CMDB: the comprehensive population genome variation database of China.

A high-quality genome variation database derived from a large-scale population is one of the most important infrastructures for genomics, clinical and translational medicine research. Here, we developed the Chinese Millionome Database (CMDB), a database that contains 9.04 million single nucleotide variants (SNV) with allele frequency information derived from low-coverage (0.06×-0.1×) whole-genome sequencing (WGS) data of 141 431 unrelated healthy Chinese individuals. These individuals were recruited from 31 out of the 34 administrative divisions in China, covering Han and 36 other ethnic minorities. CMDB, housing the WGS data of a multi-ethnic Chinese population featuring wide geographical distribution, has become the most representative and comprehensive Chinese population genome database to date. Researchers can quickly search for variant, gene or genomic regions to obtain the variant information, including mutation basic information, allele frequency, genic annotation and overview of frequencies in global populations. Furthermore, the CMDB also provides information on the association of the variants with a range of phenotypes, including height, BMI, maternal age and twin pregnancy. Based on these data, researchers can conduct meta-analysis of related phenotypes. CMDB is freely available at https://db.cngb.org/cmdb/.

VThunter: a database for single-cell screening of virus target cells in the animal kingdom.

Viral infectious diseases are a devastating and continuing threat to human and animal health. Receptor binding is the key step for viral entry into host cells. Therefore, recognizing viral receptors is fundamental for understanding the potential tissue tropism or host range of these pathogens. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology has paved the way for studying the expression of viral receptors in different tissues of animal species at single-cell resolution, resulting in huge scRNA-seq datasets. However, effectively integrating or sharing these datasets among the research community is challenging, especially for laboratory scientists. In this study, we manually curated up-to-date datasets generated in animal scRNA-seq studies, analyzed them using a unified processing pipeline, and comprehensively annotated 107 viral receptors in 142 viruses and obtained accurate expression signatures in 2 100 962 cells from 47 animal species. Thus, the VThunter database provides a user-friendly interface for the research community to explore the expression signatures of viral receptors. VThunter offers an informative and convenient resource for scientists to better understand the interactions between viral receptors and animal viruses and to assess viral pathogenesis and transmission in species. Database URL: https://db.cngb.org/VThunter/.

Identification and validation of a novel four-gene diagnostic model for neonatal early-onset sepsis with bacterial infection.

Neonatal early-onset sepsis (EOS) has unfortunately been the third leading cause of neonatal death worldwide. The current study is aimed at discovering reliable biomarkers for the diagnosis of neonatal EOS through transcriptomic analysis of publicly available datasets. Whole blood mRNA expression profiling of neonatal EOS patients in the GSE25504 dataset was downloaded and analyzed. The binomial LASSO model was constructed to select genes that most accurately predicted neonatal EOS. Then, ROC curves were generated to assess the performance of the predictive features in differentiating between neonatal EOS and normal infants. Finally, the miRNA-mRNA network was established to explore the potential biological mechanisms of genes within the model. Four genes (CST7, CD3G, CD247, and ANKRD22) were identified that most accurately predicted neonatal EOS and were subsequently used to construct a diagnostic model. ROC analysis revealed that this diagnostic model performed well in differentiating between neonatal EOS and normal infants in both the GSE25504 dataset and our clinical cohort. Finally, the miRNA-mRNA network consisting of the four genes and potential target miRNAs was constructed. Through bioinformatics analysis, a diagnostic four-gene model that can accurately distinguish neonatal EOS in newborns with bacterial infection was constructed, which can be used as an auxiliary test for diagnosing neonatal EOS with bacterial infection in the future. CONCLUSION: In the current study, we analyzed gene expression profiles of neonatal EOS patients from public databases to develop a genetic model for predicting sepsis, which could provide insight into early molecular changes and biological mechanisms of neonatal EOS. WHAT IS KNOWN: • Infants with suspected EOS usually receive empiric antibiotic therapy directly after birth. • When blood cultures are negative after 48 to 72 hours, empirical antibiotic treatment is often halted. Needless to say, this is not a short time. Additionally, because of the concern for inadequate clinical sepsis production and the limited sensitivity of blood cultures, the duration of antibiotic therapy for the kid is typically extended. WHAT IS NEW: • We established a 4-gene diagnostic model of neonatal EOS with bacterial infection by bioinformatics analysis method. The model has better diagnostic performance compared with conventional inflammatory indicators such as CRP, Hb, NEU%, and PCT.

