Search

In order to determine the possible aqueous humor (AH) proteins involved in diabetic nephropathy (DN) progression, we performed gel electrophoresis-liquid chromatography-tandem mass spectrometry protein profiling of AH samples from 5 patients with proliferative diabetic retinopathy (PDR) combined DN and 5 patients with PDR. Function enrichment analyses were carried out after the identification of differentially expressed proteins (DEPs). Protein-protein interaction networks were then built and the Search Tool for the Retrieval of Interacting Genes database and CytoNCA plugin in Cytoscape were utilized for module analysis. Ingenuity Pathway Analysis (IPA) was used to analyze disease and biological function, Tox function enrichment and upstream regulatory molecules/networks. Fifty-four DEPs were finally confirmed, whose enriched functions and pathways covered cell adhesion, extracellular exosome, complement activation, complement and coagulation cascades, etc. Nine hub genes were identified, including NCAM1, PLG, APOH, C3, PSAP, RBP4, CDH2, NUCB1, and GNS. IPA showed that C3 and PLG are involved in renal and urological system abnormalities. Conclusively, DEPs and hub proteins confirmed in this exploratory AH proteomic analysis may help us gain a deeper understanding of the molecular mechanisms involved in DN progression, providing novel candidate biomarkers for the early detection for diagnosis of DN.

The incidence and mortality of gastrointestinal (GI) tumors are high in China. Some studies suggest that the gut microbiota is related to the occurrence and development of tumors. At present, there are no prospective studies based on the correlation between gastrointestinal tumors and gut microbiota in the Chinese population. The objective of this report is to characterize the fecal microbiota in healthy control participants and patients with esophageal cancer, gastric cancer, and colorectal cancer.Patients with locally advanced or metastatic esophageal, gastric, and colorectal cancer were enrolled, and healthy people were included as controls. 16S rRNA sequencing was used to analyze the characteristics of fecal microbiota. PICRUSt software was used for functional prediction.Significant differences in the composition and abundance of fecal microbiota were identified between gastrointestinal cancer patients (n = 130) and healthy controls (n = 147). The abundance of Faecalibacterium prausnitzii, Clostridium clostridioforme and Bifidobacterium adolescent in tumor groups were all significantly lower than in the control group (P 0.05). The levels of Blautia producta and R. faecis in the gastric (n = 46) and colorectal cancer (n = 44) groups were significantly lower than those in the control group (P 0.05). The level of Butyricicoccus pullicaecorum in the esophageal cancer (n = 40) and gastric cancer groups was significantly lower than that in the control group (P 0.05). B. fragilis, Akkermansia muciniphila, Clostridium hathewayi and Alistipes finegoldii were overabundant in the different tumor groups compared with the control (P 0.05). We observed significant differences in functional metabolism and cell biological function between the tumor and control groups (P 0.05). Optimal microbial markers were identified on a random forest model and achieved an area under the curve of 85.59% between 130 GI cancer samples and 147 control samples. The respective AUC values were 86.89%, 97.11%, and 79.1% in detecting esophageal cancer, gastric cancer, and colorectal cancer.Patients with esophageal or gastric cancers had similar features of fecal bacteria as those with colorectal cancer. The metabolic function of fecal bacteria in the gastrointestinal cancer patients and the healthy controls were different. The microbial signatures may potentially be applied to distinguish GI cancer patients from healthy people as a non-invasive diagnostic biomarker.

The aim of this study was to investigate the role of depolarizing activation of NaOn postnatal days 7, 8, and 9, mice were exposed to 3 % sevoflurane for 2 h per day. The proliferation, differentiation, and myelin sheath of OPC were observed with immunofluorescence, quantitative real-time polymerase chain reaction (QRT-PCR), and transmission electron microscopy (TEM) at various time points. The open field, Y maze, and new object recognition tests were used to measure spatial learning and memory. siRNA was used for the knockdown NCX1 in human OPC (HOPC) before sevoflurane exposure; the Transwell migration assay was used to measure cell migration ability and Fluo 4-AM was used to measure intracellular Ca2+ concentration.Pretreatment with an NCX inhibitor attenuated the proliferation and differentiation of OPC induced by sevoflurane and induced a remarkable increase in platelet-derived growth factor receptor-alpha (PDGFRα), 2, 3-cyclic nucleotide 3-phosphodiesterase (CNPase), oligodendrocyte transcription factor 2 (Olig2), and homeodomain protein NK2 homeobox 2 (NKX2.2) levels. Pretreatment with an NCX inhibitor alleviated the sevoflurane-induced myelination disorder and cognitive impairment. The decreased cell migration and increased intracellular CaThis study suggests that repeated sevoflurane exposure in newborn mice leads to depolarization of OPC, which leads to Ca

