to determine whether CeNP-PEG has therapeutic value for renal fibrosis. Methods The unilateral ureteral obstructive fibrosis model was used to assess the therapeutic effects in vivo. Transforming growth factor beta1-induced epithelial-to-mesenchymal transition in HK-2 cells was used as the in vitro cell model. The seahorse bioscience X96 extracellular flux analyzer was used to measure the oxygen consumption rate and extracellular acidification rate. Results In the present study, CeNP-PEG treatment significantly ameliorated renal fibrosis by increased E-cadherin protein expression, and decreased α-SMA, Vimentin and Fibronectin expression both in vitro and in vivo. Additionally, CeNP-PEG significantly reduced the ROS formation and improved the levels of mitochondrial ATP. The seahorse analyzer assay demonstrated that the extracellular acidification rate markedly decreased, whereas the oxygen consumption rate markedly increased, in the presence of CeNP-PEG. Furthermore, the mitochondrial membrane potential markedly enhanced, hexokinase 1 and hexokinase 2 expression significantly decreased after treatment with CeNP-PEG. Conclusions CeNP-PEG can block the dysregulated metabolic status and exert protective function on renal fibrosis. This may provide another therapeutic option for renal fibrosis. Graphical Abstract

Abstract Introduction To investigate the protective effect of sevoflurane preconditioning on renal ischemia‐reperfusion injury (renalischemiareperfusionmodel, RIRI) and its related mechanism. Methods Eighty healthy adult male SD rats were randomly divided into control group (Sham group), model group (RIRI group), sevoflurane pretreatment group (Sev group) and TRPM7 inhibitor combined with sevoflurane pretreatment group (T + Sev group), 20 animals in each group. Hematoxylin‐eosin (HE) staining was used to observe the pathological changes of renal tissue, and the levels of creatinine and urea nitrogen in each group were detected. Deoxyribonucleic acid terminal transferase‐mediated dUTP nick end labeling (TUNEL) assay was used to detect renal cell apoptosis, and Western blottingwas used to detect the expression of apoptotic proteins cleaved‐caspase‐3, bax, Bcl‐2, and TRPM7 in renal tissue; Detection of oxidative stress‐related index levels in renal tissue and levels of inflammatory factors in renal tissue and serum. Results Compared with the Sham group, the renal tissue pathological damage was aggravated, the levels of creatinine and blood urea nitrogen were increased, and the apoptosis was increased in the RIR group and the Sev group. Death, malondialdehyde (MDA) levels and inflammatory factors were increased, and superoxide dismutase (SOD) levels were decreased (all p

Four new meroterpenoids, Clavilactone M-P, possessing novel aminoglycoside moiety (1–4) and a 10-membered carbocycle fused with an α,β-epoxy-γ-lactone, were isolated from Clitocybe clavipes, a basidiomycete. Their structures with absolute configurations were determined by extensive analysis of their spectroscopic data, and the ECD method. All the isolated compounds (1–4) were evaluated for their antitumor activity against three human cancer cell lines using the MTT assay. Compound 1 and 2 exhibited a significant suppression of cell viability in the Hela (IC50 = 22.8 and 19.7 μM) cell line.

Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski’s rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study.

BackgroundAlthough the implant success rate of left atrial appendage closure (LAAC) has increased and complications have decreased over time, there are still anatomically and technically complicated cases where novel LAA occluders may simplify the procedure and thus might potentially improve the clinical outcome.ObjectivesThis study aimed to assess the safety and efficacy of the newly designed device with isogenous barbs in LAAC.MethodsEight centers in China participated in this prospective study from July 2016 to April 2018. Peri- and post-procedural safety and efficacy were evaluated through scheduled follow-ups and transesophageal echocardiography (TEE).ResultsA total of 175 patients with a mean age of 68.4 ± 9.2 years old, a mean CHA2DS2-VASc score of 4.7 ± 1.8, and a mean HAS-BLED score of 3.2 ± 1.3, were included. The device was successfully implanted in 173 patients (98.9%). The device size ranged from 18 to 34 mm. Clinically relevant pericardial effusion (PEF) in the perioperative period, occurred in 3 patients (1.7%). TEE follow-up was available in 167 (96.5%) patients at 12-month. During follow-up, 9 patients suffered serious adverse event: 4 death (2.3%), 1 ischemic stroke (0.6%), and 2 gastro-intestinal bleeding (1.2%) and 2 device-related thrombus (DRT) (1.2%). Estimated annual thromboembolism rate reduced by 90% and estimated annual major bleeding rate reduced by 81% after LAAC with the newly designed device.ConclusionThe newly designed device with isogenous barbs for LAAC could be performed effectively with a low incidence of adverse events and a high incidence of anatomic closure.

