Search

Angiogenesis involves temporo-spatially coordinated endothelial cell (EC) proliferation, differentiation, migration, and sprouting. Notch signaling is essential in regulating EC behaviors during angiogenesis, but its downstream mechanisms remain incompletely defined. In the current study, we show that miR-223-3p is a downstream molecule of Notch signaling and mediates the role of Notch signaling in regulating EC migration and sprouting. In human umbilical vein endothelial cells (HUVECs), Notch activation by immobilized Dll4, a Notch ligand, upregulated miR-223-3p, and Notch activation-mediated miR-223-3p upregulation could be blocked by a γ-secretase inhibitor (DAPT). miR-223-3p overexpression apparently repressed HUVEC migration, leading to attenuated lumen formation and sprouting capacities. Transcriptome comparison and subsequent qRT-PCR validation further indicated that miR-223-3p downregulated the expression of multiple genes involved in EC migration, axon guidance, extracellular matrix remodeling, and angiogenesis. In addition, miR-223-3p antagonist transfection abolished Notch-mediated repression of EC migration and sprouting. By quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and reporter assay analysis, we confirmed that miR-223-3p directly targeted F-box and WD repeat domain-containing 7 (Fbxw7). Meanwhile, Fbxw7 overexpression could efficiently rescue the impaired migration capacity of ECs under miR-223-3p overexpression. In summary, these results identify that Notch activation-induced miR-223-3p suppresses EC migration and sprouting via Fbxw7.

Purpose Recently, a “U” hazard ratio curve between resting left ventricular ejection fraction (LVEF) and prognosis has been observed in patients referred for routine clinical echocardiograms. The present study sought to explore whether a similar “U” curve existed between resting LVEF and coronary flow reserve (CFR) in patients without severe cardiovascular disease (CVD) and whether impaired CFR played a role in the adverse outcome of patients with supra-normal LVEF (snLVEF, LVEF ≥ 65%). Methods Two hundred ten consecutive patients (mean age 52.3 ± 9.3 years, 104 women) without severe CVD underwent clinically indicated rest/dipyridamole stress electrocardiography (ECG)-gated 13 N-ammonia positron emission tomography/computed tomography (PET/CT). Major adverse cardiac events (MACE) were followed up for 27.3 ± 9.5 months, including heart failure, late revascularization, re-hospitalization, and re-coronary angiography for any cardiac reason. Clinical characteristics, corrected CFR (cCFR), and MACE were compared among the three groups categorized by resting LVEF detected by PET/CT. Dose–response analyses using restricted cubic spline (RCS) functions, multivariate logistic regression, and Kaplan–Meier survival analysis were conducted to evaluate the relationship between resting LVEF and CFR/outcome. Results An inverted “U” curve existed between resting LVEF and cCFR (p = 0.06). Both patients with snLVEF (n = 38) and with reduced LVEF (rLVEF, LVEF n = 66) displayed a higher incidence of reduced cCFR than those with normal LVEF (nLVEF, 55% ≤ LVEF n = 106) (57.9% vs 54.5% vs 34.3%, p p p p = 0.01). Conclusions Patients with snLVEF are prone to impaired cCFR, which may be related to the adverse prognosis. Further investigations are warranted to explore its underlying pathological mechanism and clinical significance.

Well-designed second near-infrared (NIR-II) fluorophores are promising in optical diagnosis and therapy of tumors. In this work, we synthesized a donor-acceptor-donor (D-A-D) NIR-II fluorophore named BBTD-BET with dithienylethene as an electron donor and benzobisthiadiazole as an electron acceptor. To the best of our knowledge, this is the first report of using dithienylethene, a typical photochromic molecule, as a building block for NIR-II fluorophores. We studied the geometrical configuration, electronic state, and optical properties of BBTD-BET by both theoretical and experimental means. BBTD-BET had absorption and emission in the NIR-I and NIR-II spectral ranges, respectively. Using PEGylated BBTD-BET as a theranostic agent, we achieved NIR-II fluorescence/photoacoustic (PA) dual-modal imaging and attained high imaging resolution, desired signal-to-noise ratio, and excellent photothermal therapy (PTT) efficacy. After one PTT treatment, the tumors established in mice were eradicated. This work provides a novel organic conjugated molecule integrating NIR-II/PA dual-modal imaging and PTT functionalities that is very promising in the theranostic of tumors.

Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.

Acute myeloid leukemia (AML) refers to one of the most lethal blood malignancies worldwide. FLT3-ITD mutation is recognized as the most common one that predicted a poorer prognosis. There have been many prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies. However, as impacted by undesirable off-target effects, differentiated metabolic issues, and clinical drug resistance problems, it remains challenging to discover alternative and promising solutions for treating FLT3-ITD+ AML. In this study, dovitinib was chemically modified and converted into CRBN-recruiting PROTACs. Two active compounds were identified, which showed enhanced antiproliferative effects against FLT3-ITD+ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin-proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD+ AML.

Purpose This single-arm, prospective, exploratory study investigated the effectiveness of ultra-low-dose radiotherapy in the treatment of ocular adnexal lymphoma (OAL). Patients and methods Patients with pathologically confirmed ocular adnexal low-grade non-Hodgkin lymphoma (predominantly mucosa-associated lymphoid tissue, MALT or follicular lymphoma) were included and treated with ultra-low-dose radiotherapy consisting of 2 successive fractions of 2 Gy at our institution between 2019 and 2021. Disease response was assessed clinically and radiographically within 4 months and at 3 to 6-month intervals after treatment. Data collected included rates of overall response, complete response (CR), partial response (PR), lesion size, and acute/chronic ocular toxic effects. Results Sixteen patients with median age of 63 years (range 23–86 years) were included in the study. The histological subtypes included MALT (11 patients; 69%); follicular lymphoma (2 patients; 12%); Lymphoid hyperplasia (3 patient, 19%). At a median follow-up time of 15.5 months (range 5.0–30.0 months), the overall response rate was 88%, with a CR rate of 75% (n = 12) and a PR rate of 13% (n = 2). The average lesion area was reduced from 117.9 ± 60.4 mm2 before radiation therapy to 38.7 ± 46.0mm2 at initial evaluation post radiation therapy (P = 0.002, n = 16), and to 8.5 ± 21.2 mm2 (P Conclusion Ultra–low-dose radiotherapy in patients with OAL is associated with excellent local disease control and long-term survival with no significant acute or late toxicities.

