Search

Mutations in hERG (human ether-a-go-go-related gene) potassium channel are closely associated with long QT syndromes. By direct Sanger sequencing, we identified a novel KCNH2 mutation W410R in the patient with long QT syndrome 2 (LQT2). However, the electrophysiological functions of this mutation remain unknown. In comparison to hERGWT channels, hERGW410R channels have markedly decreased total and surface expressions. W410R mutation dramatically reduces hERG channel currents (IKr) and shifts its steady-state activation curve to depolarization. Moreover, hERGW410R channels make dominant-negative effects on hERGWT channels. Significantly, we find hERG channel blocker E-4031 could partially rescue the function of hERGW410R channels by increasing the membrane expression. By using in silico model, we reveal that hERGW410R channels obviously elongate the repolarization of human ventricular myocyte action potentials. Collectively, W410R mutation decreases the currents of hERG channel, because of diminished membrane expression of mutant channels, that subsequently leads to elongated repolarization of cardiomyocyte, which might induce the pathogenesis of LQT2. Furthermore, E-4031 could partially rescue the decreased activity of hERGW410R channels. Thus, our work identifies a novel loss-of-function mutation in KCNH2 gene, which might provide a rational basis for the management of LQT2.

Blood coagulation is the process of changing the blood from the flowing state to the gel state. It is an important part of the hemostatic function. Coagulation is a process by which a series of coagulation factors are sequentially activated, and finally thrombin is formed to form fibrin clot. Direct thrombin inhibitors are important anticoagulant drug. These drugs can selectively bind to the active site of thrombin, inhibit thrombin activity, have strong action and high specificity, and have important significance in the clinical treatment of thrombus diseases. Some of them come from natural products of animals or plants, and many of them have been applied in the clinic. The other part is derived from the design, synthesis and activity studies of small molecule inhibitors. This review discusses the progress of direct thrombin inhibitors in recent years.

Dry eye symptoms as a complication of double-eyelid blepharoplasty are controversial. This article evaluates tear film dynamics and changes in dry eye symptoms after cosmetic double-eyelid blepharoplasty in young Asian female. One hundred and twenty patients underwent full-incisional double-eyelid blepharoplasty. Subjective and objective parameters were documented before surgery, at 1 week, 1 month and 3 months post-surgery, which included Ocular Surface Disease Index questionnaire (OSDI), tear meniscus height (TMH), noninvasive breakup time (NIBUT), Schirmer I test, corneal and conjunctival fluorescein staining scores, and palpebral fissure height. Dry eyes were defined based on the DEWS II criteria: OSDI ≥ 13 points and NIBUT

Objectives: To study the pharmacokinetics, safety and immunogenicity of Recombinant Human Tumor Necrosis Factor-α Receptor II: IgG Fc Fusion Protein for Injection (QL0902) and evaluate the pharmaco...

Objective To evaluate the differences between two types of decompression for treating large mandibular odontogenic cysts. Materials and methods This retrospective, cohort study included patients who were diagnosed for large mandibular odontogenic cysts from January 2015 to April 2018 and underwent two different types of decompression based on removal or retention of the cyst wall. The primary outcome was the percentage of the residual cyst area within 1 year after surgery. We used the propensity score matching (PSM) to balance the covariates of the two groups, and the primary outcome was analyzed by the non-inferiority test. Results A total of 93 cases were included in our study. After 1 year, the wall removal group was non-inferior to the wall retaining group in terms of cyst area, cyst volume, and the difference between the HU values of the original cyst region and the normal mandible. In subgroup analysis, we found there were no differences between two groups in the percentage of patients in whom the cystic area was reduced by 90% after 1 year. Conclusion Our findings suggest that the wall removal group showed better results than the cyst wall retaining group in large mandibular odontogenic cysts.

Mitogen-activated protein kinase (MAPK) cascades are fundamental signal transduction modules in all eukaryotic organisms, participating growth and development, as well as stress response. In the present study, three MAPK genes were successfully identified from the genome of Chlamys farreri, respectively, named CfERK1/2, CfJNK, and Cfp38, and only one copy of ERK, JNK, and p38 were detected. Domain analysis indicated that CfMAPKs possessed the typical domains, including S_TKc, Pkinase, and PKc_like domain. Phylogenetic analysis showed that three CfMAPKs of MAPK subfamilies exists in the common ancestor of vertebrates and invertebrates. All CfMAPKs specifically expressed during larval development and in adult tissues, and the expression level of CfERK1/2 and Cfp38 was apparently higher than that of CfJNK. Under heat stress, the expression of CfERK1/2 and Cfp38 were significantly downregulated and then upregulated in four tissues, while the expression of CfJNK increased in all tissues; these different expression patterns suggested a different molecular mechanism of CfMAPKs for bivalves to adapt to temperature changes. The diversity of CfMAPKs and their specific expression patterns provide valuable information for better understanding of the functions of MAPK cascades in bivalves.