CD40LG-associated X-linked Hyper-IgM Syndrome (XHIGM) with pulmonary alveolar proteinosis: a case report.

BACKGROUND: D40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis has rarely been reported, and its genotype-phenotypic correlation remains elusive. CASE PRESENTATION: We describe a five-month-old boy with CD40LG mutation (c.516T > A, p.Tyr172Ter) X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis as the first manifestation. The patient completely recovered after immunotherapy and allogeneic hematopoietic stem cell transplantation. In addition, four previously reported patients with CD40LG mutation with pulmonary alveolar proteinosis were also analyzed. All of these patients presented with early onset of pulmonary infections and a good response to immunotherapy. The structural model of CD40LG indicated that all mutations caused the X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis to be located within the tumor necrosis factor homology domain. CONCLUSIONS: A case was presented, and the characteristics of four cases of CD40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis were summarized. The variant locations may explain the phenotypic heterogeneity of patients with the CD40LG mutation.

Analysis of Prognostic Risk Factors of Sepsis Patients With Myocardial Injury: Six-month Survival Outcome.

Context: Sepsis is a systemic, comprehensive inflammatory response that can induce serious complications for patients. No uniform definition and diagnostic criteria exist internationally for sepsis related to myocardial injury. Studying factors affecting prognosis for sepsis patients with myocardial injury can be helpful in providing a theoretical basis for clinical diagnosis and treatment. Objective: The study intended to explore the predictors of the short-term prognosis for septic patients with myocardial injury and to provide a theoretical basis for improving that prognosis. Design: The research team performed a retrospective study. Setting: The study took place at the Renmin Hospital at Hubei University of Medicine in Shiyan, Hubei, China. Participants: Participants were 138 patients with sepsis and myocardial injury at the hospital between January 2018 and February 2021. Groups: The research team divided participants into a survival group with 114 patients and a mortality group with 24 patients, based on their survival status at six months after being in the hospital. Outcome Measures: The research team collected and analyzed the following data: (1) demographic and clinical characteristics, such as age, gender, underlying disease, and disease severity; (2) echocardiographic indicators, including left ventricular ejection fraction (LVEF), stroke volume (SV), left ventricular end systolic dimension (LVESD), and left ventricular end diastolic dimension (LVEDD); and (3) myocardial injury markers and inflammatory factors, including white blood cell (WBC) count and levels of cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase (CK), C-reactive protein (CRP), and procalcitonin (PCT). Results: The six-month mortality rate for patients with sepsis with myocardial injury was 17.39%. Compared to the survival group at participants' initial visits to the hospital, the mortality group had a significantly greater age (P = .046), sepsis severity (P < .001), heart rate (P < .001), APACHE II score (P < .001), SOFA score (P < .001), and use of vasoactive drugs (P = .002), and its length of hospital stay was significantly shorter (P < .001). The mortality group's LVEF was significantly lower than that of the survival group (P < .001). The mortality group's levels of WBC, cTnI, NT-proBNP, CK, CRP, and PCT were significantly higher than those in survival group (all P < .001). The univariate analysis found that an age>64 years (P < .001), a high APACHE II score (P < .001), an elevated cTnI (P = .017), an elevated NT-proBNP (P = .029), an elevated CK (P < .001), an elevated CRP (P = .031), and an elevated PCT (P < .001) were risk factors for a poor prognosis for patients. Multifactor logistic regression analysis showed that the risk factors for death were an age > 64 years (P < .001), a high APACHE II score (P < .001), and elevated levels of cTnI (P = .013), NT-proBNP (P < .001), CK (P < .001), CRP (P < .001), and PCT (P = .009). Conclusion: In summary, risk factors for poor prognosis in septic patients with myocardial injury included age>64 years, high APACHE II, elevated cTnI, elevated NT-proBNP, elevated CK, elevated CRP, and elevated PCT.

H/F Substitution on the Spacer Cations Leads to 1D-to-2D Increment of the Pyrrolidinium-Containing Lead Iodide Hybrid Perovskites.

