Assembly, maintenance and function of synaptic junctions depend on extracellular matrix (ECM) proteins and their receptors. Here we report that Tenectin (Tnc), a Mucin-type protein with RGD motifs, is an ECM component required for the structural and functional integrity of synaptic specializations at the neuromuscular junction (NMJ) in Drosophila. Using genetics, biochemistry, electrophysiology, histology and electron microscopy, we show that Tnc is secreted from motor neurons and striated muscles and accumulates in the synaptic cleft. Tnc selectively recruits αPS2/βPS integrin at synaptic terminals, but only the cis Tnc/integrin complexes appear to be biologically active. These complexes have distinct pre- and postsynaptic functions, mediated at least in part through the local engagement of the spectrin-based membrane skeleton: the presynaptic complexes control neurotransmitter release, while postsynaptic complexes ensure the size and architectural integrity of synaptic boutons. Our study reveals an unprecedented role for integrin in the synaptic recruitment of spectrin-based membrane skeleton.

Osteosarcoma (OS), the most common malignant bone tumor, accounts for the heavy healthy threat in the period of children and adolescents. OS occurrence usually correlates with early metastasis and high death rate. This study aimed to better understand the mechanism of OS metastasis.Based on Gene Expression Omnibus (GEO) database, we downloaded 4 expression profile data sets associated with OS metastasis, and selected differential expressed genes. Weighted gene co-expression network analysis (WGCNA) approach allowed us to investigate the most OS metastasis-correlated module. Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to give annotation of selected OS metastasis-associated genes.We select 897 differential expressed genes from OS metastasis and OS non-metastasis groups. Based on these selected genes, WGCNA further explored 142 genes included in the most OS metastasis-correlated module. Gene Ontology functional and KEGG pathway enrichment analyses showed that significantly OS metastasis-associated genes were involved in pathway correlated with insulin-like growth factor binding.Our research figured out several potential molecules participating in metastasis process and factors acting as biomarker. With this study, we could better explore the mechanism of OS metastasis and further discover more therapy targets.

Diagnosis-related groups (DRGs) have been receiving increasing attention in health service research in China. In the present study, we used the 2014 Beijing-Diagnosis Related Groups (BJ-DRGs) to evaluate the inpatient service performance of the clinical subspecialty "major operation of the digestive system" of a cancer specialist hospital.The research hospital is one of 16 public municipal hospitals overseen by the Beijing Health Bureau ("16 hospitals"). Discharge data collected between 2008 and 2015 were drawn from the front pages of the medical records of these hospitals. After the data were reported to the Beijing Public Health Information Centre, as well as being grouped using the BJ-DRGs. We evaluated the service performance of this subspecialty in terms of capacity, efficiency, and service quality, based on the BJ-DRGs risk adjustment tool.From 2008 to 2015, the total weight of the subspecialty in the research hospital increased annually. In 2015, the cases in this hospital accounted for 50.27% of the total in 16 hospitals. The time consumption index was 0.91, whereas the charge consumption index was 1.24, which was 24% higher than the average in16 hospitals. The mortality rates of the middle-low risk groups (GB15 and GB25) in the research hospital and the 16 hospitals were zero, while the mortality rates for the middle-high risk groups (GB11 and GB23) in the research hospital were significantly lower than those in 16 hospitals.The service capacity of the subspecialty steadily increased in the research hospital. However, the hospital must offer more attention to complex digestive disease cases (GB11/GB23) and strictly control hospitalization expenses, while maintaining the advantages of service efficiency and quality.

The relationship of CYP2C19 genotype and clinical efficacy in stroke or transient ischemic attack (TIA) patients treated with clopidogrel monotherapy or clopidogrel plus aspirin remains unknown. We thus aim to conduct a meta-analysis to appraise evidence on the association of CYP2C19 genotype and clinical efficacy for stroke or TIA.

Ophthalmoplegia is a disease that affects many people every year and is caused by reasons, such as cavernous sinus lesion, intracranial aneurysm, diabetes, and trauma. Acupuncture has been widely used to treat ophthalmological diseases especially ophthalmoplegia in China. Many clinical trials indicate that acupuncture may promote the recovery of extraocular muscles in ophthalmoplegia patients. We aim to conduct a meta-analysis to evaluate the efficacy and safety of acupuncture for ophthalmoplegia.