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

Atherosclerosis is a chronic systemic inflammatory disease that causes severe cardiovascular events. B cell lymphoma 2-associated athanogene (BAG3) was proven to participate in the regulation of tumor angiogenesis, neurodegenerative diseases, and cardiac diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the role of BAG3 in atherosclerosis and elucidate the potential molecular mechanism. In this study, ApoE−/− mice were given a tail-vein injection of BAG3-overexpressing lentivirus and fed a 12-week high-fat diet (HFD) to investigate the role of BAG3 in atherosclerosis. The overexpression of BAG3 reduced plaque areas and improved atherosclerosis in ApoE−/− mice. Our research proves that BAG3 promotes autophagy in vitro, contributing to the suppression of EndMT in human umbilical vein endothelial cells (HUVECs). Mechanically, autophagy activation is mediated by BAG3 via the interaction between BAG3 and its chaperones HSP70 and HSPB8. In conclusion, BAG3 facilitates autophagy activation via the formation of the chaperone-assisted selective autophagy (CASA) complex interacting with HSP70 and HSPB8, leading to the inhibition of EndMT during the progression of atherosclerosis and indicating that BAG3 is a potential therapeutic target for atherosclerosis.

This study aimed to further explore the underlying molecular mechanism of intracerebral hemorrhage (ICH), gene expression profile GSE24265, containing perihematomal tissues, contralateral grey matter, and contralateral white matter was retrieved and analyzed. The data was hierarchically clustered and the differentially expressed genes (DEGs) were screened. Functional analysis and protein interaction analysis of DEG hubs were performed, and the miRNA‑transcription factor (TF)‑target network was built. In addition, the candidate small-molecule compounds that might reverse the expression of an ICH‑linked gene were identified by CMap. This method revealed a total of 408 DEGs. Five modules including chemokine-related, antigen immune-related, pathogen infection, cell reaction, and positive regulation of tyrosine phosphorylation and MAPK cascade were identified. The expression levels of CCL5, CXCL8, ICAM1, IL-1B, IL-6, VCAM1, and VEGFA were correlated with ICH among the top 10 hub genes obtained in the protein protein interaction (PPI) network. A total of 237 miRNA‑TF‑target regulatory relationships were obtained, including 6 TFs, 11 miRNAs and 105 target genes. Finally, the CMap database identified Prestwick-1083, xamoterol, ifosfamide, methyldopate, nifurtimox, propranolol, and methoxamine as potential therapeutic agents for ICH while doxorubicin, menadione and azacitidine may increase its pathogenicity. Furthermore, CCL5, CXCL8 and VEGFA may be novel candidate susceptibility genes for ICH. Some small-molecule drugs, including xamoterol may be used for the treatment of ICH.

Rapid antigen detection tests are urgently needed for the early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The discovery of a binder with high affinity and selectivity for the biomarkers presented by SARS-CoV-2 is crucial to the development of the rapid antigen detection method. We utilized the surface biopanning to identify a peptide binder R1 from a phage-displayed peptide library consisting of 10

Syphilis remains a growing and resurging infectious disease in China. However, exploring the influence of environmental factors on the spatiotemporal distribution of syphilis remains under explore. This study aims to analyze the spatiotemporal distribution characteristics of syphilis in Ningxia, Northwest China, and its potential environmental influencing factors. Based on the standardized incidence ratio of syphilis for 22 administrative areas in Ningxia from 2004 to 2017, spatiotemporal autocorrelation and scan analyses were employed to analyze the spatial and temporal distribution characteristics of syphilis incidence, while a fixed-effect spatial panel regression model identified the potential factors affecting syphilis incidence. Syphilis incidence increased from 3.78/100,000 in 2004 to 54.69/100,000 in 2017 with significant spatial clustering in 2007 and 2009–2013. The “high–high” and “low–low” clusters were mainly distributed in northern and southern Ningxia, respectively. The spatial error panel model demonstrated that the syphilis incidence may be positively correlated with the per capita GDP and tertiary industry GDP and negatively correlated with the number of health facilities and healthcare personnel. Sex ratio and meteorological factors were not significantly associated with syphilis incidence. These results show that the syphilis incidence in Ningxia is still increasing and has significant spatial distribution differences and clustering. Socio-economic and health-resource factors could affect the incidence; therefore, strengthening syphilis surveillance of migrants in the economically developed region and allocating health resources to economically underdeveloped areas may effectively help prevent and control syphilis outbreaks in high-risk cluster areas of Ningxia.

Radiation therapy is widely used to treat a variety of malignant tumors, including non-small-cell lung cancer (NSCLC). However, ionizing radiation (IR) paradoxically promotes radioresistance, metastasis and recurrence by inducing epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Here, we developed two NSCLC radioresistant (RR) cell lines (A549-RR and H1299-RR) and characterized their motility, cell cycle distribution, DNA damage, and CSC production using migration/invasion assays, flow cytometry, comet assays, and sphere formation, respectively. We also evaluated their tumorigenicity in vivo using a mouse xenograft model. We found that invasion and spheroid formation by A549-RR and H1299-RR cells were increased as compared to their parental cells. Furthermore, as compared to radiation alone, the combination of β-elemene administration with radiation increased the radiosensitivity of A549 cells and reduced expression of EMT/CSC markers while inhibiting the Prx-1/NF-kB /iNOS signaling pathway. Our findings suggest that NSCLC radioresistance is associated with EMT, enhanced CSC phenotypes, and activation of the Prx-1/NF-kB/iNOS signaling pathway. They also suggest that combining β-elemene with radiation may be an effective means of overcoming radioresistance in NSCLC.

Highlights • The detection rate of hock-a-loogie saliva was higher than nasopharyngeal swabs. • Hock-a-loogie saliva sample had a higher viral load than throat swab. • Hock-a-loogie saliva sampling for SARS-CoV-2 detection is reliable., To clarify the effect of different respiratory sample types on SARS-CoV-2 detection, we collected throat swabs, nasal swabs and hock-a-loogie saliva or sputum, and compared their detection rates and viral loads. The detection rates of sputum (95.65%, 22/23) and hock-a-loogie saliva (88.09%, 37/42) were significantly higher than those in throat swabs (41.54%, 27/65) and nasal swabs (72.31%, 47/65) (P

Summertime ozone (O

Timely lysosome escape is of paramount importance for endocytosed nanomedicines to avoid premature degradation under the acidic and hydrolytic conditions in lysosomes. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs). On the basis of our experimental results, we speculate that the mechanism is associated with the specific interactions of the PBA groups with lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs; on the contrary, it enhances remarkably their tumor accumulation and penetration. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with a drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administrations. This work provides a novel strategy for facilitating the lysosome escape of nanomaterials and demonstrates that PBA modification is an effective way to improve the overall properties of nanomedicines including the tumor therapeutic efficacy.

The Jinchang Cohort was an ongoing 20-year ambispective cohort with unique metal exposures to an occupational population. From January 2014 to December 2019, the Jinchang Cohort has completed three phases of follow-up. The baseline cohort was completed from June 2011 to December 2013, and a total of 48 001 people were included. Three phases of follow-ups included 46 713, 41 888, and 40 530 participants, respectively. The death data were collected from 2001 to 2020. The epidemiological, physical examination, physiological, and biochemical data of the cohort were collected at baseline and during follow-up. Biological specimens were collected on the baseline to establish a biological specimen bank. The concentrations of metals in urine and serum were detected by inductively coupled plasma mass spectrometry (ICP-MS). The new areas of research aim to study the all-cases mortality, the burden of diseases, heavy metals and diseases, and the course of the chain from disease to high-risk outcomes using a combination of macro and micro means, which provided a scientific basis to explore the pathogenesis of multi-etiology and multi-disease and to evaluate the effects of the intervention measures in the population.

Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. Acute kidney injury (AKI) is a class of clinical conditions characterized by a rapid decline in kidney function. NAFLD and AKI, as major public health diseases with high prevalence and mortality, respectively, worldwide, place a heavy burden on societal healthcare systems. Clinical observations of patients with NAFLD with AKI suggest a possible association between the two diseases. However, little is known about the pathogenic mechanisms linking NAFLD and AKI, and the combination of the diseases is poorly treated. Previous studies have revealed that liver-derived factors are transported to distal organs via circulation, such as the kidney, where they elicit specific effects. Of note, while NAFLD affects the expression of many hepatic factors, studies on the mechanisms whereby NAFLD mediates the generation of hepatic factors that lead to AKI are lacking. Considering the unique positioning of hepatic factors in coordinating systemic energy metabolism and maintaining energy homeostasis, we hypothesize that the effects of NAFLD are not only limited to the structural and functional changes in the liver but may also involve the entire body via the hepatic factors, e.g., playing an important role in the development of AKI. This raises the question of whether analogs of beneficial hepatic factors or inhibitors of detrimental hepatic factors could be used as a treatment for NAFLD-mediated and hepatic factor-driven AKI or other metabolic disorders. Accordingly, in this review, we describe the systemic effects of several types of hepatic factors, with a particular focus on the possible link between hepatic factors whose expression is altered under NAFLD and AKI. We also summarize the role of some key hepatic factors in metabolic control mechanisms and discuss their possible use as a preventive treatment for the progression of metabolic diseases.

There is still inconsistent evidence over the protective effect of total bilirubin on the development of coronary heart disease (CHD). Therefore, we aimed to investigate the association between bilirubin in population subtypes and the risks of CHD between different gender and menstruation subgroups.In this prospective cohort study, 29,750 participants free of CHD with an average age of 47 ± 14 years were recruited at baseline; of these, 720 CHD first-attack cases were collected after 7-years of follow up. The covariate-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) of CHD with 95% confidence intervals (CIs). The serum bilirubin concentration was quarterly stratified based on the distribution of healthy population without CHD onset. The HRs of incident CHD decreased with elevated bilirubin in females (ρ trend0.05), but not males. In postmenopausal females, compared with the lowest quartile of total bilirubin, the adjusted HRs for the third and fourth quartiles were 0.64 (95% CI: 0.45, 0.93) and 0.59 (95% CI: 0.42, 0.86), the adjusted HRs in the third and fourth quartiles of direct bilirubin were 0.56 (0.39, 0.82) and 0.56 (0.38, 0.81), and for indirect bilirubin, corresponding HR in the highest quartile was 0.56 (0.38, 0.83).Elevated serum bilirubin was inversely associated with adjusted HRs of CHD in females, especially postmenopausal females. The relationship between elevated direct bilirubin and reduced HRs of CHD may be closer than indirect bilirubin in postmenopausal females.

BackgroundViral nucleic acid detection is considered the gold standard for the diagnosis of coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 infection. However, unsuitable sample types and laboratory detection kits/methods lead to misdiagnosis, which delays the prevention and control of the pandemic.MethodsWe compared four nucleic acid detection methods [two kinds of reverse transcription polymerase chain reactions (RT-PCR A: ORF1ab and N testing; RT-PCRB: only ORF1ab testing), reverse transcription recombinase aided amplification (RT-RAA) and droplet digital RT-PCR (dd-RT-PCR)] using 404 samples of 72 hospitalized COVID-19 patients, including oropharyngeal swab (OPS), nasopharyngeal swabs (NPS) and saliva after deep cough, to evaluate the best sample type and method for SARS-CoV-2 detection.ResultsAmong the four methods, dd-RT-PCR exhibited the highest positivity rate (93.0%), followed by RT-PCR B (91.2%) and RT-RAA (91.2%), while the positivity rate of RT-PCR A was only 71.9%. The viral load in OPS [24.90 copies/test (IQR 15.58-129.85)] was significantly lower than that in saliva [292.30 copies/test (IQR 20.20-8628.55)] and NPS [274.40 copies/test (IQR 33.10-2836.45)]. In addition, if OPS samples were tested alone by RT-PCR A, only 21.4% of the COVID-19 patients would be considered positive. The accuracy of all methods reached nearly 100% when saliva and NPS samples from the same patient were tested simultaneously.ConclusionsSARS-CoV-2 nucleic acid detection methods should be fully evaluated before use. High-positivity rate methods such as RT-RAA and dd-RT-PCR should be considered when possible. Furthermore, saliva after deep cough and NPS can greatly improve the accuracy of the diagnosis, and testing OPS alone is not recommended.

Background Coronary microvascular dysfunction (CMD) may precede clinically overt coronary artery disease (CAD). Overall and central obesity (CO) are major risk factors for CAD. This study sought to investigate the subclinical significance of body adiposity patterns based on the CMD risk. Methods A total of 128 patients with non-obstructive CAD were prospectively enrolled. Patients were categorized into 4 anthropometric groups: normal weight and non-CO (NWNCO, n = 41), normal weight and CO (NWCO, n = 20), excess weight and non-CO (EWNCO, n = 26), and excess weight and CO (EWCO, n = 41). Patients underwent rest/stress electrocardiography-gated 13N-ammonia positron emission tomography to measure absolute myocardial blood flow (MBF), myocardial flow reserve (MFR), hemodynamic parameters, and cardiac function. Results Resting MBF did not differ between groups (P = .36). Compared with the NWNCO group, hyperemic MBF and MFR were significantly lower in the NWCO and EWCO groups. Notably, patients with NWCO presented the lowest hyperemic MBF and MFR and the highest incidence of CMD. Waist circumference was an independent risk factor for CMD (OR 1.05, 95% CI 1.01 to 1.10, P = .02). Conclusion In patients with non-obstructive CAD, CO may be associated with an increased risk of CMD to better fit the study findings which did not assess management or monitoring of MBF and MFR.

The role of respiratory tract microbes and the relationship between respiratory tract and gut microbiomes in coronavirus disease 2019 (COVID-19) remain uncertain. Here, the metagenomes of sputum and fecal samples from 66 patients with COVID-19 at three stages of disease progression are sequenced. Respiratory tract, gut microbiome, and peripheral blood mononuclear cell (PBMC) samples are analyzed to compare the gut and respiratory tract microbiota of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between respiratory tract microbiome and immune response. In the respiratory tract, significantly fewer Streptococcus, Actinomyces, Atopobium, and Bacteroides are found in ICU than in nICU patients, while Enterococcus and Candida increase. In the gut, significantly fewer Bacteroides are found in ICU patients, while Enterococcus increases. Significant positive correlations exist between relative microbiota abundances in the respiratory tract and gut. Defensin-related pathways in PBMCs are enhanced, and respiratory tract Streptococcus is reduced in patients with COVID-19. A respiratory tract-gut microbiota model identifies respiratory tract Streptococcus and Atopobium as the most prominent biomarkers distinguishing between ICU and nICU patients. The findings provide insight into the respiratory tract and gut microbial dynamics during COVID-19 progression, considering disease severity, potentially contributing to diagnosis, and treatment strategies.