AimTo investigate the incidence and outcomes of acute high-risk chest pain diseases, including acute myocardial infarction (AMI), aortic dissection (AD), and pulmonary embolism (PE) during pregnancy and puerperium.MethodsThe National Inpatient Sample was queried to identify pregnancy-related hospitalizations from January 1, 2008 to December 31, 2017. Temporal trends in the incidence and mortality of AMI, AD and PE were extracted.ResultsAmong 41,174,101 hospitalizations, acute high-risk chest pain diseases were diagnosed in 40,285 (0.098%). The incidence increased from 79.92/100,000 in 2008 to 114.79/100,000 in 2017 (Ptrend < 0.0001). The most frequent was PE (86.5%), followed by AMI (9.6%) and AD (3.3%). The incidence of PE in pregnancy decreased after 2014 and was lower than AMI and AD, while its incidence in puerperium was higher than AMI and AD consistently (Ptrend < 0.0001). Subgroup analysis showed the incidence of these diseases was higher in black women, lowest-income households, and elderly parturients (Ptrend < 0.0001). The mortality decreased from 2.24% in 2008 to 2.21% in 2017 (Ptrend = 0.0240), exhibiting 200-fold higher than patients without these diseases. The following factors were significantly associated with these diseases: aged ≥ 45 years (OR, 4.25; 95%CI, 3.80–4.75), valvular disease (OR, 10.20; 95%CI, 9.73–10.70), and metastatic cancer (OR, 9.75; 95%CI, 7.78–12.22). The trend of elderly parturients increased from 14.94% in 2008 to 17.81% in 2017 (Ptrend < 0.0001), while no such up-trend was found in valvular disease and metastatic cancer.ConclusionThe incidence of acute high-risk chest pain diseases, especially PE in puerperium, increased consistently. Although mortality has shown a downward trend, it is still at a high level. We should strengthen monitoring and management of acute high-risk pain diseases in pregnancy and puerperium, especially for black women, lowest-income households, and elderly parturients in the future.

The main treatment for renal anemia in end-stage renal disease (ESRD) patients on hemodialysis is erythropoiesis (EPO). EPO hyporesponsiveness (EH) in dialysis patients is a common clinical problem, which is poorly understood. Recent searches reported that gut microbiota was closely related to the occurrence and development of ESRD. This study aims to explore the changes in gut microbiota between ESRD patients with different responsiveness to EPO treatment. We compared the gut microbiota from 44 poor-response (PR) and 48 good-response (GR) hemodialysis patients treated with EPO using 16S rDNA sequencing analysis. The results showed that PR patients displayed a characteristic composition of the gut microbiome that clearly differed from that of GR patients. Nine genera (Neisseria, Streptococcus, Porphyromonas, Fusobacterium, Prevotella_7, Rothia, Leptotrichia, Prevotella, Actinomyces) we identified by Lasso regression and ROC curves could excellently predict EH. In contrast, five genera (Faecalibacterium, Citrobacter, Bifidobacterium, Escherichia–Shigella, Bacteroides) identified by the same means presented a protective effect against EH. Analyzing the correlation between these biomarkers and clinical indicators, we found that gut microbiota may affect response to EPO through nutritional status and parathyroid function. These findings suggest that gut microbiota is altered in hemodialysis patients with EH, giving new clues to the pathogenesis of renal anemia.