Patients with acute myocardial infarction (AMI) complicated by heart failure with preserved ejection fraction (HFpEF) are likely to have more adverse cardiovascular events and higher mortality. The purpose of this study was to examine the predictors and outcomes in AMI patients complicated by HFpEF.We examined the demographics, clinical data, and clinical outcomes in 405 consecutive subjects who firstly presented with AMI after undergoing emergency percutaneous coronary intervention from January 2013 to June 2016.Three hundred twenty patients and eighty-five patients were classified into the nonheart failure (non-HF) group and HFpEF group, respectively. Patients with HFpEF had higher prevalence of prior hypertension, had higher levels of biomarkers, and had a larger left atrial diameter with a nondilated left ventricle were more likely to develop multivessel disease-vessels and had infarction-related artery located in left anterior descending artery than patients without HF. Moreover, patients with HFpEF had a higher probability of developing the in-hospital incident cardiovascular complications and death than non-HF patients.Two routine biomarkers, levels of hypersensitive C-reactive protein and N-terminal-pro brain natriuretic peptide, and number of diseased-vessels were independent predictors for in-hospital HFpEF incidence in AMI patients with preserved LVEF. AMI patients with HFpEF had a higher probability of in-hospital cardiovascular outcomes and mortality.

The prevalence of metabolic syndrome (MetS) and MetS-related stroke is set to increase dramatically in coming decades. MetS is a complex disease that includes endothelial dysfunction, insulin resistance, diabetes, hypertension, ectopic obesity, and dyslipidaemia and an increased risk of cardiovascular events. One function of high-density lipoprotein (HDL) cholesterol (HDL-C) is the cholesterol-efflux pathway, which is the pathway where cholesterol is removed from macrophages within the arterial walls back into the bloodstream and out to the liver. As one of the key functions of HDL, their hypothesis was that if they could measure HDL-C-efflux capacity, they would have a better handle on the role of HDL in atherosclerosis. However, there are no systematic analyses or well-conducted meta-analyses to evaluate the relationship between HDL-C functionality and MetS. The aim of this study is to examine this association of HDL-C functionality with MetS in different ages and sex.

The mixed lineage kinase type 3 inhibitor URMC-099 facilitates amyloid-beta (Aβ) clearance and degradation in cultured murine microglia. One putative mechanism is an effect of URMC-099 on Aβ uptake and degradation. As URMC-099 promotes endolysosomal protein trafficking and reduces Aβ microglial pro-inflammatory activities, we assessed whether these responses affect Aβ pathobiogenesis. To this end, URMC-099's therapeutic potential, in Aβ precursor protein/presenilin-1 (APP/PS1) double-transgenic mice, was investigated in this model of Alzheimer's disease (AD).

Organizational contextual features have been recognized as important determinants for implementing evidence-based practices across healthcare settings for over a decade. However, implementation scientists have not reached consensus on which features are most important for implementing evidence-based practices. The aims of this review were to identify the most commonly reported organizational contextual features that influence the implementation of evidence-based practices across healthcare settings, and to describe how these features affect implementation.

What is the molecular basis of infertility related to uterine dysfunction in women with polycystic ovary syndrome (PCOS)?

Eosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue, including eosinophil-rich inflammation, basal zone hyperplasia, and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored.