Purpose Abundant evidence has shown benefits of antivascular endothelial growth factor (anti-VEGF) therapies in neovascular eye diseases. However, the high cost, side effects, and inconvenience of frequent injections demand alternative novel drug candidates. This study aimed to analyze antiangiogenic effects of peptide H-KI20 and illustrated signaling mechanisms. Methods Live cell culture and tracing, wound healing assay, and tube formation were performed in human retinal microvascular endothelial cells (HRECs). The chick embryo chorioallantoic membrane and mouse oxygen-induced ischemic retinopathy model were applied to examine the effects of H-KI20 in vivo. The intracellular signaling pathways were examined. Molecular docking and surface plasmon resonance assay were used to validate the direct interaction of H-KI20 and c-Jun N-terminal kinase 2 (JNK2). Results H-KI20 had high penetration ability in vitro and in vivo. It inhibited motility, migration, and tube formation of HRECs, without cytotoxicity, and inhibited angiogenesis in vivo. Furthermore, H-KI20 treatment reduced the phosphorylation level of activating transcription factor 2 (ATF2) stimulated by VEGF via downregulating p-JNK. H-KI20 bound to JNK2 directly with a dissociation constant value of 83.68 µM. The knockdown of ATF2 attenuated VEGF-induced tube formation and decreased the movement speed of HRECs. Conclusions H-KI20 inhibited angiogenesis both in vitro and in vivo. The ratios of p-ATF2/ATF2 and p-JNK/JNK stimulated by VEGF were decreased by H-KI20, and H-KI20 targeted JNK2 directly. In addition, the pivotal role of ATF2 in VEGF-induced retinal neovascularization was elucidated for the first time. Taken together, H-KI20 displays potential for pathological retinal angiogenesis as a sustained and low-toxic peptide.

Background Radiotherapy is regarded as a milestone for the cure of cervical cancer. However, clinical outcome heavily be hindered by radioresistance. So, exploring the underlying mechanism of radioresistance, and find potential target, well deserve fully emphasis. Methods In this study, we developed two novel radiation resistance cervical cancer cell lines, which could mimic clinical radioresistance. In order to find new potential targets, RNA-Seq, database analysis, streptavidin-agarose and LC/MS were used. Pull-down, luciferase and rescue assays were conducted to explore the regulatory mechanisms. To further evaluate the correlation between therapeutic responses and HMGB3/hTERT expression, 172 cervical cancer patients were recruited. Results Knockdown of HMGB3 significantly inhibit the DNA damage repair and induced more γH2AX foci, leading to enhanced chemo- and radio-sensitivity in vitro and in vivo, whereas HMGB3 overexpression has the opposite effects. HMGB3 promotes cell growth and radioresistance by transcriptionally up-regulating hTERT via the specifical binding of HMGB3 at the hTERT promoter region from − 902 to − 321. HMGB3 knockdown-mediated radiosensitization could be reversed by the overexpressed hTERT in both cervical cancer cell lines and xenograft tumor mouse model. Furthermore, clinical data from 172 cervical cancer patients proved that there was a positive correlation between HMGB3 and hTERT expression, and high expression of HMGB3/hTERT predicted poor response to radiotherapy, worse TNM stages and shorter survival time. Conclusion Here, we have identified HMGB3/hTERT signaling axis as a new target for cervical cancer radioresistance. Our results provide new insights into the mechanism of cervical cancer radioresistance and indicate that targeting the HMGB3/hTERT signaling axis may benefit cervical cancer patients.

Here we used a meta-analysis of several clinical trials to determine whether anti-Helicobacter pylori therapy has any positive effect on IBS patients. Here we compared the effective clinical remission rates between IBS patients treated with anti-H. pylori therapy and those who were not. This data would provide more clinical evidence regarding the efficacy of novel treatments and intervention points for IBS patients. Relevant studies were identified using keyword searches on various electronic databases, including PubMed, Embase, the Cochrane Central Register of Controlled Trials, CNKI, and CBM. Keywords included “helicobacter pylori” and “irritable bowel syndrome” among others. The literature was screened using relatively strict inclusion and exclusion criteria and RevMan 5.3.5 and Stata 15.1 software were used for meta-analysis and to assess publication bias and sensitivity. A total of ten studies met all of the inclusion criteria; these included 655 IBS patients with H. pylori infection, of these, 385 patients were in the experimental group and 270 patients were in the control group. A random-effects model was used to pool the odds ratios (ORs) with a 95% confidence interval (CIs) and the combined OR was 2.87 (95% CI: 1.74-4.72), p

Stringent mitigation measures have reduced wintertime fine particulate matter (PM

Sepsis is a major cause of patient mortality and morbidity from bacterial infections. Although neutrophils are known to be important in the development of sepsis, how distinctive neutrophil subtypes regulate inflammatory processes involved in septicemia remains unclear. Preconditioning protects organisms against subsequent higher-dose exposures to the same, or even different, stimuli. Several studies have reported various effects of preconditioning on immune cells. However, the detailed mechanisms underlying neutrophil-mediated protection through preconditioning in sepsis remain unknown. Methods: Flow cytometry was conducted to sort the mice peritoneal lavage cells and the blood samples from patients with sepsis. Western blotting and ELISA were carried out to elucidate the expression of TLR9 signal transduction pathway proteins. Histological analysis was used to assess the effect of InP on intestine and liver structure in tlr9-/- and cav-1-/- mice. Fluorescence microscopy, Co-IP, and FRET were carried out to determine the association of TLR9 with Cav-1. Results: We show that membrane toll-like receptor-9 positive (mTLR9+) neutrophils exert a protective effect against fatal bacterial infections through the process of inflammatory preconditioning (InP). InP, which occurs in the setting of a low-dose bacterial challenge, active ingredient is Monophosphoryl lipid A (MPLA), triggers the membrane translocation of TLR9 from the neutrophil cytosol, where it binds to Cav-1. Our findings showed that InP enables TLR9 to facilitate MyD88-mediated TRAF3 and IRF3 signal transduction. Depletion of either TLR9 or Cav-1 largely eliminates the neutrophil-mediated InP effect in sepsis models in vitro and in vivo. Further, examination of clinical samples from patients with sepsis showed that clinical outcomes and likelihood of recovery are closely correlated with mTLR9 and Cav-1 expression in circulating neutrophils. Conclusion: These results demonstrate that the TLR9-Cav-1 axis is a critical signaling pathway involved in the regulation of neutrophil-dependent MPLA mediated InP, and the presence of mTLR9+ neutrophils could be an attractive indicator of clinical outcomes in bacterial sepsis that could be further explored as a potential therapeutic target.