Hybrid organic-inorganic perovskites (HOIPs) have emerged as multifunctional materials with remarkable optical and electronic properties. In particular, 2D-layered lead iodide-based HOIPs possess great practical application potential in the photoelectric field. In this work, we report H/F substitution-induced 1D-to-2D increment of lead iodide HOIPs. The enantiomeric HOIPs, S- and R-FPPbI3 (FP = 3-fluoropyrrolidinium), were achieved by monofluoride substitution on the spacer cations of the parent HOIP, PyPbI3 (Py = pyrrolidinium), showing mirror image structural relationship and reversible solid-state phase transition. A 2D-layered HOIP, (DFP)2PbI4 (DFP = 3,3-difluoropyrrolidinium), was achieved with a low band gap of 2.09 eV through difluoride substitution, thanks to the expansion of the Pb-I network from 1D to 2D. This work highlights the exploration of 1D chiral and 2D-layered HOIP materials with reversible phase transitions through H/F substitution strategies.

Virtual Reality in Treatment for Psychological Problems in First-Line Health Care Professionals Fighting COVID-19 Pandemic: A Case Series.

ABSTRACT: Virtual reality therapy (VRT) is a new psychotherapeutic approach integrating virtual reality technology and psychotherapy. This case series aimed to study effectiveness of VRT in treating psychological problems. We described four cases of first-line health care professionals with emerging clinically significant early psychological problems during the COVID-19 outbreak, and specifically received the VRT treatment. We compared the Patient Health Questionnaire 9 items (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), PHQ-15, and Athens Insomnia Scale to evaluate psychological symptoms and sleep quality before and after sessions. All four cases showed a reduction in scale comparison. General scores of the PHQ-9 reduced 65%, GAD-7 reduced 52.17%, PHQ-15 decreased 38.17%, and scores of the Athens Insomnia Scale reduced 67.44%. Meanwhile, a reduction in depression, anxiety, psychosomatic, and sleeping symptoms was also found, which decreased 76.92% in general. These results are highly significant statistically. This case series demonstrated the effectiveness of VRT on psychological problems as a promising approach to apply on various psychological distress and disorders.

An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma.

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.

SHCBP1 interacting with EOGT enhances O-GlcNAcylation of NOTCH1 and promotes the development of pancreatic cancer.

O-GlcNAcylation is important in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The glycosyltransferase EGF domain-specific O-linked GlcNAc transferase (EOGT) acts as a key participant in glycosylating NOTCH1. High-throughput sequencing of specimens from 30 advanced PDAC patients identified SHCBP1 and EOGT as factors of poor prognosis. We hypothesized that they could mediate PDAC progression by influencing NOTCH1 O-GlcNAcylation. Thus, 186 PDAC tissue specimens were immunostained for EOGT and SHCBP1. Pancreatic cancer cell lines and nude mouse models were used for in vitro and in vivo experiments. Respectively, The protein expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation, migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice, whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. We further clarified the molecular mechanisms by which EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, Subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells.

TA-Unet: Integrating Triplet Attention Module for Drivable Road Region Segmentation.

Road segmentation has been one of the leading research areas in the realm of autonomous driving cars due to the possible benefits autonomous vehicles can offer. Significant reduction of crashes, greater independence for the people with disabilities, and reduced traffic congestion on the roads are some of the vivid examples of them. Considering the importance of self-driving cars, it is vital to develop models that can accurately segment drivable regions of roads. The recent advances in the area of deep learning have presented effective methods and techniques to tackle road segmentation tasks effectively. However, the results of most of them are not satisfactory for implementing them into practice. To tackle this issue, in this paper, we propose a novel model, dubbed as TA-Unet, that is able to produce quality drivable road region segmentation maps. The proposed model incorporates a triplet attention module into the encoding stage of the U-Net network to compute attention weights through the triplet branch structure. Additionally, to overcome the class-imbalance problem, we experiment on different loss functions, and confirm that using a mixed loss function leads to a boost in performance. To validate the performance and efficiency of the proposed method, we adopt the publicly available UAS dataset, and compare its results to the framework of the dataset and also to four state-of-the-art segmentation models. Extensive experiments demonstrate that the proposed TA-Unet outperforms baseline methods both in terms of pixel accuracy and mIoU, with 98.74% and 97.41%, respectively. Finally, the proposed method yields clearer segmentation maps on different sample sets compared to other baseline methods.

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Low-Latency QC-LDPC Encoder Design for 5G NR.