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common type of primary glomerular disease in adults worldwide. Several studies have reported that galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgAN.MethodsThirty-five patients with IgAN diagnosed with renal biopsy for the first time served as the experimental group, who were hospitalized in our department. Twenty normal healthy cases in the physical examination center of our hospital served as the control group. Then the levels of Gd-IgA1 in serum and urine, and intestinal mucosal barrier injury indexes [diamine oxidase (DAO), serum soluble intercellular adhesion molecule-1 (sICAM-1), D-lactate (D-LAC), and lipopolysaccharide (LPS)] and inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] in the serum samples were detected. Fecal samples were collected to detect intestinal microbiota using 16 s rDNA sequencing. Then, we assessed possible correlations among clinical and laboratory findings.ResultsIn patients with IgAN, the levels of Gd-IgA1 both in the serum and urine were higher than that of the healthy control. Furthermore, urine Gd-IgA1 level was positively correlated with the serum creatinine level, 24 h urine protein, and M, S, and T parameters in the Oxford classification. ROC curve analysis showed that urine Gd-IgA1 has a greater diagnostic value (AUC = 0.9714, 95% CI, 0.932–1; P < 0.0001) for IgAN. The best cutoff value for urine Gd-IgA1 was 0.745 ng·l/ml·μmol (sensitivity, 94%; specificity, 95%). The intestinal mucosal barrier damage indexes (DAO, sICAM-1, D-LAC, and LPS) were increased in the patients with IgAN, which were positively correlated with Gd-IgA1 levels (P < 0.05) both in serum and urine. The levels of inflammatory factors in the patients with IgAN were increased. 16 s rDNA analysis showed that the intestinal microbiota in these patients was disordered compared to that observed in the healthy subjects. Actinobacteria, Bifidobacterium, Blautia, Bifidobacteriaceae, and Bifidobacteriales were decreased and Shigella was increased in IgAN. The decreased populations of these flora were negatively and significantly correlated with urine Gd-IgA1 and the levels of DAO, sICAM-1, D-LAC, and LPS.ConclusionThe urine Gd-IgA1 levels may be a non-invasive biological marker for evaluating kidney injury in IgAN. Gut flora dysbiosis and intestinal barrier dysfunction may be involved in Gd-IgA1 expression.

Cryptorchidism is a common congenital malformation in pediatric urology. Although there have been many studies on the etiology of the disease, it has not been fully clarified, and while its diagnostic and treatment models have gradually approached standardization and systematization, some controversies regarding treatment remain. Additionally, although ultrasound is a non-invasive examination without ionizing radiation, its role in the evaluation of cryptorchidism remains controversial. The main basis for treating cryptorchidism is orchidopexy, and the main view on treatment age is that treatment should be performed between 6 and 12 months after birth, but no more than 18 months after birth. The view on hormone therapy is still controversial because most scholars believe that early surgery is the key to treatment. There are many surgical treatment methods for cryptorchidism, including traditional open surgery and laparoscopic surgery, which provide satisfactory results. In conclusion, the treatment of undescended testis (UDT) had been largely standardized, apart from the treatment of high intra-abdominal testis (IAT), which remains a matter of debate.

Introduction: Inflammation is a key factor in myocardial ischemia/reperfusion (MI/R) injury. Targeting leucocyte-mediated inflammation is an important strategy for MI/R therapy. Iminostilbene (ISB), a simple dibenzoazepine small molecule compound, has a strong anti-neurodegenerative effect. However, no study has shown the cardioprotective effect of ISB. Objectives: This study aimed to investigate the role of ISB against MI/R injury and identify its molecular target. Methods: To verify the cardiac protection of ISB in vivo and in vitro, we performed rat MI/R surgery and subjected inflammatory modeling of macrophages. In terms of molecular mechanisms, we designed and synthesized a small molecular probe of ISB and employed it on the click chemistry-activity-based protein profiling technique to fish for ISB targets in macrophages. To identify the target, we applied the competitive inhibition assay, surface-plasmon resonance (SPR), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. Results: In vivo, ISB showed robust anti-myocardial injury activity by improving cardiac function, reducing myocardial infarction, and inhibiting macrophage-mediated inflammation. In vitro, ISB strongly inhibited the transcription and the expression levels of inflammatory cytokines in macrophages. The pyruvate kinase isozyme type M2 (PKM2) was identified as the potential target of ISB through proteomic analysis and the competitive assay was performed for specific binding verification. Further thermodynamic and kinetic experiments showed that ISB was bound to PKM2 in a dose-dependent manner. Moreover, in terms of the biological function of ISB on PKM2, ISB reduced the expression of PKM2, thereby reducing the expression of HIF1α and the phosphorylation of STAT3. Conclusion: This study for the first time demonstrated that ISB targeted PKM2 to reduce macrophage inflammation thereby significantly alleviating MI/R injury.