Traditional organic fluorophores generally have hydrophobic conjugated backbones and exhibit an aggregation-caused quenching emission property, which limits greatly their applications in the biological field. Aggregation-induced emission (AIE) fluorophores can breakthrough this shortcoming and are more promising in biological imaging. In this paper, we synthesized three novel donor-acceptor-donor-type second near-infrared (NIR-II) fluorophores and studied their geometric and electronic structures and photophysical properties by both theoretical and experimental studies. All the three fluorophores had typical AIE characteristics, and their emission wavelength spanned the traditional near-infrared and NIR-II regions. They exhibited much stronger fluorescence after being encapsulated in polymer nanoparticles (NPs) than in solutions, and the fluorophore-loaded NPs had desirable biosafety and significant tumor accumulation, indicating that they have great application potentials in tumor detection.

Background. Recently, a large-scale novel coronavirus pneumonia (NCP) outbreak swept China. As of Feb. 9, 2020, a total of 40,260 patients have been diagnosed with NCP, and 23,589 patients were suspected to have infected by the 2019 novel coronavirus (COVID-19), which puts forward a great challenge for public health and clinical treatment in China. Until now, we are in the high-incidence season of NCP. Thus, the analysis of the transmissibility change of NCP and its potential factors may provide a reliable reference for establishing effective prevention and control strategies. Method. By means of the method of calculating the instantaneous basic reproduction number R0t proposed by Cori et al. (2013), we use R0t to describe the transmissibility change of COVID-19 in China, 2019-2020. In addition, the Baidu Index (BDI) and Baidu Migration Scale (BMS) were selected to measure the public awareness and the effect of Wuhan lockdown (restricted persons in Wuhan outflow from the epidemic area) strategy, respectively. The Granger causality test (GCT) was carried out to explore the association between public awareness, the effect of the Wuhan lockdown strategy, and the transmissibility of COVID-19. Results. The estimated averaged basic reproduction number of NCP in China was 3.44 with 95% CI (2.87, 4.0) during Dec. 8, 2019, to Feb. 9, 2020. The instantaneous basic reproduction numbers (R0t) have two waves and reaching peaks on Jan. 8 and Jan. 27, respectively. After reaching a peak on Jan. 27, R0t showed a continuous decline trend. On Feb. 9, R0t has fallen to 1.68 (95% CI: 1.66, 1.7), but it is still larger than 1. We find a significantly negative association between public awareness and the transmissibility change of COVID-19, with one unit increase in cumulative BDI leading to a decrease of 0.0295% (95% CI: 0.0077, 0.051) R0t. We also find a significantly negative association between the effect of the Wuhan lockdown strategy and the transmissibility change of COVID-19, and a one unit decrease in BMS may lead to a drop of 2.7% (95% CI: 0.382, 4.97) R0t. Conclusion. The current prevention and control measures have effectively reduced the transmissibility of COVID-19; however, R0t is still larger than the threshold 1. The results show that the government adopting the Wuhan lockdown strategy plays an important role in restricting the potential infected persons in Wuhan outflow from the epidemic area and avoiding a nationwide spread by quickly controlling the potential infection in Wuhan. Meanwhile, since Jan. 18, 2020, the people successively accessed COVID-19-related information via the Internet, which may help to effectively implement the government’s prevention and control strategy and contribute to reducing the transmissibility of NCP. Therefore, ongoing travel restriction and public health awareness remain essential to provide a foundation for controlling the outbreak of COVID-19.

Dopamine projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and from the substantia nigra (SN) to the dorsal striatum are involved in addiction. However, relatively little is known about the implication of these circuits in Internet gaming disorder (IGD). This study examined the alteration of resting-state functional connectivity (RSFC) and diffusion tensor imaging (DTI) -based structural connectivity of VTA/SN circuits in 61 young male participants (33 IGD and 28 healthy controls). Correlation analysis was carried out to investigate the relationship between the neuroimaging findings and the behavioral Internet Addiction Test (IAT). Both the NAc and medial orbitofrontal cortex (mOFC) showed lower RSFC with VTA in IGD subjects compared with controls. Moreover, the RSFC strength of VTA-right NAc and VTA-left mOFC correlated negatively with IAT in IGD subjects. The IGD subjects also showed lower structural connectivity in bilateral VTA-NAc tracts compared with controls, but the connectivity did not correlate with IAT in IGD. We provide evidence that functional and structural connectivity of the VTA-NAc pathway, and functional connectivity of the VTA-mOFC pathway are implicated in IGD. Since these pathways are important for dopamine reward signals and salience attribution, the findings suggest involvement of the brain DA reward system in the neurobiology of IGD. The association of functional but not structural connectivity of VTA circuits with IAT suggests that while lower structural connectivity might underlie vulnerability for IGD, lower functional connectivity may modulate severity. These results strengthen the evidence that IGD shares similar neuropathology with other addictions.

Background The population structure of human diarrheagenic Escherichia coli (DEC) isolates derived from worldwide collections remains undefined. Methods A total of 1196 clinical isolates were obtained from a multilocus sequence typing (MLST) database. Genetic diversity analysis, MLST analysis, and phylogenetic analysis combined with different pathotypes were performed through a variety of calculation software applications. Results All isolates were categorized as one of 579 different sequence types (STs). The eBURST algorithm resolved these 579 STs into 27 clonal complexes (CCs), 37 concatemers, and 210 singletons, revealing a high level of genetic diversity in the population structure of DEC. CC10 was the most prevalent CC, comprising 276 (23.08%, 276/1196) isolates with 85 (14.68%, 85/579) STs widely distributed in 20 countries. The population structure of five common pathotypes was highly diversified, and isolates with the same ST or CC were heterogeneous for different pathotypes. Sequence variations were more abundant in fumC and gyrB than in the other five genes, and these exhibited the highest degree of nucleotide diversity (0.03886 and 0.03075, respectively) and the greatest number of polymorphic nucleotide sites (137 and 139, respectively). The dN/dS ratios of seven analyzed loci varied from 0.0083 ( recA ) to 0.0434 ( purA ), and the ratio for the concatenated sequence was 0.2518, revealing the effects of purifying selection on housekeeping genes during the evolutionary process. Significant allele linkage disequilibrium was detected when the standardized index of association ( I S A ) was calculated both for the entire collection of isolates (0.3174, p 0.001) and for the 579 STs (0.1475, p 0.001). Conclusions This study facilitated a comprehensive understanding of the genetic diversity of human DEC distributed across the global population. The results provide genetic evidence that will allow us to uncover the microevolutionary relationships among different pathogenic isolates of DEC.