This study was conducted to investigate the effect of dietary Yucca schidigera extract (YSE) supplementation to sow performance, nutrients digestibility and ammonia emission of manure. Total 80 sows were randomly divided into 4 groups and fed with either control, control + 0.06% YSE, control + 0.12% YSE or control + 0.24% YSE diet from day 80 of gestation to day 21 of lactation. The results showed that dietary YSE supplementation resulted in trends toward a reduced number of stillbirth piglets (P = 0.08), weak piglets (P = 0.06), pre-weanling mortality (P = 0.04) and diarrhea (P = 0.03), and improved apparent digestibility of dry matter (P = 0.04). Besides, YSE supplementation significantly increased catalase activity (P = 0.02) while decreasing malonaldehyde levels (P = 0.04) in sow blood. Furthermore, the loss of total nitrogen, urea nitrogen and ammonia nitrogen in sow manure were significantly reduced with supplementation of YSE. In summary, supplementation of YSE in sow diet during late gestation and lactation could improve sow and litter performance, nutrient digestibility, and reduce nitrogen loss in sow manure during storage.

The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases1,2. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous 'lactate clock' in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

Tiwari et al. identify metabolically activated macrophages in obese mammary adipose tissue as an important source of IL-6, which fuels triple-negative breast cancer stemness and tumorigenesis through GP130 signaling. These mechanistic insights provide potential targets for treating obesity-associated triple-negative breast cancer., Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)–dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity., Graphical Abstract

The development of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides significant advances to cell therapy, disease modeling, and drug screening applications. However, the current differentiation protocol is inefficient in mimicking biophysical and biochemical characteristics of cardiac niche. Hence, immature cardiomyocytes are often generated. In this study, hiPSC-CMs were generated on a new family of substrates called monolayer binary colloidal crystals (BCCs). Four BCCs were fabricated with different sizes (2 or 5 or 0.4 or 0.2 μm) and materials [Si or polystyrene (PS) or poly(methyl methacrylate)] abbreviated as 2PS, 5PS, 2PM, and 5PM. BCCs have complex surface micro-/nanotopographies and heterogeneous chemistries which are important modulators in microenvironments in vitro. The results showed that hiPSCs formed adhered spheroids with strong pluripotent markers ( Oct4, Nanog, and Sox2) on PM surfaces compared to PS and flat surfaces. After 30-day differentiation, hiPSC-CMs on PM surfaces showed markedly improved myofibril ultrastructures, Ca

Phagocytes destroy pathogens by trapping them in a transient organelle called the phagosome, where they are bombarded with reactive oxygen species (ROS) and reactive nitrogen species (RNS). Imaging reactive species within the phagosome would directly reveal the chemical dynamics underlying pathogen destruction. Here we introduce a fluorescent, DNA-based combination reporter, cHOClate, which simultaneously images hypochlorous acid (HOCl) and pH quantitatively. Using cHOClate targeted to phagosomes in live cells, we successfully map phagosomal production of a specific ROS, HOCl, as a function of phagosome maturation. We found that phagosomal acidification was gradual in macrophages and upon completion, HOCl was released in a burst. This revealed that phagosome-lysosome fusion was essential not only for phagosome acidification, but also for providing the chloride necessary for myeloperoxidase activity. This method can be expanded to image several kinds of ROS and RNS and be readily applied to identify how resistant pathogens evade phagosomal killing.

Peripheral blood mononuclear cells (PBMCs) were harvested and reprogramed to induced pluripotent stem cells (iPSCs) from a 46-year-old male patient with familial dilated cardiomyopathy and atrial fibrillation via a non-integrating system. A missense mutation in the LMNA gene (c.1003C > T) was identified by whole-exome sequencing and verified by Sanger sequencing. The pluripotency, differentiation potential, and karyotype of this cell line were also tested. This model is helpful to study the phenotype, mechanism, and therapy for laminopathy.

Human-induced pluripotent stem cell (hiPSC) technology and directed cardiac differentiation technology can provide a continuous supply of cells for disease modeling, drug screening, and cell therapy. However, two-dimensional (2D) cells often fail to faithfully reflect the physiological structure and function of the heart. Considering the contractile function is the most critical and easy-to-understand function of cardiomyocytes, the engineered cardiac tissues (ECT) with mechanical properties may serve as an appropriate three-dimensional (3D) platform for drug evaluation. At present, there are various methods to generate ECTs, some of which are quite costly. In the present study, we proposed that human foreskin fibroblast (HFF) cells, as a cost-effective and accessible cell source, can promote the compaction and remodeling of ECTs. The HFFs derived ECTs displayed stable structural and functional characteristics with a higher performance-to-price ratio. Moreover, both ECTs made from atrial and ventricular cardiomyocytes showed an excellent drug response, demonstrating that the ECT with HFFs as an easy and reliable platform for drug evaluation.