BackgroundLow protein supplemented with α-ketoacid diet (LKD) was recommended to be an essential intervention to delay the progression of chronic kidney disease (CKD) in patients who were not yet on dialysis. Aberrant gut microbiota and metabolism have been reported to be highly associated with CKD. However, the effect of LKD on gut microbiota and related fecal metabolism in CKD remains unclear.MethodsMice were fed with normal protein diet (NPD group), low protein diet (LPD group), and low protein diet supplemented with α-ketoacid (LKD group) after 5/6 nephrectomy. At the end of the study, blood, kidney tissues, and feces were collected for biochemical analyses, histological, 16S rRNA sequence of gut microbiome, and untargeted fecal metabolomic analyses.ResultsBoth LKD and LPD alleviate renal failure and fibrosis, and inflammatory statement in 5/6 nephrectomized mice, especially the LKD. In terms of gut microbiome, LKD significantly improved the dysbiosis induced by 5/6Nx, representing increased α-diversity and decreased F/B ratio. Compared with NPD, LKD significantly increased the abundance of g_Parasutterella, s_Parabacteroides_sp_CT06, f_Erysipelotrichaceae, g_Akkermansia, g_Gordonibacter, g_Faecalitalea, and s_Mucispirillum_sp_69, and decreased s_Lachnospiraceae_bacterium_28-4 and g_Lachnoclostridium. Moreover, 5/6Nx and LKD significantly altered fecal metabolome. Then, multi-omics analysis revealed that specific metabolites involved in glycerophospholipid, purine, vitamin B6, sphingolipid, phenylalanine, tyrosine and tryptophan biosynthesis, and microbes associated with LKD were correlated with the amelioration of CKD.ConclusionLKD had a better effect than LPD on delaying renal failure in 5/6 nephrectomy-induced CKD, which may be due to the regulation of affecting the gut microbiome and fecal metabolic profiles.

Natural products have been used to prevent and treat human diseases for thousands of years, especially the extensive natural small molecules (NSMs) such as terpenoids, steroids and glycosides. A quantity of studies are confined to concern about their chemical structures and pharmacological activities at the monomolecular level, whereas the spontaneous assemblies of them in liquids yielding supramolecular structures have not been clearly understood deeply. Compared to the macromolecules or synthetic small molecular compounds, NSMs have the inherent advantages of lower toxicity, better biocompatibility, biodegradability and biological activity. Self-assembly of single component and multicomponent co-assembly are unique techniques for designing supramolecular entities. Assemblies are of special significance due to their range of applications in the areas of drug delivery systems, pollutants capture, materials synthesis, etc. The assembled mechanism of supramolecular NSMs which are mainly driven by multiple non-covalent interactions are summarized. Furthermore, a new hypothesis aimed to interpret the integration effects of multi-components of traditional Chinese medicines (TCMs) inspired on the theory of supramolecular assembly is proposed. Generally, this review can enlighten us to achieve the qualitative leap for understanding natural products from monomolecule to supramolecular structures and multi-component interactions, which is valuable for the intensive research and application.

Abstract Introduction Kidney transplantation has surpassed dialysis as the optimal therapy for end-stage kidney disease (ESKD). Yet, most patients could suffer from a slow but continuous deterioration of kidney function leading to graft loss mostly due to chronic allograft nephropathy (CAN) after KT. The dysregulated gene expression for CAN is still poorly understood. Methods To explore the pathogenesis of genomics in CAN, we analyzed the differentially expressed genes (DEGs) of kidney transcriptome between CAN and non-rejecting patients by downloading gene expression microarrays from the Gene Expression Omnibus (GEO) database. Then, we used weighted gene co-expression network analysis (WGCNA) to analyze the co-expression of DEGs to explore key modules, hub genes, and transcription factors in CAN. Functional enrichment analysis of key modules was performed to explore pathogenesis. ROC curve analysis was used to validate hub genes. Results As a result, 3 key modules and 15 hub genes were identified by WGCNA analysis. 3 key modules had 21 mutual Gene Ontology (GO) term enrichment functions. Extracellular structure organization, extracellular matrix organization, and extracellular region were identified as significant functions in CAN. Furthermore, transcription factor 12 was identified as the key transcription factor regulating key modules. All 15 hub genes: Yip1 interacting factor homolog B, membrane trafficking protein(YIF1B), toll like receptor 8 (TLR8), neutrophil cytosolic factor 4 (NCF4), glutathione peroxidase 8 (GPX8), mesenteric estrogen dependent adipogenesis (MEDAG), decorin(DCN), serpin family F member 1 (SERPINF1), integrin subunit beta like 1 (ITGBL1), SRY-box transcription factor 15 (SOX15), trophinin associated protein (TROAP), SRY-box transcription factor 1 (SOX1), metallothionein 3 (MT3), lysosomal protein transmembrane (5LAPTM5), FERM domain containing kindlin 3 (FERMT3), cathepsin S (CTSS) had a great diagnostic performance (AUC>0.7). Conclusion This study updates information and provides a new perspective for understanding the pathogenesis of CAN by bioinformatics means. More research is needed to validate and explore the results we have found to reveal the mechanisms underlying CAN.