Thyroid hormones are key hormones involved in growth and development. Changes in their levels can cause embryonic brain developmental damage in the first trimester. Studies have shown that polybrominated diphenyl ethers (PBDEs) have developmental neurotoxicity as environmental pollutants, and exposure during pregnancy can cause irreversible brain damage in offspring, similar to the interference effects of thyroid hormones, but its mechanism has not yet been understood. Since the physiological environment for placental cells is highly hypoxic, in the current study, the human placenta-derived JEG cells were cultured at 1% oxygen, 4% carbon dioxide and 94% nitrogen, to reflect in vivo scenario, and the possible protection of taurine on BDE 209-mediated toxicity in JEG cells was studied. Our data showed that different concentrations of BDE 209 can have profound effects on cell viability and placental deiodinase 3 expression under hypoxic culture condition. Taurine was found to improve BDE 209-induced reductions in cell viability and altered gene and protein expressions of placental deiodinases. The results provide a reference for the establishment of early biomarkers and effective preventive measures.

PBDEs (stands for polybrominated diphenyl ethers) are extensively utilized flame retardants, and BDE 209 is one of the most widely used congeners. Studies have suggested the general toxic effects of PBDEs on the endocrine system and neural development. Our previous studies found that BDE 209 changed Type 3 iodothyronine deiodinase (Dio 3) expression in human SK-N-AS neuroblastoma cells. The current study was designed to examine the potential protection of taurine on alterations of Dio 3 expression induced by BDE 209 in SK-N-AS cells. Briefly, SK-N-AS cells were pretreated with taurine prior to the BDE 209 treatment, and the cell viability was evaluated by the MTT (methyl-thiazolyl-tetrazolium) assay. The disturbance or restoration in the levels of Dio 3 proteins and mRNA were observed separately by the western blot and qRT-PCR. Our data showed that taurine moderately attenuated BDE 209-mediated the loss of cell viability. Also, taurine moderately prevented the reduction in the Dio 3 protein expression and mRNA expression induced by BDE 209 in the SK-N-AS cells. Our findings indicated that taurine potentially provide the protection on PBDEs-induced toxicity on endocrine and neuro-development.

Taurine is an important amino acid for the growth and development of the central nervous system and plays an important role in the development of the nervous system. Many studies have shown that taurine can prevent and repair neurodevelopmental damage, and its mechanism has also become a research hotspot. While most studies focus on nerve cells, less on placental cells that are closely related to early neurodevelopment (developmental neurotoxicity) by modulating fetal circulation level of thyroid hormones. Studies have shown that exposure of placental cells to the common environmental endocrine disruptor BDE 209 during early pregnancy may lead to developmental neurotoxicity due to thyroid hormone interference caused by abnormal expression of deiodinases. Therefore, in this study, the placenta-derived JEG cells cultured at 95% air/5% CO2 was used as a in vitro model, and the potential protection from taurine on BDE 209-mediated cytotoxicity was examined. When BDE 209 was found to cause a decrease in cell viability and disturbance in the gene and protein expressions of placental deiodinase 3, pretreatment of the JEG cells with taurine can moderately reduce the BDE 209-meditated cytotoxicity, and restore gene and protein expressions of placental deiodinase, so that thyroid hormone levels tend to be normal in cell culture medium. Our data suggest that taurine may have some protection on the developmental neurotoxicity caused by BDE 209.

Acute diarrhea is an important public health issue. Here, we focused on the differences of enteropathogens in acute diarrhea between urban and rural areas in southeast China. Laboratory- and sentinel-based surveillance of acute diarrhea (≥ 3 loose or liquid stools/24 hours) was conducted at 16 hospitals. Fecal specimens were tested for bacterial (Aeromonas sp., Campylobacter sp., diarrheagenic Escherichia coli, Plesiomonas shigelloides, non-typhoidal Salmonella, Shigella sp., Vibrio sp., and Yersinia sp.) and viral (adenovirus, astrovirus, Norovirus, Rotavirus, and Sapovirus) pathogens. Descriptive statistics were used. Between January 1, 2010, and December 31, 2014, 4,548 outpatients with acute diarrhea were enrolled (urban, n = 3,220; rural, n = 1,328). Pathogens were identified in 2,074 (45.6%) patients. Norovirus (25.7%), Vibrio parahaemolyticus (10.2%), enteroaggregative Escherichia coli (EAEC) (8.8%), group A Rotavirus (7.0%), and enterotoxigenic Escherichia coli (ETEC) (5.6%) were the most common pathogens. Enteropathogens were less common in urban than in rural areas (42.0% versus 54.4%, P < 0.001). In urban areas, EAEC and ETEC were more common in high-income than in middle-income regions. Interventions targeting the most common enteropathogens can substantially reduce the burden of acute diarrhea in southeast China.

Decabromodiphenyl ether (BDE209) has been widely used as a flame retardant in the past four decades, leading to human health consequences, especially neurological impairments. Our previous in vivo studies have suggested that developmental neurotoxicity in offspring may be the result of BDE209-induced placental type III iodothyronine deiodinase (Dio3) disturbance and consequent thyroid hormone (TH) instability. Dio3 is paternally imprinted gene, and its balanced expression is crucial in directing normal development and growth. In this study, we used placenta-derived cells to investigate how BDE209 affected Dio3 expression through interfering imprinting mechanisms in the delta-like homolog 1 (Dlk1)-Dio3 imprinted region. Gene chip analysis and RT-qPCR identified miR409-3p, miR410-5p, miR494-3p, miR668-3p and miR889-5p as potential candidates involved in Dio3 deregulation. The sodium bisulfite-clonal sequencing revealed the BDE209 affect methylation status of two differentially methylated regions (DMRs), intergenic-DMR (IG-DMR) and maternally expressed gene 3-DMR (MEG3-DMR). Our data indicate that placental Dio3 may be a potential molecular target for future study of BDE209 developmental toxicity. In particular, miRNAs, IG-DMR and MEG3-DMR in the Dlk1-Dio3 imprinted locus may be informative in directing studies in TH disturbance and developmental toxicity induced by in utero exposure to environmental persistent organic pollutants (POPs), and those candidate miRNAs may prove to be convenient and noninvasive biomarkers for future large-scale population studies.

Objectives During surveillance, we found a new type of Vibrio parahaemolyticus named ‘O4:KUT-recAin' and studied the phenotypic, pathogenic and epidemiological characteristics of O4:KUT-recAin. Methods V. parahaemolyticus were isolated from acute diarrhoeal patients in coastal hospitals of China. Serum agglutination test, specific PCR assay, growth curves under different conditions and rabbit diarrhoeal models were using to characterize O4:KUT-recAin. Results The O4:KUT-recAin strain has a new type of K antigen and a 25 043-bp-large fragment encoding 20 proteins inserted in the housekeeping gene recA. Retrospective analysis found that only one O4:KUT-recAin strain was detected in 563 V. parahaemolyticus strains in 2014; then the proportion increased rapidly and reached 17.8% (105/590) in 2016 and 31.1% (224/721) in 2017, making O4:KUT-recAin the second dominant serotype following O3:K6. O4:KUT-recAin strains (100%, 14/14) exhibited increased acid resistance and could reproduce in medium at pH 4.9, while 92.9% (13/14) of the O3:K6 strains could not grow at this pH value. O4:KUT-recAin could cause diarrhoea and small intestinal tissue lesions in infant rabbits, but its diarrhoeal (93.1%, 27/29) and mortality (78.6%, 22/28) rates were slightly lower than those of O3:K6 (100% 16/16, 100% 16/16). Based on diarrhoea patients, there were no significant differences in the two groups for most clinical symptoms and laboratory results, except media age, haemoglobin and the number of red blood cells in stool samples. Conclusions O4:KUT-recAin had enhanced acid resistance, was capable of causing infectious diarrhoea in both rabbits and humans, and has become widespread during a short period of time in China.