In order to meet the low latency and high throughput requirements of data transmission in 5th generation (5G) New Radio (NR), it is necessary to minimize the low power encoding hardware latency on transmitter and achieve lower base station power consumption within a fixed transmission time interval (TTI). This paper investigates parallel design and implementation of 5G quasi-cyclic low-density parity-check (QC-LDPC) codes encoder. The designed QC-LDPC encoder employs a multi-channel parallel structure to obtain multiple parity check bits and thus reduce encoding latency significantly. The proposed encoder maps high parallelism encoding algorithms to a configurable circuit architecture, achieving flexibility and support for all 5G NR code length and code rate. The experimental results show that under the 800 MHz system frequency, the achieved data throughput ranges from 62 to 257.9 Gbps, and the maximum code length encoding time under base graph 1 (BG1) is only 33.75 ns, which is the critical encoding time of our proposed encoder. Finally, our proposed encoder was synthesized on SMIC 28 nm CMOS technology; the result confirmed the effectiveness and feasibility of our design.

Fatigue Crack Monitoring of T-Type Joints in Steel Offshore Oil and Gas Jacket Platform.

Several approaches have been used in the past to predict fatigue crack growth rates in T-joints of the offshore structures, but there are relatively few cases of applying structural health monitoring during the non-destructive testing of jacket platforms. This paper presents an experimental method based on the sensing of the piezoelectric sensors and finite element analysis method for studying the fatigue cracks in the offshore steel jacket structure. Three types of joints are selected in the current research work: T-type plate, T-type tube-plate, and T-type tube joints. The finite element analysis model established in the current study computes and analyzes the high stress and high strain regions in the T-type joints. The fatigue damage in the T-type joints was successfully detected by utilizing both the finite element analysis and experimental methods. The results showed that fatigue cracks of the three types of joints are prone to appear at the weld toe and spread in the welding direction. The fatigue damage location of T-type plate and T-type tube-plate joints is more concentrated in the upper weld toe area, and the fatigue damage location of the T-type tube joint is closer to the lower weld toe area.

Higher body mass index deteriorates postoperative outcomes of pancreaticoduodenectomy.

BACKGROUND: Previous studies presented controversies in impact of body mass index (BMI) on perioperative complications in pancreatectomy, and mainly focused on Western population. This study aimed to explore the impact of BMI on perioperative outcomes in Chinese patients undergoing pancreaticoduodenectomy. METHODS: Seven hundred and seven adult patients undergoing open pancreaticoduodenectomy between January 2005 and December 2016 at Ruijin Hospital were studied retrospectively and categorized as obese (BMI ≥25 kg/m2), overweight (BMI ≥23 kg/m2 and <25 kg/m2), or normal weight (BMI ≥18.5 kg/m2 and <23 kg/m2). Associations of these BMI groups with perioperative outcomes were evaluated. RESULTS: The overweight and obese groups experienced higher risk of clinically related postoperative pancreatic fistula (CR-POPF) (7.6% vs. 9.9% vs. 17.6%, P = 0.002) and re-operation (1.1% vs. 2.5%  vs. 5.1%, P = 0.017), and longer systemic inflammation response syndrome (SIRS) duration [2 (1-9) d vs. 2 (1-7) d vs. 3 (1-10) d, P = 0.003] and postoperative hospital stay [19 (2-84) d vs. 19 (7-158) d vs. 23 (8-121) d, P = 0.023] than the normal weight group did. The multiple logistic regression models showed obese as an independent risk factor for CR-POPF (P = 0.013). The multiple linear regression analysis confirmed BMI as a predictor for prolonged postoperative hospital stay (P = 0.005). CONCLUSIONS: Higher BMI results in higher morbidity of Chinese patients undergoing open pancreaticoduodenectomy. Pancreaticoduodenectomy is still a safe surgery procedure for overweight and obese patients, with intensive perioperative management.

Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K.

Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR-185-5p were differently expressed in plasma from patients with ACS by high-throughput RNA sequencing. The expressional levels of miR-185-5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT-PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR-185-5p. In HUVECs, miR-185-5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR-185-5p inhibitors performed the opposites. Further, the inhibitory effects of miR-185-5p up-regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus-mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain-function of miR-185-5p by agomir infusion down-regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR-185-5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR-185-5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.

Induction of microRNA-199 by Nitric Oxide in Endothelial Cells Is Required for Nitrovasodilator Resistance via Targeting of Prostaglandin I2 Synthase.