The extracellular contractile injection systems (eCISs) are encoded in the genomes of a large number of bacteria and archaea. We have previously characterized the overall structure of Photorhabdus Virulence Cassette (PVC), a typical member of the eCIS family. PVC resembles the contractile tail of bacteriophages and exerts its action by the contraction of outer sheath and injection of inner tube plus central spike. Nevertheless, the biological function of PVC effectors and the mechanism of effector translocation are still lacking. By combining cryo-electron microscopy and functional experiments, here we show that the PVC effectors Pdp1 (a new family of widespread dNTP pyrophosphatase effector in eCIS) and Pnf (a deamidase effector) are loaded inside the inner tube lumen in a "Peas in the Pod" mode. Moreover, we observe that Pdp1 and Pnf can be directly injected into J774A.1 murine macrophage and kill the target cells by disrupting the dNTP pools and actin cytoskeleton formation, respectively. Our results provide direct evidence of how PVC cargoes are loaded and delivered directly into mammalian macrophages.

Acute kidney injury (AKI) is a common clinical critical disease. Due to its high morbidity, increasing risk of complications, high mortality rate, and high medical costs, it has become a global concern for human health problems. Initially, researchers believed that kidneys have a strong ability to regenerate and repair, but studies over the past 20 years have found that kidneys damaged by AKI are often incomplete or even unable to repair. Even when serum creatinine returns to baseline levels, renal structural damage persists for a long time, leading to the development of chronic kidney disease (CKD). The mechanism of AKI-to-CKD transition has not been fully elucidated. As an important regulator of gene expression, epigenetic modifications, such as histone modification, DNA methylation, and noncoding RNAs, may play an important role in this process. Alterations in epigenetic modification are induced by hypoxia, thus promoting the expression of inflammatory factor-related genes and collagen secretion. This review elaborated the role of epigenetic modifications in AKI-to-CKD progression, the diagnostic value of epigenetic modifications biomarkers in AKI chronic outcome, and the potential role of targeting epigenetic modifications in the prevention and treatment of AKI to CKD, in order to provide ideas for the subsequent establishment of targeted therapeutic strategies to prevent the progression of renal tubular-interstitial fibrosis.

Although ginsenoside Rb1 (G-Rb1) has exerted an inhibitory effect on renal fibrosis and progression of chronic kidney disease (CKD), its mechanism remains unknown. This study aims to explore the anti-fibrosis effect of G-Rb1 in unilateral ureter obstruction (UUO) mouse model and underlying mechanisms in HBSS-induced HK-2 cells. In vivo, renal function, kidney histological pathology, and autophagy-related protein molecules were assessed. Additionally, rapamycin, Deptor overexpression plasmid, Akt inhibitor, metformin, and a p38-MAPK inhibitor, as well as an ERK-MAPK inhibitor were used to evaluate the effect of AMPK/mTOR, Akt and MAPK signal pathways on the protective effect of G-Rb1 in HK-2 cells. Treatment with G-Rb1 significantly improved renal dysfunction. G-Rb1 reversed UUO-induced downregulation of p62, and upregulation of LC3 and the ratio of LC3 I/II, indicating that G-Rb1 restrained UUO-induced activation of autophagy. Furthermore, we found that treatment of HBSS-induced HK-2 cells with G-Rb1 resulted in AMPK/mTOR and ERK, p38 MAPKs signaling pathways regulated autophagy inhibition. These findings may explain, in part, the molecular mechanisms by which G-Rb1 could be applied in the treatment of patients with CKD, further suggesting that autophagy and its associated molecular signaling pathway may be new targets for the treatment of renal fibrosis and CKD.

Proton-linked monocarboxylate transporters (MCTs) must transport monocarboxylate efficiently to facilitate monocarboxylate efflux in glycolytically active cells, and transport monocarboxylate slowly or even shut down to maintain a physiological monocarboxylate concentration in glycolytically inactive cells. To discover how MCTs solve this fundamental aspect of intracellular monocarboxylate homeostasis in the context of multicellular organisms, we analyzed pyruvate transport activity of human monocarboxylate transporter 2 (MCT2). Here we show that MCT2 transport activity exhibits steep dependence on substrate concentration. This property allows MCTs to turn on almost like a switch, which is physiologically crucial to the operation of MCTs in the cellular context. We further determined the cryo-electron microscopy structure of the human MCT2, demonstrating that the concentration sensitivity of MCT2 arises from the strong inter-subunit cooperativity of the MCT2 dimer during transport. These data establish definitively a clear example of evolutionary optimization of protein function., Proton-linked monocarboxylate transporters (MCTs) facilitate monocarboxylate efflux in glycolytically active cells and regulate transport down in glycolytically inactive cells. Here authors show a steep dependence of human MCT2 activity on substrate concentration and show the structural basis of cooperative transport.