Objectives: To evaluate the accuracy of the CapitalBio Mycobacterium real-time polymerase chain reaction (RT-PCR) detection test for pulmonary Mycobacterium tuberculosis (MTB) and nontuberculous mycobacterial (NTM) infection. Methods: This study analyzed 2,460 samples from patients with suspected pulmonary mycobacterial infection collected between 01 June 2018 and 31 July 2019. It aimed to determine the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of the CapitalBio Mycobacterium detection test for MTB and NTM infections, and to evaluate its diagnostic accuracy compared with mycobacterial culture. Results: The sensitivity, specificity, PPV, NPV, and AUC of the CapitalBio Mycobacterium detection test for MTB was 83.0%, 79.9%, 80.8%, 82.2%, and 0.81, respectively. This was similar to the diagnostic accuracy of Xpert MTB/RIF for MTB and was significantly higher than that of smear. For pulmonary NTM infection, the sensitivity, specificity, PPV, NPV, and AUC of the test was 82.0%, 99.6%, 94.1%, 98.5%, and 0.91, respectively. The diagnostic accuracy of the CapitalBio Mycobacterium detection test was also significantly higher than that of smear for NTM. Conclusions: The CapitalBio Mycobacterium detection test had good diagnostic accuracy for MTB and NTM infections. This is of great significance for the differential diagnosis of early pulmonary mycobacterial infection.

[This corrects the article DOI: 10.1371/journal.pone.0232383.].

Utilization of infrared light in photocatalytic water splitting is highly important yet challenging given its large proportion in sunlight. Although upconversion material may photogenerate electrons with sufficient energy, the electron transfer between upconversion material and semiconductor is inefficient limiting overall photocatalytic performance. In this work, a TiO2/graphene quantum dot (GQD) hybrid system has been designed with intimate interface, which enables highly efficient transfer of photogenerated electrons from GQDs to TiO2. The designed hybrid material with high photogenerated electron density displays photocatalytic activity under infrared light (20 mW cm-2) for overall water splitting (H2: 60.4 μmol gcat.-1 h-1 and O2: 30.0 μmol gcat.-1 h-1). With infrared light well harnessed, the system offers a solar-to-hydrogen (STH) efficiency of 0.80% in full solar spectrum. This work provides new insight into harnessing charge transfer between upconversion materials and semiconductor photocatalysts and opens a new avenue for designing photocatalysts toward working under infrared light.

Introduction: Numerous research works have shown that serum Gal-deficient (Gd) IgA1 levels are increased in IgA nephropathy (IgAN) patients and these levels are a dangerous risk factor for IgAN. A relationship between the gut microbiota and IgAN has been reported. Whether the gut microbiota participates in the pathogenesis of IgAN was still controversial. Methods: We evaluated changes in the gut flora and the levels of Gd-IgA1 in IgAN patients and healthy controls (HCs). We investigated the Gd-IgA1 levels in both blood and urine specimens. C57BL/6 mice were given a broad-spectrum antibiotic cocktail to deplete the endogenous gut flora. We established a model of IgAN in pseudosterile mice and investigated the expression of the markers of intestinal permeability, inflammation, and local immune responses. Results: Studies have shown that the levels of certain gut flora differ between IgAN patients and HCs. Moreover, elevated Gd-IgA1 levels were found in both the serum and urine. Interestingly, Coprococcus, Dorea, Bifidobacterium, Blautia, and Lactococcus, selected from 10 candidate biomarkers to predict risk in IgAN patients according to random forest analysis, were inversely associated with urinary Gd-IgA1 levels. Notably, the urine level of Gd-IgA1 could best distinguish IgAN patients from HCs. Additionally, the degree of kidney damage in pseudosterile mice with IgAN was more severe than that in mice with IgAN. Furthermore, the markers of intestinal permeability were significantly elevated in pseudosterile IgAN mice. Moreover, the inflammation responses (TLR4, MyD88, and NF-κB in intestinal and renal tissues; TNF-α and IL-6 in serum) and local immune responses (BAFF and APRIL in intestinal tissue) were upregulated in pseudosterile IgAN mice. Conclusions: The urine Gd-IgA1 level may be as a biomarker for the early screening of potential IgAN, and gut microbiota dysbiosis was demonstrated in IgAN, which might involve the dysfunction of the mucosal barrier, inflammation, and local immune responses.