BACKGROUND: Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, because of the dysfunction of prostaglandin I2 synthase (PTGIS). MicroRNAs repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of PTGIS gene expression. METHODS: Nitrovasodilator resistance was induced by nitroglycerin (100 mg·kg-1·d-1, 3 days) infusion in Apoe-/- mice. The responses of aortic arteries to nitric oxide donors were assessed in an organ chamber. The expression levels of microRNA-199 (miR-199)a/b were assayed by quantitative reverse transcription polymerase chain reaction or fluorescent in situ hybridization. RESULTS: In cultured human umbilical vein endothelial cells, nitric oxide donors induced miR-199a/b endogenous expression and downregulated PTGIS gene expression, both of which were reversed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt or silence of serum response factor. Evidence from computational and luciferase reporter gene analyses indicates that the seed sequence of 976 to 982 in the 3'-untranslated region of PTGIS mRNA is a target of miR-199a/b. Gain functions of miR-199a/b resulting from chemical mimics or adenovirus-mediated overexpression increased PTGIS mRNA degradation in HEK293 cells and human umbilical vein endothelial cells. Furthermore, nitroglycerin-decreased PTGIS gene expression was prevented by miR-199a/b antagomirs or was mirrored by the enforced expression of miR-199a/b in human umbilical vein endothelial cells. In Apoe-/- mice, nitroglycerin induced the ectopic expression of miR-199a/b in the carotid arterial endothelium, decreased PTGIS gene expression, and instigated nitrovasodilator resistance, all of which were abrogated by miR-199a/b antagomirs or LNA-anti-miR-199. It is important that the effects of miR-199a/b inhibitions were abolished by adenovirus-mediated PTGIS deficiency. Moreover, the enforced expression of miR-199a/b in vivo repressed PTGIS gene expression and impaired the responses of aortic arteries to nitroglycerin/sodium nitroprusside/acetylcholine/cinaciguat/riociguat, whereas the exogenous expression of the PTGIS gene prevented nitrovasodilator resistance in Apoe-/- mice subjected to nitroglycerin infusion or miR-199a/b overexpression. Finally, indomethacin, iloprost, and SQ29548 improved vasorelaxation in nitroglycerin-infused Apoe-/- mice, whereas U51605 induced nitrovasodilator resistance. In humans, the increased expressions of miR-199a/b were closely associated with nitrate tolerance. CONCLUSIONS: Nitric oxide-induced ectopic expression of miR-199a/b in endothelial cells is required for nitrovasodilator resistance via the repression of PTGIS gene expression. Clinically, miR-199a/b is a novel target for the treatment of nitrate tolerance.

Splenic irradiation combined with tumor irradiation promotes T cell infiltration in the tumor microenvironment and helps in tumor control.

Locally applied radiation to the tumor is reported to stimulate systemic immune response. During radiotherapy to the abdominal cancer, spleen often receives certain dose, though as an important immune organ, little is known about the impact of splenic irradiation (SI) on systemic immune and local tumor control. Through a mice model, we found that the combination of SI with tumor irradiation (TI) helped in local control. The analysis of the tumor infiltrating leucocytes demonstrated that SI plus TI brought more T cell aggregation in the tumor microenvironment (TME), which helped in tumor control. Increased T cell infiltration may be partly due to higher expression of T cell chemokine in the TME and more expression of CXCR3 on the T cells in the spleen after SI. SI produced more IL-1ß in the spleen, IL-1ß stimulated the expression of CXCR3 on the T cells, and enhanced their migration ability. Taken together, radiation to the spleen combined with TI helped in local control through promoting T cell infiltration, and may be a considerable means to enhance the immunomodulatory of radiotherapy.

Cinobufacini Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through Inhibiting M1 Macrophage Polarization.

Cinobufacini is a traditional Chinese medicine used clinically that has antitumor and anti-inflammatory effects. It improves colitis outcomes in the clinical setting, but the mechanism underlying its function yet to be uncovered. We investigated the protective effects and mechanisms of cinobufacini on colitis using a dextran sulfate sodium (DSS)-induced colitis mouse model, mainly focusing on the impact of macrophage polarization. Our results showed that cinobufacini dramatically ameliorated DSS-induced colitis in mice. Cinobufacini treatment reduced the infiltration of activated F4/80+ and/or CD68+ macrophages into the colon in DSS-induced colitis mice. More importantly, cinobufacini significantly decreased the quantity of M1 macrophages and the expression of proinflammatory cytokines such as interleukin-6, tumor necrosis factor α, and inducible nitric oxide synthase. Cinobufacini also increased the population of M2 macrophages and the expression of anti-inflammatory factors such as interleukin-10 and arginase-1 in DSS-induced colitis mice. Furthermore, our study demonstrated that cinobufacini inhibited M1 macrophage polarization in lipopolysaccharide-induced RAW 264.7 cells. Mechanistically, our in vivo and in vitro results showed that cinobufacini inhibition of M1 macrophage polarization may be associated with the suppression of nuclear factor κB activation. Our study suggests that cinobufacini could ameliorate DSS-induced colitis in mice by inhibiting M1 macrophage polarization.