Studies showed that vitamin D (25-hydroxyvitamin D) level in the human blood circulation could be affected by exogenous estrogen exposure. This study aims to explore the relationships between urinary phytoestrogens metabolites and serum total 25(OH)D in general population, urinary phytoestrogens metabolites (daidzein, enterodiol, enterolactone, equol, genistein and o-desmethylangolensin). Totally 2,609 adults ≥6 y old from the 2009-2010 National Health and Nutrition Examination Surveys (NHANES) were recruited into the cross-sectional analyses and information including demographic, socioeconomic, examinations and laboratory test were collected. All analyses were performed using Stata13.0, one-way analysis of variance and multivariable regression were utilised according to data characteristics, respectively. It showed that age, race, education level, body mass index (BMI), and sampling season had significant effects on serum 25(OH)D level (all p0.001). In the whole population, urinary enterodiol and equol were significantly positively associated with serum total 25(OH)D level (β=0.86, 95%CI=0.08-1.65, p0.05; β=1.68, 95%CI=0.91-2.45, p0.001). Equol was also found significantly positively correlated with total 25(OH)D in both female and male separately (β=1.69, 95%CI=0.51-2.87, p0.05; β=1.66, 95%CI=0.63-2.69, p0.05). Phytoestrogen concentrations in the urinary and 25(OH)D levels in the serum had proved a positive correlation in our study, which provide theoretical basis and reference for the dietary nutrient intake in the population.

Background Previous studies have explored the association between parenting style and offspring’s psychological well-being, and the association between offspring’s achievement attribution pattern and psychological well-being. However, little is known about the role of offspring’s achievement attribution in the relationship between parenting and offspring’s psychological well-being. We aimed to find the role of adolescents’ achievement attribution pattern in the relationship between parent–child communication quality and adolescents’ mental health. Methods A cross-sectional analysis was conducted on 2,725 adolescents aged from 9 to 18 years who are participating in the China Family Panel Studies. Participants supplied demographic information and completed a series of psychological scales including the Center for Epidemiologic Studies Depression scale, an adapted version of the Parental Bonding Instrument, an achievement attribution scale, and single-item measures of subjective well-being and subjective interpersonal popularity. Results Linear regression analysis revealed that after controlling for demographic factors good parent–child communication negatively correlated with depression symptoms, and positively associated with subjective well-being and subjective interpersonal popularity. Next, mediation analysis found that internal attribution of achievement partly mediated the effects of parent–child communication quality on adolescents’ depression, subjective well-being, and subjective interpersonal popularity. The result was robust after controlling demographic variables. Conclusions An internal attribution pattern of achievement partially accounted for the associations between parent–child communication quality and adolescents’ psychological outcomes including depression, subjective well-being, and subjective interpersonal popularity. Future interventions for adolescents’ mental health promotion can target parent–child communication and adolescents’ positive achievement attribution pattern.

Background The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC). Methods Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8–10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA. Results A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6–26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70–50.69; P = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29–15.70; P = 0.0008). Conclusions Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information.

Tumor suppressor gene cyclin-dependent kinase inhibitor 2B (p15(INK4B)) methylation has been frequently reported in myelodysplastic syndromes (MDS). However, the association between p15(INK4B) methylation and MDS remains elusive. Thus, this meta-analysis was first conducted to evaluate the clinical significance of p15(INK4B) methylation in MDS.Eligible studies were identified via an online electronic databases search. The overall odds ratios (ORs) or hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.Twenty-eight studies published between 1997 and 2017 were identified, including 1205 MDS patients and 243 nontumor controls. No evidence of heterogeneity was found in our study. p15(INK4B) methylation was significantly elevated in MDS compared with nontumor controls (OR, 10.37; P .001). In addition, p15(INK4B) methylation was significantly higher in advanced MDS than in early MDS (OR, 4.70; P .001) and was linked to an unfavorable overall survival (multivariate analysis: HR, 1.78; 95% CI, 1.23-2.71). Subgroup analyses on the basis of ethnicity and detection method showed that the results remained significant in different subgroups (all Ps .05).Our findings suggest that p15(INK4B) methylation might play an important role in the development, progression, and poor prognosis of MDS. More prospective studies with larger study populations are needed.

Cancer cell survival, function and fate strongly depend on endoplasmic reticulum (ER) proteostasis. Although previous studies have implicated the ER stress signaling network in all stages of cancer development, its role in cancer metastasis remains to be elucidated. In this study, we investigated the role of Gremlin-1 (GREM1), a secreted protein, in the invasion and metastasis of colorectal cancer (CRC) cells in vitro and in vivo. Firstly, public datasets showed a positive correlation between high expression of GREM1 and a poor prognosis for CRC. Secondly, GREM1 enhanced motility and invasion of CRC cells by epithelial–mesenchymal transition (EMT). Thirdly, GREM1 upregulated expression of activating transcription factor 6 (ATF6) and downregulated that of ATF4, and modulation of the two key players of the unfolded protein response (UPR) was possibly through activation of PI3K/AKT/mTOR and antagonization of BMP2 signaling pathways, respectively. Taken together, our results demonstrate that GREM1 is an invasion-promoting factor via regulation of ATF6 and ATF4 expression in CRC cells, suggesting GREM1 may be a potential pharmacological target for colorectal cancer treatment.