Atherosclerosis is an epidemic across the globe[A1], and its morbidity and mortality remain high, involving various complications and poor prognoses. In atherosclerosis, endothelial cells (ECs) dysfunction, vascular smooth muscle cells (VSMCs) migration and proliferation, foam cell formation, and inflammatory cell recruitment contribute to disease progression. Vascular stem cells (VSCs) also play a critical role in the cardiovascular system. Important data showed that the simultaneous increase of proliferation and apoptosis of VSMCs is the main cause of graft vein stenosis, suggesting that inhibition of VSMCs proliferation and apoptosis simultaneously is an important strategy for the treatment of atherosclerotic stenosis. Complementary and alternative medicine use among patients with cardiovascular disease (CVD) is growing. Berberine is an extract of Chinese traditional herbs that is known for its antimicrobial and anti-inflammatory effects in the digestive system. Its underlying anti-CVD mechanisms are currently attracting interest, and its pharmacological actions, such as antioxidation, regulation of neurotransmitters and enzymes, and cholesterol-lowering effects, have been substantiated. Recent studying found that berberine could inhibit both the proliferation and apoptosis of VSMCs induced by mechanical stretch stress simultaneously, which suggests that berberine might be an excellent drug to treat atherosclerosis. This review will focus on the recent progress of the effect of berberine on vascular cells, especially VSMCs, to provide important data and a new perspective for the application of berberine in anti-atherosclerosis.

Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure–activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure–activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.

Phytochemical studies on the rhizomes of Actaea asiatica led to the isolation of seven new cycloartane triterpenes, actaticas A−G (1−7). Their structures were determined by NMR, HRESIMS, and chemical analysis. All the isolates were evaluated for their antiproliferative activity against HT-29 and McF-7 cell lines. The results showed that all the compounds displayed cytotoxicity. All compounds showed significant inhibitory effects with IC50 values of 9.2–26.4 μM.

Four new daphnane-type diterpenes named tianchaterpenes C-F (1–4) and six known ones were isolated from Stelleropsis tianschanica. Their structures were elucidated based on chemical and spectral analyses. The comparisons of calculated and experimental electronic circular dichroism (ECD) methods were used to determine the absolute configurations of new compounds. Additionally, compounds 1–10 were evaluated for their cytotoxic activities against HGC-27 cell lines; the results demonstrate that compound 2 had strong cytotoxic activities with IC50 values of 8.8 µM, for which activity was better than that of cisplatin (13.2 ± 0.67 µM).

From the dried vines of Aspidopterys obcordata Hemsl, five new polyoxypregnane glycosides, named obcordatas J–N (1–5), were obtained. Their structures were fully elucidated and characterized by HRESIMS and extensive spectroscopic data. In addition, all of the new compounds were screened for their antinephrolithiasis activity in vitro. The results showed that compounds 1–3 have prominent protective effects on calcium oxalate crystal-induced human kidney 2 (HK-2) cells, with EC50 values ranging from 6.72 to 14.00 μM, which is consistent with the application value of A. obcordata in folk medicine for kidney stones.

Background: To evaluate the efficacy and safety of 2nd-stage laparoscopic traction orchiopexy (Shehata technique) compared to Fowler-Stephens (F-S technique) for high intra-abdominal testes (IATs) in children.Patients and Methods: We performed a retrospective review of all children (

Purpose: This study evaluated the outcomes of laparoscopic repair (LR) and open repair (OR) surgery for communicating hydrocele in children.Patients and Methods: We collected the clinical data and follow-up data of all boys (

BackgroundSmall cell lung cancer (SCLC) is a highly malignant lung cancer with a very poor prognosis. Clinical treatment options for SCLC are still limited, especially for patients who have failed first or second line therapy. Anlotinib is a potentially beneficial new treatment option for SCLC. The aim of this meta-analysis is to evaluate the efficacy and safety of anlotinib-containing regimen for the treatment of SCLC.MethodsWe will search SinoMed, Wanfang Database, China National Knowledge Infrastructure, Embase, Cochrane Library, and PubMed for relevant articles that may meet the criteria published before March 31, 2021. We will perform a meta-analysis to evaluate the efficacy and safety of anlotinib-containing regimen for the treatment of SCLC. Clinical randomized controlled trials comparing anlotinib-containing regimens with other treatment regimens for advanced SCLC will be included in this study. The risk of bias will be evaluated for each included study using the Cochrane Handbook for Systematic Reviews of Interventions. We will use RevMan 5.3 software for statistical analysis of the data.ResultsThe results of this study will provide evidence of anlotinib-containing regimens for advanced SCLC, and provide clinicians and patients with another convenient and effective treatment regimen for SCLC. This meta-analysis will be submitted to a peer-reviewed journal for publication.ConclusionThis meta-analysis will provide clinical evidence of anlotinib-containing regimens for advanced SCLC, which may or may not be found for anlotinib use.Systematic review registrationINPLASY202110034.