Crying is the principal means by which newborn infants shape parental behavior to meet their needs. While this mechanism can be highly effective, infant crying can also be an aversive stimulus that leads to parental frustration and even abuse. Fathers have recently become more involved in direct caregiving activities in modern, developed nations, and fathers are more likely than mothers to physically abuse infants. In this study, we attempt to explain variation in the neural response to infant crying among human fathers, with the hope of identifying factors that are associated with a more or less sensitive response. We imaged brain function in 39 first-time fathers of newborn infants as they listened to both their own and a standardized unknown infant cry stimulus, as well as auditory control stimuli, and evaluated whether these neural responses were correlated with measured characteristics of fathers and infants that were hypothesized to modulate these responses. Fathers also provided subjective ratings of each cry stimulus on multiple dimensions. Fathers showed widespread activation to both own and unknown infant cries in neural systems involved in empathy and approach motivation. There was no significant difference in the neural response to the own vs. unknown infant cry, and many fathers were unable to distinguish between the two cries. Comparison of these results with previous studies in mothers revealed a high degree of similarity between first-time fathers and first-time mothers in the pattern of neural activation to newborn infant cries. Further comparisons suggested that younger infant age was associated with stronger paternal neural responses, perhaps due to hormonal or novelty effects. In our sample, older fathers found infant cries less aversive and had an attenuated response to infant crying in both the dorsal anterior cingulate cortex (dACC) and the anterior insula, suggesting that compared with younger fathers, older fathers may be better able to avoid the distress associated with empathic over-arousal in response to infant cries. A principal components analysis revealed that fathers with more negative emotional reactions to the unknown infant cry showed decreased activation in the thalamus and caudate nucleus, regions expected to promote positive parental behaviors, as well as increased activation in the hypothalamus and dorsal ACC, again suggesting that empathic over-arousal might result in negative emotional reactions to infant crying. In sum, our findings suggest that infant age, paternal age and paternal emotional reactions to infant crying all modulate the neural response of fathers to infant crying. By identifying neural correlates of variation in paternal subjective reactions to infant crying, these findings help lay the groundwork for evaluating the effectiveness of interventions designed to increase paternal sensitivity and compassion.

Kalanchoe flammea Stapf (Crassulaceae) is a medicinal plant grown in the South of Mexico (State of Tabasco), which is commonly used in traditional medicine for the treatment of fever, wounds, inflammation, and cancer.

Tumors are characterized by leaky blood vessels, and by an abnormal and heterogeneous vascular network. These pathophysiological characteristics contribute to the enhanced permeability and retention (EPR) effect, which is one of the key rationales for developing tumor-targeted drug delivery systems. Vessel abnormality and heterogeneity, however, which typically result from excessive pro-angiogenic signaling, can also hinder efficient drug delivery to and into tumors. Using histidine-rich glycoprotein (HRG) knockout and wild type mice, and HRG-overexpressing and normal t241 fibrosarcoma cells, we evaluated the effect of genetically induced and macrophage-mediated vascular normalization on the tumor accumulation and penetration of 10-20 nm-sized polymeric drug carriers based on poly(N-(2-hydroxypropyl)methacrylamide). Multimodal and multiscale optical imaging was employed to show that normalizing the tumor vasculature improves the accumulation of fluorophore-labeled polymers in tumors, and promotes their penetration out of tumor blood vessels deep into the interstitium.

The aim of this study is to develop an innovative imaging guided approach based on Boron Neutron Capture Therapy, for the treatment of mesothelioma, assisted by the quantification of the in vivo boron distribution by MRI. The herein reported results demonstrate that overexpressed Low Density Lipoproteins receptors can be successfully exploited to deliver to mesothelioma cells a therapeutic dose of boron (26 μg/g), significantly higher than in the surrounding tissue (3.5 μg/g). Boron and Gd cells uptake was assessed by ICP-MS and MRI on two mesothelioma (ZL34, AE17) and two healthy (MRC-5 and NMuMg) cell lines. An in vivo model was prepared by subcutaneous injection of ZL34 cells in Nu/Nu mice. After irradiation with thermal neutrons, tumor growth was evaluated for 40 days by MRI. Tumor masses of boron treated mice showed a drastic reduction of about 80-85%. The obtained results appear very promising providing patients affected by this rare disease with an improved therapeutic option, exploiting LDL transporters.

We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3-22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC50 = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.