Background Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). Methods A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). Results The authors identified several novel loci reaching the threshold of genome-wide significance level (P −8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10−8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. Conclusions The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

The present study focused on the protective effects of melatonin against cisplatin-induced acute kidney injury in mice and its possible mechanism of action in relation to the major regulator of fatty acid oxidation (FAO), peroxidase proliferative receptor α (PPARα). The experiment consisted of the following four groups: vehicle control, cisplatin (15 mg/kg), cisplatinmelatonin (20 mg/kg/day), and melatonin (20 mg/kg/day). Concomitant administration of melatonin significantly ameliorated cisplatin-induced acute kidney injury in mice by decreasing serum levels of triglyceride, blood urea nitrogen and creatinine, reducing the number and size of lipid droplets in tubular epithelial cells, and decreasing the incidence of histopathological changes including tubular cell apoptosis. Moreover, melatonin administration protected kidney tissue by significantly upregulating the levels of PPARα reduced by cisplatin injection, resulting in increased FAO pathway-associated genes (PGC-1a, Acadm, Acat1, Acsm2, Acsm3, Bdh2, Echs and Pecr) as well as reducing protein levels of caspase-3, -9 and Bax. Melatonin not only partially modulated FAO via PPARα signaling, but also decreased cisplatin-induced apoptosis by inhibiting the caspase-3, -9 and Bax pathways. Our findings suggest that melatonin prevents cisplatin-induced acute kidney injury in mice, possibly by upregulating the expression of PPARα, resulting in enhanced FAO and anti-apoptotic properties.

Background Epidemiological studies have shown increased risk of suicide in cancer patients compared with the general population. The present study aimed to examine the association between physical symptoms and suicidal ideation in Chinese hospitalized cancer patients and test the modifying effect of health self-efficacy on the association. Methods A cross-sectional study was conducted with 544 hospitalized cancer patients in two general hospitals in northeast China via face-to-face interviews. Suicidal ideation was measured by using the first four items on the Yale Evaluation of Suicidality scale and then dichotomized into a positive and negative score. Multivariate logistic regression analyses were conducted to examine the impacts of physical symptoms, health self-efficacy, and their interactions on suicidal ideation. Results The suicidal ideation rate was 26.3% in the enrolled cancer patients. Logistic regression showed that insomnia (aOR = 1.84, 95% CI 1.13 to 3.00, p = 0.015) and lack of appetite (aOR = 2.14, 95% CI 1.26 to 3.64, p = 0.005) were significantly associated with suicidal ideation. Low health self-efficacy had a marginally significant exaggerating effect on the association between pain and suicidal ideation (aOR = 2.77, 95% CI 0.99 to 7.74, p = 0.053), after adjusting for significant socio-demographics, clinical characteristics, and depression. Conclusions These findings demonstrate significant associations between physical symptoms (insomnia and/or lack of appetite) and suicidal ideation and highlight the potential modifying role of health self-efficacy in the identification and prevention of suicide among cancer patients.

Objective To investigate the efficacy and mechanism of ultrasound-targeted microbubble destruction (UTMD) combined with radiotherapy (XRT) on glioblastoma. Methods The enhanced radiosensitization by UTMD was assessed through colony formation and cell apoptosis in Human glioblastoma cells (U87MG). Subcutaneous transplantation tumors in 24 nude mice implanted with U87MG cells were randomly assigned to 4 different treatment groups (Control, UTMD, XRT, and UTMD + XRT) based on tumor sizes (100–300 mm3). Tumor growth was observed for 10 days after treatment, and then histopathology stains (HE, CD34, and γH2AX) were applied to the tumor samples. A TUNEL staining experiment was applied to detect the apoptosis rate of mice tumor samples. Meanwhile, tissue proteins were extracted from animal specimens, and the expressions of dsDNA break repair-related proteins from animal specimens were examined by the western blot. Results When the radiotherapy dose was 4 Gy, the colony formation rate of U87MG cells in the UTMD + XRT group was 32 ± 8%, lower than the XRT group (54 ± 14%, p p p > 0.05). In addition, γH2AX increased due to the addition of UTMD to radiotherapy compared to XRT in immunohistochemistry (p Conclusions Our study clearly demonstrated the enhanced destructive effect of UTMD combined with 4 Gy radiotherapy on glioblastoma. This could be partly achieved by the increased ability of DNA damage of tumor cells.