Background and aims Observational studies have suggested that plasma lipids contribute substantially to cardiovascular disease, but “cholesterol paradox” in atrial fibrillation (AF) remains. We sought to investigate the causal effects of lipid profiles on the risk of AF. Methods and results Two-sample Mendelian randomization (MR) framework was implemented to examine the causality of association. Summary estimations of genetic variants associated with low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total cholesterol, triglycerides, lipoprotein-a [Lp(a)], apolipoprotein A1 (ApoA 1), and apolipoprotein B (ApoB) were 81, 99, 96, 61, 30, 10, and 23 single nucleotide polymorphisms, respectively. Genetic association with AF were retrieved from a genome-wide association study that included 1,030,836 individuals. The complications for AF were predefined as cardioembolic stroke (CES) and heart failure (HF). In the multivariable MR, the odds ratios for AF per standard deviation (SD) increase were 1.030 (95% confidence interval (CI) 0.979–1.083; P = 0.257) for LDL-cholesterol, 0.986 (95% CI 0.931–1.044; P = 0.622) for HDL-cholesterol, 0.965 (95% CI 0.896–1.041; P = 0.359) for triglycerides, 1.001 (95% CI 1.000–1.003; P = 0.023) for Lp(a), 1.017 (95% CI 0.966–1.070; P = 0.518) for ApoA1, and 1.002 (95% CI 0.963–1.043; P = 0.923) for ApoB. There was no evidence that other lipid components were causally associated with AF, CES, or HF, other than for a marginal association between triglycerides and HF. Conclusions This MR study provides robust evidence that high Lp(a) increases the risk of AF, suggesting that interventions targeting Lp(a) may contribute to the primary prevention of AF.

Roller pumps have been widely used in the ventricular assist field for many years, while the significant hemolysis caused by its mechanical stress is still a fundamental problem. Although the usual under-occlusion setting was considered as an effective method to reduce the hemolysis rate, its nonocclusive condition of the whole process may cause serious backflow results, which exactly places many restrictions on this method. In this study, the simulation experiments based on computational fluid dynamics (CFD) is conducted, and the occlusion angle is proposed and used to explore a more reliable adjustment form of the occlusion condition. The parameterized geometry of a roller pump is established based on the occlusion angle and other parameters. In order to simulate the motion of the roller, the dynamic mesh mode is introduced to the CFD model, and the analytic formulations used to determine the boundary position are derived. In the whole operation process of the roller pump, four feature positions of the rollers were focused and extracted, and the flow characteristics and the shear stress distribution at these positions were demonstrated. It was found that the entry and exit of the rollers could cause clear shear stress peak, especially when one roller entered, the peak got extremely high. Furthermore, the roller pumps with different occlusion angles were compared, and the results showed that decreasing the occlusion angle could lead to a notable decrease in the amplitude and range of high shear stress and the hemolysis index with a small loss of the occlusion duration. It can be concluded that appropriately decreasing the occlusion angle may be an effective method to alleviate the hemolysis which should be given more attention.

© 2020 Annual Reviews Inc.. All rights reserved. Ribonucleotide reductases (RNRs) catalyze the de novo conversion of nucleotides to deoxynucleotides in all organisms, controlling their relative ratios and abundance. In doing so, they play an important role in fidelity of DNA replication and repair. RNRscentral role in nucleic acid metabolism has resulted in five therapeutics that inhibit human RNRs. In this review, we discuss the structural, dynamic, and mechanistic aspects of RNR activity and regulation, primarily for the human and Escherichia coli class Ia enzymes. The unusual radical-based organic chemistry of nucleotide reduction, the inorganic chemistry of the essential metallo-cofactor biosynthesis/maintenance, the transport of a radical over a long distance, and the dynamics of subunit interactions all present distinct entry points toward RNR inhibition that are relevant for drug discovery. We describe the current mechanistic understanding of small molecules that target different elements of RNR function, including downstream pathways that lead to cell cytotoxicity. We conclude by summarizing novel and emergent RNR targeting motifs for cancer and antibiotic therapeutics.

Background Idiopathic isolated fibrotic atrial cardiomyopathy (IIF-ACM) is a novel subtype of cardiomyopathy characterized by atrial fibrosis that does not involve the ventricular myocardium and is associated with significant atrial tachyarrhythmia. The mechanisms underlying its pathogenesis are unknown. Methods Atrium samples were obtained from 3 patients with IIF-ACM via surgical intervention. Control samples were consisted of 3 atrium biopsies from patients with congenital heart disease and normal sinus rhythm, matched for gender, age and basic clinical characteristics. Comparative histology, immunofluorescence staining, electron microscopy and proteomics analyses were carried out to explore the unique pathogenesis of IIF-ACM. Results IIF-ACM atria displayed disordered myofibrils, profound fibrosis and mitochondrial damages compared to the control atria. Proteomics profiling identified metabolic pathways as the most profound changes in IIF-ACM. Conclusions Our study suggested that metabolic changes in the atrial myocardium caused mitochondrial oxidative stress and potential cell damage, which further led to atrial fibrosis and myofibril disorganization, the characteristic phenotype of IIF-ACM.