Primary insomnia (PI) is associated with deteriorating attention, memory, physical and mood complaints. Based on the extensive literature demonstrating the critical roles of the thalamus in sleep regulation, we hypothesized that insomnia would be associated with functional and structural changes of the thalamus. This information is needed to better understand the neural mechanisms of insomnia, and would be useful for informing future attempts to alleviate or treat insomnia symptoms. Twenty-seven PI patients and 39 matched healthy controls were included in the present study. Subcortical volume and resting state functional connectivity (RSFC) of thalamus were compared between groups, and the relationships between neuroimaging differences and clinical features, including the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index Scale (ISI), the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS), also be explored. Compared with the control group, the PI group showed significantly reduced volume of thalamus. In addition, several brain regions showed reduced RSFC with thalamus in PI patients, such as anterior cingulate cortex (ACC), orbitofrontal cortex, hippocampus, caudate and putamen. Correlation analyses revealed that, several of these RSFC patterns were negatively correlated with PSQI score among PI patients, including thalamic connections with the putamen, caudate, hippocampus. Negative correlation was also observed between the RSFC strength of right thalamus–right ACC and SDS score in PI patients. This work demonstrates the structural and functional abnormalities of the thalamus in PI patients that were associated with key clinical features of insomnia. These data further highlight the important role of the thalamus in sleep and PI.

The aim of this study was to evaluate the 18F-sodium fluoride (18F-NaF) coronary uptake compared to coronary intravascular ultrasound (IVUS) in patients with symptomatic coronary artery disease. 18F-NaF PET enables the assessment of vascular osteogenesis by interaction with surface hydroxyapatite, while IVUS enables both identification and quantification of intra-plaque components. Forty-four patients with symptomatic coronary artery disease were included in this prospective controlled trial, 32 of them (30 patients with unstable angina and 2 patients with stable angina), representing the final study cohort, got additional IVUS. All patients underwent cardiac 18F-NaF PET/CT and IVUS within 2 days. 18F-NaF maximum tissue-to-blood ratios (TBRmax) were calculated for 69 coronary plaques and correlated with IVUS plaque classification. Significantly increased 18F-NaF uptake ratios were observed in fibrocalcific lesions (meanTBRmax = 1.42 ± 0.28), thin-cap atheroma with spotty calcifications (meanTBRmax = 1.32 ± 0.23), and thick-cap mixed atheroma (meanTBRmax = 1.28 ± 0.38), while fibrotic plaques showed no increased uptake (meanTBRmax = 0.96 ± 0.18). The 18F-NaF uptake ratio was consistently higher in atherosclerotic lesions with severe calcification (meanTBRmax = 1.34 ± 0.22). The regional 18F-NaF uptake was most likely localized in the border region of intensive calcification. Coronary lesions with positive 18F-NaF uptake showed some increased high-risk anatomical features on IVUS in comparison to 18F-NaF negative plaques. It included a significant severe plaque burden (70.1 ± 13.8 vs. 61.0 ± 13.8, p = 0.01) and positive remodeling index (1.03 ± 0.08 vs. 0.99 ± 0.07, p = 0.05), as well as a higher percentage of necrotic tissue (37.6 ± 13.3 vs. 29.3 ± 15.7, p = 0.02) in positive 18F-NaF lesions. 18F-NaF coronary uptake may provide a molecular insight for the characterization of coronary atherosclerotic lesions. Specific regional uptake is needed to be determined by histology.

Dysfunctions in frontostriatal circuits have been associated with craving and cognitive control in smokers. However, the relevance of white matter (WM) diffusion properties of the ventral and dorsal frontostriatal tracts for behaviors associated with smoking remains relatively unknown, especially in young adulthood, a critical time period for the development and maintenance of addiction. Here, diffusion tensor imaging (DTI) and probabilistic tractography were used to investigate the WM tracts of the ventral and dorsal frontostriatal circuits in two independent studies (Study1: 36 male smokers (21.3 ± 1.3 years) vs. 35 male nonsmokers (21.2 ± 1.3 years); Study2: 29 male smokers (21.4 ± 1.1 years) vs. 25 male nonsmokers (21.0 ± 1.4 years)). Subjective craving was measured by the Questionnaire on Smoking Urges (QSU) and cognitive control ability was assessed with the Stroop task. In both studies, smokers committed more response errors than nonsmokers during the incongruent condition of the Stroop task. Relative to controls, smokers showed lower fractional anisotropy (FA) and higher radial diffusivity in left medial orbitofrontal cortex-to-nucleus accumbens fiber tracts (ventral frontostriatal path) and also lower FA in right dorsolateral prefrontal cortex-to-caudate fiber tracts (dorsal frontostriatal path). The FA values of the right dorsal fibers were negatively correlated with incongruent response Stroop errors in smokers, whereas the mean diffusivity values of the left ventral fibers were positively correlated with craving in smokers. Thus, WM diffusion properties of the dorsal and ventral frontostriatal tracts were associated with cognitive control and craving, respectively, in young male tobacco smokers. These data highlight the importance of studying WM in relation to neuropsychological changes underlying smoking.

Previous diffusion tensor imaging (DTI) studies had investigated the white matter (WM) integrity abnormalities in some specific fiber bundles in smokers. However, little is known about the changes in topological organization of WM structural network in young smokers. In current study, we acquired DTI datasets from 58 male young smokers and 51 matched nonsmokers and constructed the WM networks by the deterministic fiber tracking approach. Graph theoretical analysis was used to compare the topological parameters of WM network (global and nodal) and the inter-regional fractional anisotropy (FA) weighted WM connections between groups. The results demonstrated that both young smokers and nonsmokers had small-world topology in WM network. Further analysis revealed that the young smokers exhibited the abnormal topological organization, i.e., increased network strength, global efficiency, and decreased shortest path length. In addition, the increased nodal efficiency predominately was located in frontal cortex, striatum and anterior cingulate gyrus (ACG) in smokers. Moreover, based on network-based statistic (NBS) approach, the significant increased FA-weighted WM connections were mainly found in the PFC, ACG and supplementary motor area (SMA) regions. Meanwhile, the network parameters were correlated with the nicotine dependence severity (FTND) scores, and the nodal efficiency of orbitofrontal cortex was positive correlation with the cigarette per day (CPD) in young smokers. We revealed the abnormal topological organization of WM network in young smokers, which may improve our understanding of the neural mechanism of young smokers form WM topological organization level.