Ribosome biogenesis is an elaborate and energetically expensive program that involve two hundred protein factors in eukaryotes. Nuclear export of pre-ribosomal particles is one central step which also serves as an internal structural checkpoint to ensure the proper completion of nuclear assembly events. Here we present four structures of human pre-60S particles isolated through a nuclear export factor NMD3, representing assembly stages immediately before and after nuclear export. These structures reveal locations of a dozen of human factors, including an uncharacterized factor TMA16 localized between the 5S RNA and the P0 stalk. Comparison of these structures shows a progressive maturation for the functional regions, such as peptidyl transferase centre and peptide exit tunnel, and illustrate a sequence of factor-assisted rRNA maturation events. These data facilitate our understanding of the global conservation of ribosome assembly in eukaryotes and species-specific features of human assembly factors., Ribosome biogenesis in eukaryotes is a complex process that involves more than 200 protein factors. Here the authors present a structural analysis of a collection of human pre-60S structures sampled through a nuclear export adaptor NMD3, representing structural snapshots of pre-60S particles immediately before and after passing through nuclear pore complex.

BackgroundThe link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause–effect relationship remains unclear.AimsWe conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia.MethodWe performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results.ResultsThe associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results.ConclusionsCigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.

Tuberous sclerosis complex (TSC) integrates upstream stimuli and regulates cell growth by controlling the activity of mTORC1. TSC complex functions as a GTPase-activating protein (GAP) towards small GTPase Rheb and inhibits Rheb-mediated activation of mTORC1. Mutations in TSC genes cause tuberous sclerosis. In this study, the near-atomic resolution structure of human TSC complex reveals an arch-shaped architecture, with a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7. This asymmetric complex consists of two interweaved TSC1 coiled-coil and one TBC1D7 that spans over the tail-to-tail TSC2 dimer. The two TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1. Structural and biochemical analyses reveal TSC2 GAP-Rheb complimentary interactions and suggest a catalytic mechanism, by which an asparagine thumb (N1643) stabilizes γ-phosphate of GTP and accelerate GTP hydrolysis of Rheb. Our study reveals mechanisms of TSC complex assembly and GAP activity., Tuberous sclerosis complex (TSC) regulates cell growth by controlling the activity of mTORC1. The structure of human TSC complex reveals an arch-shaped, asymmetric architecture and a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7 subunits and suggests a mechanism by which TSC2 accelerates GTP hydrolysis against a small GTPase Rheb.

Purpose To evaluate the effect of silicone oil (SO) on peripapillary blood flow using OCT angiography. Methods This prospective case series recruited patients with unilateral rhegmatogenous retinal detachment (RRD) who underwent vitrectomy and SO tamponade. Patients were examined before SO removal and at 10 days, 1 month, and 3 months after SO removal on a spectral domain OCT angiography device (RTVue XR Avanti, Optovue Inc., CA, USA) for the measurement of radial peripapillary capillaries (RPC) vessel density (VD) in global field, superior hemifield, and inferior hemifield. Changes in RPC VD following SO removal were compared between affected eyes and contralateral eyes. Results Twenty-two patients were analyzed. The average duration of SO tamponade was 101.3 days (range, 90 to 119 days). After SO removal, global RPC VD increased by 1.3% (95%CI, 0.3 to 2.3%), compared with a − 0.4% (95%CI, − 1.4 to 0.7%) change in contralateral eyes (P = 0.007). The increase in RPC VD after SO removal mainly occurred in the superior hemifield, which was 1.6% (95%CI, 0.6 to 2.7%). The increase in RPC VD in the inferior hemifield was 1.0% (95%CI, − 0.2 to 2.1%) after SO removal. Conclusions We detected a mild increase in peripapillary capillary density after SO removal, mainly in the superior hemifield. Our results suggested that SO tamponade could have negative effect on peripapillary blood flow, possibly by capillary compression.

The transcription factors of the MYC family play pivotal roles in the initiation and progression of human cancers. High oncogenic level of MYC invades low‐affinity sites and enhancer sequences, which subsequently alters the transcriptome, causes metabolic imbalance, and induces stress response. The endoplasmic reticulum (ER) not only plays a central role in maintaining proteostasis, but also contributes to other key biological processes, including Ca2+ metabolism and the synthesis of lipids and glucose. Stress conditions, such as shortage in glucose or oxygen and disruption of Ca2+ homeostasis, may perturb proteostasis and induce the unfolded protein response (UPR), which either restores homeostasis or triggers cell death. Crucial roles of ER stress and UPR signaling have been implicated in various cancers, from oncogenesis to treatment response. Here, we summarize the current knowledge on the interaction between MYC and UPR signaling, and its contribution to cancer development. We also discuss the potential of targeting key UPR signaling nodes as novel synthetic lethal strategies in MYC‐driven cancers., This article reviews the current knowledge on the interactions between endoplasmic reticulum stress, unfolded protein response (UPR), and MYC family, and discusses recent publications that highlight the therapeutic potential of targeting key UPR signaling as a novel strategy in MYC‐driven cancers.