SUMMARY Type 2 diabetes (T2D) is associated with increased risk for atherosclerosis; however, the mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. Here, we use proteomics to show that diet-induced obesity and insulin resistance (obesity/IR) modulate a pro-atherogenic “macrophage-sterol-responsive-network” (MSRN), which, in turn, predisposes macrophages to cholesterol accumulation. We identify IFNγ as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFNγ production. Accordingly, myeloid cell-specific deletion of the IFNγ receptor (Ifngr1−/−) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis, and uncouples the strong relationship between hyperinsulinemia and aortic root lesion size in hypercholesterolemic Ldlr−/− mice with obesity/IR, but does not affect these parameters in Ldlr−/− mice without obesity/IR. Collectively, our findings identify an IFNγ-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis., Graphical Abstract In Brief: Obesity and insulin resistance are major risk factors for cardiovascular disease, but the underlying mechanisms are poorly understood. Reardon et al. show that obesity and insulin resistance induce an IFNγ-macrophage pathway that exacerbates foam cell formation and aortic lesion size in atherosclerotic mice.

Background/Aims: Heart failure induced by tachycardia, the most common arrhythmia, is frequently observed in clinical practice. This study was designed to investigate the underlying mechanisms. Methods: Rapid electrical stimulation (RES) at a frequency of 3 Hz was applied on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for 7 days, with 8 h/day and 24 h/day set to represent short-term and long-term tachycardia, respectively. Age-matched hiPSC-CMs without electrical stimulation or with slow electrical stimulation (1 Hz) were set as no electrical stimulation (NES) control or low-frequency electrical stimulation (LES) control. Following stimulation, JC-1 staining flow cytometry analysis was performed to examine mitochondrial conditions. Apoptosis in hiPSC-CMs was evaluated using Hoechst staining and Annexin V/propidium iodide (AV/PI) staining flow cytometry analysis. Calcium transients and L-type calcium currents were recorded to evaluate calcium homeostasis. Western blotting and qPCR were performed to evaluate the protein and mRNA expression levels of apoptosis-related genes and calcium homeostasis-regulated genes. Results: Compared to the controls, hiPSC-CMs following RES presented mitochondrial dysfunction and an increased apoptotic percentage. Amplitudes of calcium transients and L-type calcium currents were significantly decreased in hiPSC-CMs with RES. Molecular analysis demonstrated upregulated expression of Caspase3 and increased Bax/Bcl-2 ratio. Genes related to calcium re-sequence were downregulated, while phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) was significantly upregulated following RES. There was no significant difference between the NES control and LES control groups in these aspects. Inhibition of CaMKII with 1 µM KN93 partly reversed these adverse effects of RES. Conclusion: RES on hiPSC-CMs disturbed calcium homeostasis, which led to mitochondrial stress, promoted cell apoptosis and caused electrophysiological remodeling in a time-dependent manner. CaMKII played a central role in the damages induced by RES, pharmacological inhibition of CaMKII activity partly reversed the adverse effects of RES on both structural and electrophysiological properties of cells.

Background Norovirus (NoV), a member of the Caliciviridae, is now recognized as the leading cause of acute gastroenteritis (AGE) worldwide. Globally, the GII.4 Sydney_2012 variant has predominated in NoV-related AGE since 2012, although the novel variant GII.17 has also been reported as responsible for gastroenteritis outbreaks in East Asia since 2014. This study aimed to disclose the recent genotype patterns of NoV genogroup II (GII) presenting in AGE patients in Pudong New Area of Shanghai through a laboratory-based syndromic surveillance system. The study further aimed to delineate the predominant strains circulating in the population. Methods Pudong New Area is located in eastern Shanghai and covers 20.89% of the Shanghai population. The laboratory-based syndromic surveillance system is composed of 12 sentinel hospitals among the 68 general hospitals in this area. AGE patients who sought medical care were sampled following an AGE surveillance protocol. Stool samples were collected from participating patients, and a standardized questionnaire was given to each patient by trained nurses to gain information on the disease profiles and demographics of the patients. Real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to screen the GI nd GII NoV and RT-PCR was used to amplify NoV GII partial capsid protein open reading frame 2 (ORF2). NoV Genotyping Tool (version 1.0, RIVM, MA Bilthoven, Netherlands) was used for genotyping, and a phylogenetic analysis was conducted by MEGA 7.0. Results During 2014–2016, among the 2069 virus-infected AGE cases, 65.88% were caused by NoV. NoV-AGE occurred most frequently in the periods from October to March. The patients with more severe diarrheal symptoms and vomiting were more likely to be infected by NoV. The main genotypes were GII.17 (44.69%) and GII.4 (39.26%), which dominated the NoV-AGE epidemics jointly or in turn, whereas a slight increase in GII.2 was observed beginning in May 2016. The GII.17 strains tended to cluster more with the Hu/JP/2014/GII.P17_GII.17/Kawasaki323 variants, representing novel prevalent strains. Among the GII.4 strains, the GII.4 Sydney_2012 variant was still the predominant strain. Conclusions NoV GII has become the main cause of virus-infected AGE in Pudong New Area, Shanghai. The predominant genotypes of NoV GII were GII.17 and GII.4. Comprehensive laboratory-based surveillance is important for clinical diagnosis and treatment. Identification of emerging new genotypes is also crucial for the prevention and control of NoV-infected AGE.