BackgroundNontuberculous mycobacteria (NTM) infection is similar to Mycobacterium tuberculosis (MTB) infection. Early clinical identification and differentiation of NTM and MTB infections continues to be a major challenge. Nucleic acid amplification tests (NAATs) have the ability to efficiently and rapidly detect pathogens and are widely used in mycobacterial infections. The objective of this study is to estimate the diagnostic accuracy of NAATs for NTM.MethodsWe will search candidate studies that assessing the accuracy of NAATs for diagnosis of NTM through PubMed, Embase and the Cochrane Library until May 2021. Studies with full text that meet the inclusion criteria will be included. Following a revised tool for Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), two researchers will independently evaluate the study quality. The STATA software (version 15.0) will be used to carry out meta-analyses. When heterogeneity is observed, subgroup analyses and meta-regression analyses will be used to explore sources of heterogeneity. Sensitivity analyses will be used to check the robustness of analyses.ConclusionWe hope that this study will provide meaningful evidence for the early and rapid diagnosis of NAATs for NTM, which will help to guide the treatment of NTM and improve the prognosis of patients.

BackgroundEsophageal cancer is a highly malignant cancer with a very poor prognosis. For resectable esophageal cancer, neoadjuvant treatment could improve the prognosis of esophageal cancer. However, current clinical neoadjuvant treatment options for esophageal cancer are still limited. The application of immunotherapy is a potentially beneficial new neoadjuvant treatment option for esophageal cancer. The objective of this meta-analysis is to evaluate the efficacy and safety of immunotherapy for the neoadjuvant treatment of esophageal cancer.MethodsWe will search Wanfang Database, SinoMed, China National Knowledge Infrastructure, Embase, Web of Science, Pubmed, and Cochrane Library for relevant articles published before July, 2021. We will also search the unpublished clinical trials of neoadjuvant immunotherapy in esophageal cancer in preprint website (such as bioRXiv and medRxiv) up to July, 2021. We will perform a meta-analysis to evaluate the efficacy and safety of neoadjuvant immunotherapy for resectable esophageal cancer. Randomized controlled trials (RCTs) will be included in this study. The risk of bias will be evaluated for each included study using the Cochrane Handbook for Systematic Reviews of Interventions. We will use RevMan 5.3 software for statistical analysis of the data.ResultsThe results of this study will provide evidence of immunotherapy using as neoadjuvant treatment for esophageal cancer. This meta-analysis will be submitted to a peer-reviewed journal seeking for publication.ConclusionThe results of this study will provide a reliable basis for clinicians and patients to formulate the best pre-surgical treatment plan for resectable esophageal cancer.Systematic review registrationINPLASY202120026.

Increasing evidence has shown that DNA methylation is involved in gene regulation in prokaryotes. However, there have been very limited reports about the role of DNA methylation in regulation of gene expression and physiological functions in cyanobacteria. In Synechocystis sp. PCC 6803, four genes on the plasmid pSYSX are predicted to encode the type I restriction-methylation system, slr6095 and slr6096 for the M subunit, slr6097 for the S subunit and slr6102 for the R subunit. Compared to the wild type, slr6095, slr6096, and slr6097 mutants lacked the GGm6AN7TTGG/CCAm6AN7TCC methylation in genomic DNA. Transcriptomic analysis indicated that 171 genes were reproducibly up- or down-regulated in all three mutants relative to the wild type. The changed expression of some genes, including sll1356 for glycogen phosphorylase (GlgP), was associated with the loss of GGm6AN7TTGG/CCAm6AN7TCC methylation in the coding regions or the upstream non-coding sequences. Inactivation of slr6095, slr6096, or slr6097 increased the expression of sll1356 and the GlgP activity but lowered the glycogen content. These results indicated that the DNA methylation by a type I RM system could alter the expression of certain genes and physiological functions in Synechocystis sp. PCC 6803.