The mitochondrial trifunctional protein (TFP) catalyzes three reactions in the fatty acid β-oxidation process. Mutations in the two TFP subunits cause mitochondrial trifunctional protein deficiency and acute fatty liver of pregnancy that can lead to death. Here we report a 4.2-Å cryo-electron microscopy α2β2 tetrameric structure of the human TFP. The tetramer has a V-shaped architecture that displays a distinct assembly compared with the bacterial TFPs. A concave surface of the TFP tetramer interacts with the detergent molecules in the structure, suggesting that this region is involved in associating with the membrane. Deletion of a helical hairpin in TFPβ decreases its binding to the liposomes in vitro and reduces its membrane targeting in cells. Our results provide the structural basis for TFP function and have important implications for fatty acid oxidation related diseases.

Background Metabolic syndrome (MetS) is prevalent in patients receiving atypical antipsychotic drugs (AADs), but there are few effective interventions. The Traditional Chinese herbal decoction Liu-Yu-Tang (LYT) has achieved clinical improvement for AAD-induced MetS, but its pharmacological mechanism remains unclear. Method A network pharmacology-based method was utilized in this study. First, the TCMSP and SwissTargetPrediction database were used to acquire plasma-absorbed components and putative targets of LYT, respectively. Second, an interaction network between shared targets of LYT and MetS was constructed using STRING online tool. Topological analyses were performed to extract hub gene targets. Finally, we did a pathway analysis of gene targets using the Kyoto Encyclopedia of Genes and Genomes (KEGG) to find biological pathways of LYT. Results We obtained 655 putative targets of LYT, 434 known targets of AADs, and 1577 MetS-related gene targets. There are 232 shared targets between LYT and MetS. Interaction network construction and topological analysis yielded 60 hub targets, of which 18 were major hub targets, among which IL-6, IL-8, TNF, PI3K, MAPK, and NF-κB (RELA) are the most important in LYT's treatment of AAD-induced MetS. Pathway enrichment analysis revealed a statistically high significance of the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis and the insulin resistance pathway. Conclusions LYT may control activities of the pro-inflammatory cytokines IL-6, IL-8, TNF and the important signal transduction molecules PI3K, MAPKs, and NF-κB (RELA), regulating metabolic disturbance-related pathways like the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis, and the insulin resistance pathway, generating therapeutic effects for AAD-induced MetS.

TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca2+ permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols. Two distinct states of mTRPML1 in Amphipols are added to the closed state, on which could represent two different confirmations upon activation and regulation. The polycystin-mucolipin domain (PMD) may sense the luminal/extracellular stimuli and undergo a “move upward” motion during endocytosis, thus triggering the overall conformational change in TRPML1. Based on the structural comparisons, we propose TRPML1 is regulated by pH, Ca2+, and phosphoinositides in a combined manner so as to accommodate the dynamic endocytosis process. Electronic supplementary material The online version of this article (doi:10.1007/s13238-017-0476-5) contains supplementary material, which is available to authorized users.

Many studies have indicated that immune dysfunction might be involved in the physiopathology of schizophrenia and aggression. This study aimed to investigate the correlation between high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-10 and clinical characteristics, especially aggression, and to explore the potential role of hsCRP and IL-10 as plasma biomarkers of schizophrenia.Forty-one patients with schizophrenia and forty healthy individuals were enrolled. Psychopathological severity and aggression were assessed using the Positive and Negative Syndrome Scale (PANSS) and Modified Overt Aggression Scale (MOAS). Plasma concentrations of hsCRP and IL-10 were assessed by enzyme-linked immunosorbent assay (ELISA).(1) Higher levels of hsCRP (p0.001), lower levels of logIL-10 (p0.001) and higher ratio of hsCRP to IL-10 (p0.001) were observed in the plasma of patients with schizophrenia, compared to healthy controls; (2) ROC (receiver operating characteristic) curve analysis revealed that ratio of hsCRP/IL-10 (predictive value: 0.783, p0.01; sensitivity: 85.4%; specificity: 67.5%) was more applicable as a biomarker to distinguish patients with schizophrenia from the control group than hsCRP and IL-10 alone (predictive value: 0.718, p0.01; 0.275, p0.001, respectively); (3) we found positive correlations between hsCRP and the total score and verbal aggression score of MOAS (r=0.654, p0.01; r=0.678, p0.05), and between hsCRP/IL-10 and the total score of MOAS (r=0.636, p0.01).Our results suggest the possible function of hsCRP and IL-10 in the pathogenesis of schizophrenia and the possible value of hsCRP/IL-10 as a potential peripheral biomarker of schizophrenia. This finding also suggests a relationship between hsCRP, IL-10 and their ratio with aggression in patients with schizophrenia.