Aims Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT. Methods and results Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment. Conclusion Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.

More than 30 residents and nursing assistants in a geriatric nursing hospital developed acute gastroenteritis from December 7th to December 18th, 2014 in Shanghai, China. An immediate epidemiological investigation was conducted to identify the etiological agent of the outbreak, mode of transmission and the risk factors. Cases were investigated according to an epidemiological questionnaire. Samples from cases, highly transmissible environmental surfaces and drinking water were collected for pathogens detection. A retrospective cohort study was conducted to explore the transmission mode. A total of 34 cases were affected in this acute gastroenteritis outbreak, including 23 residents, 9 nursing assistants and 2 doctors. 13 out of 30 samples were positive for GII.17 norovirus, no other pathogen was detected. Nursing assistants who developed gastroenteritis symptoms had a higher attack rate in residents they cared than those who did not develop any gastroenteritis symptoms (p

Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. ELANE attenuates primary tumor growth and produces a CD8+T cell-mediated abscopal effect to attack distant metastases. Porcine pancreatic elastase (ELANE homolog) resists tumor-derived protease inhibitors and exhibits markedly improved therapeutic efficacy. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy.

Human exposure to polybrominated diphenyl ethers (PBDEs) has been increasing over the last three decades in China and around the world. Animal studies suggest that PBDEs could reduce blood levels of thyroid hormones, but it is unclear whether PBDEs disrupt thyroid function in humans. We used data from a prospective birth cohort of 123 pregnant women who were enrolled between September 2010 and March 2011 in Shandong, China. We measured the concentrations of eight PBDE congeners (n = 106) and five thyroid hormones (n = 107) in cord serum samples. We examined the relationship between prenatal exposure to PBDEs and thyroid function (n = 90). Median concentrations of BDEs 47, 99, 100, and 153 (detection frequencies > 75%) were 3.96, 8.27, 3.31, and 1.89 ng/g lipid, respectively. A 10-fold increase in BDE-99 and Σ 4 PBDEs (the sum of BDEs 47, 99, 100, and 153) concentrations was associated with a 0.41 μg/dL (95% confidence interval [CI]: 0.10 to 0.72) and 0.37 μg/dL (95% CI: 0.06 to 0.68) increase in total thyroxine levels (TT 4 ), respectively. No associations were found between other individual congeners and any of the five thyroid hormones. Our study suggests that prenatal exposure to PBDEs may be associated with higher TT 4 in cord blood. Given the inconsistent findings across existing studies, our results need to be confirmed in additional studies.

Human induced pluripotent stem cells (hiPSCs) can proliferate infinitely. Their ability to differentiate into cardiomyocytes provides abundant sources for disease modeling, drug screening and regenerative medicine. However, hiPSC-derived cardiomyocytes (hiPSC-CMs) display a low degree of maturation and fetal-like properties. Current in vitro differentiation methods do not mimic the structural, mechanical, or physiological properties of the cardiogenesis niche. Recently, we present an efficient cardiac maturation platform that combines hiPSCs monolayer cardiac differentiation with graphene substrate, which is a biocompatible and superconductive material. The hiPSCs lines were successfully maintained on the graphene sheets and were able to differentiate into functional cardiomyocytes. This strategy markedly increased the myofibril ultrastructural organization, elevated the conduction velocity, and enhanced both the Ca2+ handling and electrophysiological properties in the absence of electrical stimulation. O...