A previous study showed that a single amino acid difference in the cucumber mosaic virus (CMV) capsid protein (CP) elicits unusual symptoms. The wild-type strain (CMV-R) induces green mosaic symptoms and malformation while the mutant strain (CMV-R3E79R) causes chlorotic lesions on inoculated leaves and strong stunting with necrosis on systemic leaves. Virion preparations of CMV-R and CMV-R3E79R were partially purified from Nicotiana clevelandii A. Gray and analysed by two-dimensional gel electrophoresis. Their separated protein patterns showed remarkable differences at the 50-75 kDa range, both in numbers and intensity of spots, with more protein spots for the mutant CMV. Mass spectrometry analysis demonstrated that the virion preparations contained host proteins identified as ATP synthase alpha and beta subunits as well as small and large Rubisco subunits, respectively. Virus overlay protein binding assay (VOPBA), immunogold electron microscopy and modified ELISA experiments were used to prove the direct interaction between the virus particle and the N. clevelandii ATP synthase F1 motor complex. Protein-protein docking study revealed that the electrostatic change in the mutant CMV can introduce stronger interactions with ATP synthase F1 complex. Based on our findings we suggest that the mutation present in the CP can have a direct effect on the long-distance movement and systemic symptoms. In molecular view the mutant CMV virion can lethally block the rotation of the ATP synthase F1 motor complex which may lead to cell apoptosis, and finally to plant death.

Interleukin-6 (IL-6) production facilitates a shift from acute to chronic inflammation that may induce the development of some diseases and aging. Several studies have suggested that adiposity is closely related to serum IL-6 level, but their authors examined relatively young older adults (aged 60-80 years), so it is not clear whether this association would also occur in people at a more advanced age.

Public health guidance recommends limiting sun exposure to sub-sunburn levels, but it is unknown whether these can gain vitamin D (for musculoskeletal health) while avoiding epidermal DNA damage (initiates skin cancer). Well-characterized healthy humans of all skin types (I-VI, lightest to darkest skin) were exposed to a low-dose series of solar simulated UVR of 20%-80% their individual sunburn threshold dose (minimal erythema dose). Significant UVR dose responses were seen for serum 25-hydroxyvitamin D and whole epidermal cyclobutane pyrimidine dimers (CPDs), with as little as 0.2 minimal erythema dose concurrently producing 25-hydroxyvitamin D and CPD. Fractional MEDs generated equivalent levels of whole epidermal CPD and 25-hydroxyvitamin D across all skin types. Crucially, we showed an epidermal gradient of CPD formation strongly correlated with skin darkness (r = 0.74, P < 0.0001), which reflected melanin content and showed increasing protection across the skin types, ranging from darkest skin, where high CPD levels occurred superficially, with none in the germinative basal layer, to lightest skin, where CPD levels were induced evenly across the epidermal depth. People with darker skin can be encouraged to use sub-sunburn UVR-exposure to enhance their vitamin D. In people with lighter skin, basal cell damage occurs concurrent with vitamin D synthesis at exquisitely low UVR levels, providing an explanation for their high skin cancer incidence; greater caution is required.

Type-2 ryanodine receptors (RyR2s) play a pivotal role in cardiac excitation-contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR) via a Ca2+ -induced Ca2+ release (CICR) mechanism. Two strategies have been used to study the structure-function characteristics of RyR2 and its disease associated mutations: (1) heterologous cell expression of the recombinant mutant RyR2s, and (2) knock-in mouse models harboring RyR2 point mutations. Here, we establish an alternative approach where Ca2+ signaling aberrancy caused by the RyR2 mutation is studied in human cardiomyocytes with robust CICR mechanism. Specifically, we introduce point mutations in wild-type RYR2 of human induced pluripotent stem cells (hiPSCs) by CRISPR/Cas9 gene editing, and then differentiate them into cardiomyocytes. To verify the reliability of this approach, we introduced the same disease-associated RyR2 mutation, F2483I, which was studied by us in hiPSC-derived cardiomyocytes (hiPSC-CMs) from a patient biopsy. The gene-edited F2483I hiPSC-CMs exhibited longer and wandering Ca2+ sparks, elevated diastolic Ca2+ leaks, and smaller SR Ca2+ stores, like those of patient-derived cells. Our CRISPR/Cas9 gene editing approach validated the feasibility of creating myocytes expressing the various RyR2 mutants, making comparative mechanistic analysis and pharmacotherapeutic approaches for RyR2 pathologies possible.