ObjectiveTo assess the efficacy and toxicity of anlotinib for the treatment of refractory advanced non-small-cell lung cancer (NSCLC).MethodsWe systematically searched databases for randomized controlled trials on anlotinib treatment for patients with advanced NSCLC published until November 6, 2020. Articles were assessed and data were extracted independently by two investigators. Further, we analyzed hazard ratios (HRs) for progression-free and overall survival (PFS and OS, respectively). In addition, we analyzed risk ratio (RR) for overall response and disease control rates (ORR and DCR, respectively) and the odds ratio (OR) for the main adverse events (AEs) using RevMan 5.3 software.ResultsThis analysis included 594 patients from three clinical studies. The pooled HRs for PFS and OS were 0.27 (95% confidence interval (CI): 0.22-0.33, P < 0.001) and 0.68 (95% CI: 0.56-0.83, P < 0.001), respectively, indicating that anlotinib administration significantly improved PFS and OS in patients with advanced NSCLC. The pooled RRs for ORR and DCR were 11.62 (95% CI: 2.75-49.14, P < 0.001) and 2.30 (95% CI: 1.91-2.77, P < 0.001), respectively, indicating that anlotinib administration in patients with advanced NSCLC improved ORR and DCR. The pooled OR for AEs of grade 3 or higher was 2.94 (95% CI: 1.99-4.35, P < 0.001), indicating that AEs of grade 3 or higher were more prevalent in the anlotinib group than in the placebo group.ConclusionAnlotinib, an effective choice of third- or later line therapy for patients with refractory advanced NSCLC, provides clinical benefits in terms of PFS, OS, ORR, and DCR. AEs associated with anlotinib were tolerable.

Background and Objective: Qing-Kai-Ling (QKL) is derived from a famous ancient Chinese patent medicine Angong Niuhuang pills (ANP) which has been used across Asia, especially in China, for the treatment of “febrile disease,” such as stroke, encephalitis and meningitis for hundreds of years. As an extract of ANP without heavy metal, the clinical applicability of QKL is more intensive, of which its injection is commonly used in acute and serious diseases. This study aims to clarify the potential mechanisms of immediate hypersensitivity reaction (IHR) induced by QKL injection (QKLI).Methods: β-hexosaminidase release assay was performed on the human mast cell line LAD2 and mouse peritoneal mast cells. T helper 2 (Th2) immunity-amplified mice were prepared by aluminum adjuvant. Anaphylactic shock was detected by measuring rectal thermometry in propranolol-pretreated mice. For evaluating microvascular permeability, Evans Blue extravasation assay was used. Serum total IgE (tIgE) and the activated complement-derived anaphylatoxin C3 (C3a) levels were measured by ELISA.Results: QKLI was unable to elevate serum tIgE level in the Th2 immunity-amplified mice, but can increase vasopermeability and trigger anaphylaxis after the first injection. By screening seven fractions of QKLI, only the extract of Isatidis Radix (Isatis tinctoria L.) induced hindpaw Evans Blue extravasation, which was disappeared in Isatidis Radix-free QKLI. Mechanism study indicated that QKLI or Isatidis Radix-caused IHR could be blocked by the antagonists for histamine or C3a, rather than PAF or C5a. Consistently, QKLI and Isatidis Radix could also directly activate human serum complement-derived anaphylatoxin 3 (C3) in vitro with the half effective concentration values of 0.69% and 218.6 μg/ml, respectively.Conclusion: QKLI-IHR is complement activation-related pseudoallergy, rather than an IgE-mediated allergy. QKLI activates C3 and might consequently provoke mast cells to release histamine, which is a principal effector of its IHR. The pseudoallergic reaction induced by QKLI was attributed to the extract of Isatidis Radix. This study suggests a potential therapeutic strategy for the prophylaxis and treatment of QKLI-IHR.

HetR and PatS/PatX-derived peptides are the activator and diffusible inhibitor for cell differentiation and patterning in heterocyst-forming cyanobacteria. HetR regulates target genes via HetR-recognition sites. However, some genes (such as patS/patX) upregulated at the early stage of heterocyst differentiation possess DIF1 (or DIF+) motif (TCCGGA) promoters rather than HetR-recognition sites; hetR possesses both predicted regulatory elements. How HetR controls heterocyst-specific expression from DIF1 motif promoters remains to be answered. This study presents evidence that the expression from DIF1 motif promoters of hetR, patS and patX is more directly dependent on hetZ, a gene regulated by HetR via a HetR-recognition site. The HetR-binding site upstream of hetR is not required for the autoregulation of hetR. PatU3 (3' portion of PatU) that interacts with HetZ may modulate the expression of hetR, hetZ and patS. These findings contribute to understanding of the mutual regulation of hetR, hetZ-patU and patS/patX in a large group of multicellular cyanobacteria.