How organ growth is regulated in multicellular organisms is a long-standing question in developmental biology. It is known that coordination of cell apoptosis and proliferation is critical in cell number and overall organ size control, while how these processes are regulated is still under investigation. In this study, we found that functional loss of a gene in Drosophila, named Drosophila defender against apoptotic cell death 1 (dDad1), leads to a reduction of tissue growth due to increased apoptosis and lack of cell proliferation. The dDad1 protein, an orthologue of mammalian Dad1, was found to be crucial for protein N-glycosylation in developing tissues. Our study demonstrated that loss of dDad1 function activates JNK signaling and blocking the JNK pathway in dDad1 knock-down tissues suppresses cell apoptosis and partially restores organ size. In addition, reduction of dDad1 triggers ER stress and activates unfolded protein response (UPR) signaling, prior to the activation of JNK signaling. Furthermore, Perk-Atf4 signaling, one branch of UPR pathways, appears to play a dual role in inducing cell apoptosis and mediating compensatory cell proliferation in this dDad1 knock-down model.

Jing Wang,1,2,* Jie Huang,1,3,* Shuang Yang,1,3 Chang Cui,1,3 Ling Ye,1,3 Sai-ying Wang,4 Guo-ping Yang,1,3 Qi Pei1,2 1Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 2Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Clinical Trails Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 4Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-ping Yang; Qi PeiThe Third Xiangya Hospital, Central South University, Yinpenling Street, Yuelu District, Changsha, Hunan 410013, People’s Republic of ChinaTel +86 131 7041 9804Fax +86 731 8861 8326Email ygp9880@126.com; peiqi1028@126.comPurpose: To assess the pharmacokinetics and safety of pure S-ketamine (esketamine) in Chinese patients undergoing painless gastroscopy and evaluate the potential advantage of esketamine in clinical treatment compared with racemate ketamine hydrochloride injection.Patients and methods: A randomized, open-label, parallel-controlled, Phase I study was performed with 32 patients undergoing painless gastroscopy. Patients received a single dose of esketamine (0.5 mg/kg) or racemic ketamine (1 mg/kg, esketamine:R-ketamine=1:1), injected in 10 s. Blood samples were collected for pharmacokinetic analysis. The concentrations of esketamine, R-ketamine, S-norketamine, and R-norketamine were measured with a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.Results: After administering a single dose of esketamine and racemate ketamine, the pharmacokinetics parameters of esketamine and S-norketamine are both similar in treatment groups. The clearance of esketamine in two groups was 18.1±3.2 and 18.4±3.4 mL/min•kg, respectively. However, in the ketamine group, esketamine has a larger clearance than R-ketamine (18.4±3.4 mL/min·kg vs 15.8±3.1 mL/min·kg, P

SUMMARYObesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Macrophages, which accumulate in adipose tissue and are activated during obesity, are an attractive mechanistic link. Here, we show that, during obesity, murine and human mammary adipose tissue macrophages adopt a pro-inflammatory, metabolically- activated (MMe) macrophage phenotype that promotes TNBC stem-like markers and functions, including increased tumorsphere growthin vitroand tumor-initiating potentialin vivo. We demonstrate that MMe macrophages release cytokines in an NADPH oxidase 2 (NOX2)-dependent manner that signal through glycoprotein 130 (GP130) on TNBC cells to promote their stem-like properties. Accordingly, deletingNox2in myeloid cells or depleting GP130 in TNBC cells attenuates the ability of obesity to drive TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue during obesity as a mechanism for promoting TNBC stemness and tumorigenesis.HIGHLIGHTS⁘Obesity promotes TNBC tumor formation and stemness.⁘Mammary adipose tissue macrophages are metabolically activated (MMe) in obese mice and humans.⁘MMe macrophages in mammary adipose tissue contribute to obesity-induced stemness.⁘MMe macrophages promote TNBC stemness through GP130 signaling.

Polycystic ovary syndrome (PCOS), known as a common endocrine disorder among females, plagues many PCOS patients. The current study aimed to explore the correlations of sex hormone-binding globulin (SHBG) polymorphisms with the outcome of in vitro fertilization-embryo transfer (IVF-ET) in PCOS patients. PCOS patients who underwent IVF-ET and patients with non-PCOS-related infertility were selected in the study. Correlations of SHBG rs6259 and rs727428 with the risk factors in PCOS were analyzed, followed by the evaluation of the effect of SHBG polymorphisms on the outcome of IVF-ET in PCOS patients. At last, unconditional logistic regression analysis was performed to study the risk factors for IVF-ET treatment outcome. Compared with SHBG rs6259 GG carriers, the incidence of PCOS was found to be elevated in SHBG rs6259 GA+AA carriers which indicated that the A allele was a risk factor for PCOS. Compared with SHBG rs6259 TT carriers, the number of retrieved oocytes and embryo as well as the fertility rate in SHBG rs6259 GA+AA carriers was found to be decreased, while the abortion rate, incidence of ovarian hyperstimulation syndrome, transplant rejection rate, estradiol, and testosterone in serum, as well as testosterone in follicular fluid were elevated. The luteal hormone, serum testosterone, and progesterone and GA+AA genotype of rs6259 were the risk factors for IVF-ET treatment outcome. Taken together, the study showed that SHBG rs6259 polymorphisms might be correlated with the risk of PCOS and the outcome of IVF-ET treatment.