Efficacy and safety of endovascular thrombectomy in mild ischemic stroke: results from a retrospective study and meta-analysis of previous trials.

BACKGROUND: Mechanical thrombectomy has been proven as a standard care for moderate to severe ischemic stroke with anterior large vessel occlusion (LVO); however, whether it is equally effective in mild ischemic stroke (MIS) is controversial. METHODS: In this retrospective study, a total of 177 Chinese patients presenting with MIS (NIHSS ≤8) and LVO between January 2014 and September 2017 from seven comprehensive stroke centers were identified. Odds of good outcome with endovascular thrombectomy versus medical treatment were obtained by logistic regression analysis and propensity-score matching method, and a meta-analysis pooled results from six studies (n = 733). RESULTS: Good outcome (mRS: 0-1) was 58.2% (46/79) in the thrombectomy and 46.9% (46/98) in the medical group, which showed no statistical significance before adjustment (P = 0.13; OR = 1.57, 95% CI: 0.86 to 2.86). The adjusted ORs of thrombectomy versus medical group were 3.23 (95% CI, 1.35 to 7.73; P = 0.008) by multivariable logistic analysis, 2.78 (1.12 to 6.89; P = 0.02) by propensity score matching analysis, and 3.20 (1.22 to 8.37; P = 0.01) by propensity score matching analysis with additional adjustments, respectively. Thrombectomy treatment did not result in excessive mortality or symptomatic intracranial hemorrhage after adjustments. The meta-analysis did not confirm the associations between good outcome and endovascular treatment. CONCLUSIONS: The current study indicates that endovascular thrombectomy is associated with good functional outcome in MIS patients with LVO, and without additional risk of symptomatic intracranial hemorrhage and mortality. Although the meta-analysis failed to demonstrate its superiority compared to medical treatment, randomized clinical trials are needed.

Rescue fecal microbiota transplantation for antibiotic-associated diarrhea in critically ill patients.

BACKGROUND: Antibiotic-associated diarrhea (AAD) is a risk factor for exacerbating the outcome of critically ill patients. Dysbiosis induced by the exposure to antibiotics reveals the potential therapeutic role of fecal microbiota transplantation (FMT) in these patients. Herein, we aimed to evaluate the safety and potential benefit of rescue FMT for AAD in critically ill patients. METHODS: A series of critically ill patients with AAD received rescue FMT from Chinese fmtBank, from September 2015 to February 2019. Adverse events (AEs) and rescue FMT success which focused on the improvement of abdominal symptoms and post-ICU survival rate during a minimum of 12 weeks follow-up were assessed. RESULTS: Twenty critically ill patients with AAD underwent rescue FMT, and 18 of them were included for analysis. The mean of Acute Physiology and Chronic Health Evaluation (APACHE) II scores at intensive care unit (ICU) admission was 21.7 ± 8.3 (range 11-37). Thirteen patients received FMT through nasojejunal tube, four through gastroscopy, and one through enema. Patients were treated with four (4.2 ± 2.1, range 2-9) types of antibiotics before and during the onset of AAD. 38.9% (7/18) of patients had FMT-related AEs during follow-up, including increased diarrhea frequency, abdominal pain, increased serum amylase, and fever. Eight deaths unrelated to FMT occurred during follow-up. One hundred percent (2/2) of abdominal pain, 86.7% (13/15) of diarrhea, 69.2% (9/13) of abdominal distention, and 50% (1/2) of hematochezia were improved after FMT. 44.4% (8/18) of patients recovered from abdominal symptoms without recurrence and survived for a minimum of 12 weeks after being discharged from ICU. CONCLUSION: In this case series studying the use of FMT in critically ill patients with AAD, good clinical outcomes without infectious complications were observed. These findings could potentially encourage researchers to set up new clinical trials that will provide more insight into the potential benefit and safety of the procedure in the ICU. TRIAL REGISTRATION: ClinicalTrials.gov, Number NCT03895593 . Registered 29 March 2019 (retrospectively registered).