Survival of patients with glioblastoma remains within the range of several months despite advances in therapeutic options. We have already shown that 5-hydroxy-1,4-naphthalenedione (juglone) exerts antiproliferative, anti-invasive, and cytotoxic effects on glioma C6 cells. Here, we further revealed that juglone is relatively selective to glioma cells as compared to the normal glial culture, and investigated its mechanisms of action. The incubation of glioma C6 cells with juglone generated high levels of reactive oxygen species (ROS). The produced ROS accounted for the anticancer effect of juglone as antioxidant N-acetylcysteine reduced both cytotoxic and antiproliferative activities of juglone. Furthermore, high resolution respirometry revealed that juglone decreased oxygen consumption mainly by affecting pyruvate/malate- and glutamate/malate-induced mitochondrial respiration. The inhibition of respiratory complex I by amytal decreased juglone-triggered generation of ROS and diminished its anticancer activity. Thus, our results indicate that juglone generates ROS through interaction with respiratory complex I in glioma C6 cells, and, in turn, induces the anticancer effects.

Fibroblast‐myofibroblast transdifferentiation (FMT) is widely recognized as the major pathological feature of renal fibrosis. Although melatonin has exerted antifibrogenic activity in many diseases, its role in renal FMT remains unclear. In the present study, the aim was to explore the effect of melatonin on renal FMT and the underlying mechanisms. We established the transforming growth factor (TGF)‐β1 stimulated rat renal fibroblast cells (NRK‐49F) model in vitro and unilateral ureteral obstruction (UUO) mice model in vivo. We assessed levels of α‐smooth muscle actin (α‐SMA), col1a1 and fibronectin, STAT3 and AP‐1, as well as miR‐21‐5p and its target genes (Spry1, PTEN, Smurf2 and PDCD4). We found that melatonin reduced the expression of α‐SMA, col1a1 and fibronectin, as well as the formation of α‐SMA filament in TGF‐β1‐treated NRK‐49F cells. Meanwhile, melatonin inhibited STAT3 phosphorylation, down‐regulated miR‐21‐5p expression, and up‐regulated Spry1 and PTEN expression. Moreover, miR‐21‐5p mimics partially antagonized the anti‐fibrotic effect of melatonin. For animal experiments, the results revealed that melatonin remarkably ameliorated UUO‐induced renal fibrosis, attenuated the expression of miR‐21‐5p and pro‐fibrotic proteins and elevated Spry1 and PTEN expression. Nevertheless, agomir of miR‐21‐5p blocked the renoprotective effect of melatonin in UUO mice. These results indicated that melatonin could alleviate TGF‐β1‐induced renal FMT and UUO‐induced renal fibrosis through down‐regulation of miR‐21‐5p. Regulation of miR‐21‐5p/PTEN and/or miR‐21‐5p/Spry1 signal might be involved in the anti‐fibrotic effect of melatonin in the kidneys of UUO mice.

Hefty structures of IgA and IgM complexesImmunoglobulin M (IgM) and IgA are antibody isotypes that can form higher-order secretory complexes (sIgM and sIgA), which allows them to effectively bind and neutralize antigens with low-affinity repetitive epitopes, such as those found on the surface of many bacteria and viruses. The assembly and transport of these molecules is also dependent on the joining chain (J-chain) and the polymeric immunoglobulin receptor (pIgR) secretory component (SC). The architecture of these complex, multimeric structures has remained elusive. Liet al.resolved cryo–electron microscopy structures of the sIgM-Fc pentamer in complex with the J-chain and SC. Using similar techniques, Kumaret al.visualized dimeric, tetrameric, and pentameric structures of secretory sIgA-Fc interacting with the J-chain and SC. Both groups report highly similar mechanisms wherein the J-chain serves as a template for antibody oligomerization. An unanticipated, amyloid-like assembly of the oligomerized structure is present in both cases, with the J-chain conferring asymmetry for pIgR binding and transcytosis. These studies may inform structure-based engineering of these molecules for future therapeutic purposes.Science, this issue p.1014, p.1008

The αβ T cell receptor (TCR), in association with the CD3γε-CD3δε-CD3ζζ signalling hexamer, is the primary determinant of T cell development and activation, and of immune responses to foreign antigens. The mechanism of assembly of the TCR-CD3 complex remains unknown. Here we report a cryo-electron microscopy structure of human TCRαβ in complex with the CD3 hexamer at 3.7 Å resolution. The structure contains the complete extracellular domains and all the transmembrane helices of TCR-CD3. The octameric TCR-CD3 complex is assembled with 1:1:1:1 stoichiometry of TCRαβ:CD3γε:CD3δε:CD3ζζ. Assembly of the extracellular domains of TCR-CD3 is mediated by the constant domains and connecting peptides of TCRαβ that pack against CD3γε-CD3δε, forming a trimer-like structure proximal to the plasma membrane. The transmembrane segment of the CD3 complex adopts a barrel-like structure formed by interaction of the two transmembrane helices of CD3ζζ with those of CD3γε and CD3δε. Insertion of the transmembrane helices of TCRαβ into the barrel-like structure via both hydrophobic and ionic interactions results in transmembrane assembly of the TCR-CD3 complex. Together, our data reveal the structural basis for TCR-CD3 complex assembly, providing clues to TCR triggering and a foundation for rational design of immunotherapies that target the complex.