The present study aimed to identify differentially expressed microRNAs (miRNAs) and mRNAs in hepatitis B virus‑associated hepatocellular carcinoma (HCC). A total of five HCC tissues and paired adjacent non‑tumor tissues were screened to identify the differentially expressed miRNAs and target mRNAs using polymerase chain reaction microarrays. The interaction between differential miRNA and mRNA expression was concurrently analyzed using bioinformatics methods. A total of 32 differentially expressed miRNAs (four upregulated miRNAs and 28 downregulated miRNAs) and 16 differentially expressed mRNAs (11 upregulated mRNAs and five downregulated mRNAs) were identified. Among these, upregulated hsa‑miRNA (miR)‑96‑5p and hsa‑miR‑18b‑5p suppressed their target mRNAs forkhead box O1 and MET transcriptional regulator MACC1 (MACC1). Downregulation of hsa‑miR‑199a‑5p led to upregulation of its target mRNAs, cyclin dependent kinase 4 and insulin like growth factor 2 (IGF2). The high‑level expression of IGF2 mRNA and cyclin E1 mRNA was due to the low‑level expression of hsa‑miR‑145‑5p, hsa‑miR‑181a‑5p, hsa‑miR‑199a‑5p and hsa‑miR‑223a‑3p, and hsa‑miR‑26a‑5p and hsa‑miR‑26b‑5p, respectively. The low‑level expression of coronin 1A mRNA and MACC1 mRNA was due to overexpression of hsa‑miR‑517a‑3p and hsa‑miR‑18a‑5p, and hsa‑miR‑18b‑5p, respectively. Numerous gene ontology terms were associated with oncogenesis. The most enriched pathways targeted by the dysregulated miRNAs and mRNAs were associated with cancer and oncogenesis pathways. The present data suggested that differential miRNA and mRNA expression is present in HCC. Thus, interactions between certain miRNAs and mRNAs may be involved in the pathogenesis of HCC.

Ovarian cancer characterizes as the fourth leading consequence of death associated with cancer for women. Accumulating evidence underscores the vital roles of microRNAs (miRNAs) in preventing ovarian cancer development. Besides, induction of the phosphatidylinositol-3 kinase/serine/threonine kinase (PI3K/Akt) pathway associated with the ovarian cancer cell migration and invasion. The study aims to examine the effects of miR-15b on the proliferation, apoptosis, and senescence of human ovarian cancer cells by binding to lysophosphatidic acid receptor 3 (LPAR3) with the involvement of the PI3K/Akt pathway. The positive expression of LPAR3 protein was detected by immunohistochemistry. Then the interaction between miR-15b and LPAR3 was examined. The possible role of miR-15b in ovarian cancer was explored using gain- and loss-of-function experiments. Subsequently, the functions of miR-15b on PI3K/Akt pathway, proliferation, migration, invasion, senescence and apoptosis of ovarian cancer cells were assessed. Furthermore, in vivo tumorigenicity assay in nude mice was performed. LPAR3 was overexpressed, whereas miR-15b was poorly expressed in ovarian cancer tissues. LPAR3 is a direct target of miR-15b. Restored miR-15b promoted Bax expression, apoptosis, and senescence, inhibited expression of LPAR3 and Bcl-2, the extent of PI3K and Akt phosphorylation, as well as ovarian cancer cell proliferation, migration, and invasion. Further, tumor growth was observed to be prevented by miR-15b overexpression. Collectively, our study demonstrates that miR-15b represses the proliferation and drives the senescence and apoptosis of ovarian cancer cells through the suppression of LPAR3 and the PI3K/Akt pathway, highlighting an antitumorigenic role of miR-15b.

We explored whether polybrominated diphenyl ethers (PBDEs) exposed in cord blood could have any potential relationship with perinatal outcomes. Participants were pregnant females (n = 222) who were recruited from a prospective birth cohort (Laizhou Wan Birth Cohort, LWBC) between September 2010 and February 2012. We measured eight PBDE congeners (BDE-28, BDE-47, BDE-85, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183) in cord serum and examined their relationship with perinatal outcomes. The median levels of BDE-28, BDE-47, BDE-85, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183 were 2.92, 3.93, 2.29, 7.03, 3.03, 3.14, 1.46, and 2.55 ng/g lipids, respectively. For each log unit increase in BDE-47, BDE-100, and ∑4PBDEs, gestational age increased by 0.70 weeks (95% confidence interval [CI] 0.25, 1.15), 0.48 weeks (95% CI 0.03, 0.94), and 0.73 weeks (95% CI 0.12, 1.34), respectively. We also found that BDE-47 was positively associated with head circumference (β = 0.42, 95% CI 0.00, 0.84). Given that our study area is one of the major brominated flame retardant production areas in China, and the cord PBDEs levels were relatively higher than those reported in most other Asian areas, more studies on the effects of in utero PBDE exposure on fetal growth and child development are warranted.