This 8-week, randomized, double-blind, parallel-group study compared the efficacy and safety of aliskiren with ramipril in Asian patients with mild to moderate hypertension. Following a 2- to 3-week placebo run-in period, patients with mean sitting diastolic blood pressure (msDBP) ⩾95 and

A total of 98 paired soil and outdoor dust samples were collected across mainland China for survey of perchlorate. Perchlorate was detected in all of the soil and outdoor dust samples. High levels of perchlorate were found in soil, ranging from 0.001 to 216 mg/kg in Northern China and from 0.001 to 25.8 mg/kg in Southern China. Even higher perchlorate concentrations were detected in dust samples, with concentrations ranging from 0.132 to 5300 mg/kg in Northern China, and from 0.270 to 3700 mg/kg in Southern China. This is the first known report of perchlorate in dust samples. The high perchlorate levels in soil and dust may raise concern on the potential risk for organisms and human. The daily perchlorate intakes were evaluated based on our measured perchlorate concentrations via inhalation, ingestion, and dermal contact of soil and dust for both children and adults, respectively. In general, the exposure from soil does not appear to lead to perchlorate intakes exceeding the US EPA reference for both children and adults. However, children can be at risk from exposure to perchlorate via dust, and it needs considerable concern for both children and adults at the sites with high dust perchlorate concentrations. After comparison with other possible exposure pathways, such as from drinking water, we suggested that dust may be an important potential source of perchlorate exposure in China, and further study is needed, especially for indoor dust.

Vibrio parahaemolyticus is a leading cause of food-borne diarrhoea in coastal countries. Although V. parahaemolyticus cases have been reported since 1950, they have been poorly documented. From July 2009 to June 2013, we collected 6951 faecal specimens for pathogen detection; V. parahaemolyticus strains were isolated from 563 specimens (8.1%). We then analysed the characteristics of the 501 V. parahaemolyticus strains that were isolated as the sole pathogen. Twenty-one serotypes were identified among these strains; O3:K6 was the most common serotype (65.1%), followed by O4:K8, O4:K68 and O1:K36. One strain of the O4:K18 serotype was isolated from clinical patients for the first time. Pandemic O3:K6 clones were predominant and accounted for 69.1% of all of the pandemic strains. This is the first report of one strain expressing the O3:K8 serotype with a pandemic genotype. The presence of the haemolysin gene tdh (93.0%) was the key characteristic of the virulent strains; however, a few strains carried the trh gene. We also confirmed the presence of the type III secretion system 2 (T3SS2) genes in all of the pathogenic strains. Subsequent multilocus sequence typing split the isolates into 16 sequence types (STs), with ST3 and ST88 as the most prevalent in southeastern China. Most isolates were sensitive to common antimicrobial agents, apart from ampicillin. However, the resistance rate to ampicillin has apparently increased in this area. In conclusion, our results indicate that pandemic O3:K6 V. parahaemolyticus isolates are predominant in southeastern China, and additional surveillance should be conducted to facilitate control of the transmission of this pathogen.

A majority of hypertensives require treatment with ≥2 antihypertensive therapies to achieve blood pressure (BP) goals. Single-pill combinations (SPC) may improve convenience and adherence to therapy and reduce health care resource use and costs. The antihypertensive effects of amlodipine and valsartan are well established. This study evaluated the efficacy and safety of amlodipine/valsartan 5/160 mg SPC for the treatment of hypertension in predominantly Chinese patients not adequately controlled on valsartan 160 mg alone.In this multicentre study (24 centres), adults with stage 1 or 2 hypertension not adequately controlled with valsartan monotherapy were randomised to receive double-blind amlodipine/valsartan 5/160 mg SPC or valsartan 160 mg once daily for 8 weeks.The least-square mean change (standard error) from baseline to endpoint in mean sitting diastolic blood pressure (MSDBP) at trough, the primary efficacy variable, was -10.3 (0.39) mm Hg with amlodipine/valsartan and -6.6 (0.40) mm Hg with valsartan (difference: -3.7 [0.54] mm Hg, p0.0001). The corresponding results for mean sitting systolic blood pressure (MSSBP) were -14.9 (0.61) mm Hg and -7.0 (0.61) mm Hg, respectively (difference: -7.9 [0.84] mm Hg, p0.0001). A significantly greater proportion of patients achieved overall BP control (MSSBP/MSDBP140/90 mm Hg) with combination therapy (61.3%) versus monotherapy (39.3%; p0.0001). Both treatments were well tolerated.Amlodipine/valsartan 5/160 mg SPC is a safe and effective therapy for lowering BP in predominantly Chinese adults with stage 1 or 2 hypertension not adequately controlled with valsartan 160 mg monotherapy.

The antihypertensive efficacy of amlodipine/valsartan combination has not been evaluated in Asian patients as previous large-scale studies enrolled very few patients. This multicentre, randomised, double-blind study assessed the efficacy and safety of a single-pill combination of amlodipine/valsartan versus amlodipine in Asian hypertensive patients.After a 1-4-week washout period, patients (mean sitting diastolic BP [msDBP]:or=95-110 mmHg) were treated with amlodipine 5 mg for 4 weeks. Patients inadequately controlled on amlodipine (msDBPor=90 and110 mmHg) were randomised to receive amlodipine/valsartan 5/80 mg (n = 349) or amlodipine 5 mg (n = 349) for 8 weeks. Efficacy variables were change in msDBP, mean sitting systolic BP (msSBP) from baseline (at randomisation) to week 8 endpoint, and BP control rate (140/90 mmHg) at week 8 endpoint. Safety assessments included monitoring and recording of adverse events (AEs).Baseline characteristics were comparable between the groups. Most patients were Chinese (86.4%), men (65.1%), with a baseline BP 139.5/94.5 mmHg. At week 8 endpoint, the least square mean reduction in BP was significantly greater with amlodipine/valsartan combination than amlodipine monotherapy (-11.4/-9.7 vs. -7.4/-7.1 mmHg; p0.0001) with a higher BP control rate (69.2 vs. 57.6%; p = 0.0013). Ambulatory BP monitoring in a subgroup of patients (n = 82), showed a significant 24-h mean BP reduction from baseline with amlodipine/valsartan (-7.3/-6.3 mmHg; p0.0001), whereas the reduction was not significant with amlodipine (-0.2/+0.3 mmHg; p0.05). The overall incidence of AEs was similar in both groups. Peripheral oedema occurred only in the amlodipine group n = 4 (1.1%) and not in the amlodipine/valsartan combination. Hypotension was reported in only one patient in the amlodipine/valsartan combination. Six patients (0.9%) experienced serious AEs, of which only one SAE, i.e. gastric ulcer, was reported to be related to amlodipine treatment.The single-pill combination of amlodipine/valsartan was efficacious and well-tolerated in Asian hypertensive patients who were inadequately controlled on amlodipine alone. As with all clinical trials, the entry criteria may limit the extrapolation of these results to a broader population. ClinicalTrials.gov Identifier: NCT00413049.