Background Long-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro. Methods Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing. Results Compared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the ICa, L in paced VCMs. Conclusions The results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0566-6) contains supplementary material, which is available to authorized users.

To explore the optimal pre-sintering temperature for graded glass/zirconia material, glass/zirconia specimens were prepared and pre-sintered at 900, 1,000 and 1,100°C respectively, glass infiltration and densification at 1,450°C. Monolith Y-TZP specimens were sintered at 1,450°C. Nanoindentation was used to test Young's modulus and Hardness. Compressive strength test and cycling fatigue test were conducted. Nanoindentation test showed graded change of Young's modulus in glass/zirconia structure. The compressive strength and the number of cycles to failure of specimens pre-sintered at 1,000°C were significantly higher than those of Y-TZP and the specimens pre-sintered at 900 and 1,000°C (p

Polybrominated diphenyl ethers (PBDEs) are widely used in commercial and household products. Few human studies have examined the effects of PBDE exposure on female reproductive function. We recruited 207 pregnant women when they were admitted for labor from September 2010 to February 2012 as part of a birth cohort study, the Laizhou Wan Birth Cohort study. Maternal sera were analyzed for eight PBDE congeners (BDE-28, -47, -85, -99, -100, -153, -154, and -183) and four sex hormones. BDE-153 exhibited the highest serum level (median 4.67ng/g lipid), followed by BDE-99 (median 3.45ng/g lipid) and BDE-28, -47, and -100 (medians near 2ng/g lipid). BDE-28, -47, -99, -100, and -153 were the most frequently detected (>90%) congeners. Follicle-stimulating hormone (FSH) levels were negatively associated with PBDE exposure. For each natural log unit increase in BDE-47, 100, and ∑5PBDEs, FSH levels changed -1.19IU/L (95% confidence interval [CI]: -1.32, -1.02), -1.17IU/L (95%CI: -1.36, -1.01) and -1.26IU/L (95%CI: -1.55, -1.02) respectively. BDE-85, -153, and -183 were associated with adverse reproductive effects, including an increased risk of threatened abortion (odds ratio [OR] [95% CI]: 1.30 [1.03, 1.62], 1.04 [1.01, 1.08], and 1.03 [1.01, 1.06], respectively). BDE-153 was associated with an increased risk of premature birth (adjusted OR [95% CI]:1.05 [1.01, 1.09]), and BDE-28 was associated with longer time to pregnancy (adjusted OR [95% CI]: 1.34 [1.03, 1.76]). These findings suggest that maternal PBDE exposure may be inversely associated with female reproductive function.

Arrhythmia is a common disease around the world and Helicobacter pylori (H. pylori) is a bacterium infecting 28% to 84% of subjects, depending on the population tested. However, the implication of H. pylori in cardiac arrhythmia is poorly understood. We performed this meta-analysis with an aim to identify the association between arrhythmia and H. pylori. We searched PubMed, Embase, Web of Science, and the Cochrane library databases to select studies on the association between arrhythmia and H. pylori. In the arrhythmia group, 392 (58.1%) were H. pylori-positive and in the control group 640 (47.8%) were H. pylori-positive. Compared to the controls, the infection rate of H. pylori was higher in patients with arrhythmia than in controls (odds ratio (OR) = 1.797, 95% confidence interval (CI): 1.081–2.988, p < 0.05). Subgroup analysis indicated that H. pylori infection was a risk factor for atrial fibrillation in Asia and Africa. Therefore, a correlation between H. pylori infection and arrhythmia may exist and H. pylori eradication may decrease the occurrence of arrhythmia, especially in Asia and Africa.

In the winter of 2014–2015, a novel norovirus (NoV) strain (GII.17) was reported to be the major cause of gastroenteritis outbreaks in East Asia. To determine the time course of gastroenteritis infections associated with the GII.17 strain and whether GII.17 was the main epidemic strain in diarrheal patients in Shanghai, 2169 stool samples were collected and tested. The detection rate of NoV GI and GII NoV strains was 0.83 and 24.02%, respectively. Phylogenetic analysis confirmed that there were seven NoV genotypes, among which GII.4 and GII.17 were the main genotypes. The GII.17 strain was first detected in a sample collected on August 14th, 2014, and beginning in January 2015, the novel GII.17 strain replaced the GII.4 strain as the dominant NoV genotype causing acute gastroenteritis in patients in Shanghai.