Increasing evidence indicates that immune inflammatory processes, especially autoimmune reaction, should be considered in the pathophysiology of schizophrenia and aggressive behavior. The present study aimed to explore the correlation between immune factors (C3 and Th17-related cytokines) and aggressive behavior in schizophrenia patients. Forty schizophrenia patients and forty age- and gender-matched healthy controls participated in the study. Blood samples were assessed by ELISA upon enrollment. Positive and negative syndrome scale (PANSS) and modified overt aggression scale (MOAS) were used to estimate the severity and aggressive symptoms of schizophrenia patients. Plasma levels of IL-17, IL-23, and TGF-β1 in schizophrenia patients were significantly higher than those in healthy controls [(37.63±17.82) vs. (29.34±10.38)pg/ml, p=0.02; (101.40±135.26) vs. (13.09±5.94) pg/ml, p=0.01; (2864.57±2163.61) vs. (1839.69±1797.73)pg/ml, p=0.04], whereas C3 levels were significantly lower in schizophrenia patients [( 120,479.67± 65,612.50) vs. ( 208,060.21± 217,008.21)ng/ml, p=0.02]. IL-17, IL-23, and TGF-β1 levels were positively related to total scores of MOAS (p=0.02, p=0.02 and p=0.03, respectively) and PANSS (p=0.04, p=0.04 and p=0.02, respectively), whereas C3 levels were negatively related to total PANSS scores (p=0.03). IL-17 and IL-23 levels were positively correlated with PANSS excited component scores (p=0.04 and p=0.01, respectively). Our findings suggested that the Th17-related cytokine levels were positively related to the severity of schizophrenia and aggressive behavior, whereas C3 levels were negatively related to the severity of schizophrenia. This study demonstrated that elevated levels of Th17-related cytokines and decreased levels of C3 could be potential biomarkers for schizophrenia and aggressive behavior.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long‐term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients.

The human Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease caused by mutations in a highly conserved ribosome assembly factor SBDS. The functional role of SBDS is to cooperate with another assembly factor, elongation factor 1-like (Efl1), to promote the release of eukaryotic initiation factor 6 (eIF6) from the late-stage cytoplasmic 60S precursors. In the present work, we characterized, both biochemically and structurally, the interaction between the 60S subunit and SBDS protein (Sdo1p) from yeast. Our data show that Sdo1p interacts tightly with the mature 60S subunit in vitro through its domain I and II, and is capable of bridging two 60S subunits to form a stable 2:2 dimer. Structural analysis indicates that Sdo1p bind to the ribosomal P-site, in the proximity of uL16 and uL5, and with direct contact to H69 and H38. The dynamic nature of Sdo1p on the 60S subunit, together with its strategic binding position, suggests a surveillance role of Sdo1p in monitoring the conformational maturation of the ribosomal P-site. Altogether, our data support a conformational signal-relay cascade during late-stage 60S maturation, involving uL16, Sdo1p, and Efl1p, which interrogates the functional P-site to control the departure of the anti-association factor eIF6. Electronic supplementary material The online version of this article (doi:10.1007/s13238-015-0242-5) contains supplementary material, which is available to authorized users.

BACKGROUND Superb microvascular imaging (SMI) is a new blood flow imaging technique used to evaluate microvascular blood flow. This study evaluated whether SMI was superior to color Doppler flow imaging (CDFI) for evaluating placental microcirculation. MATERIAL AND METHODS This prospective study included pregnant women in their third trimester who were evaluated at General Hospital of Hebei Province from February to June 2017. The distribution of vascular patterns, including pulsatility index (PI), resistance index (RI), S/D, time average velocity (TAV), and vessels per unit area, were evaluated by SMI and CDFI. RESULTS This study evaluated 110 pregnant women of mean age 29.53 years. SMI and CDFI yielded statistically significant differences in PI (0.76 vs. 0.62), RI (0.71 vs. 0.47), S/D (2.23 vs. 1.71), TAV (14.35 vs. 22.45), and vessels per unit area (0.26 vs. 0.05) (P

An ultrasensitive aptasensor is described for the voltammetric determination of the Mycobacterium tuberculosis antigen MPT64 in human serum. Firstly, an amino-modified Zr(IV) based metal-organic framework (MOF; type UiO-66-NH2; made up from Zr6O32 units and 2-amino-terephthalate linkers) with a high specific surface was synthesized and used as the carrier of the gold nanoparticles and the aptamers. Then the signalling nanoprobe was fabricated after the horseradish peroxidase was cast on the nanomaterials. The two aptamers with synergistic effect on binding MPT64 were anchored on the gold electrode. Differential pulse voltammetry indicated that the peak current is highest if the ratio of the two aptamers is 1:1. The assay has a wide linear response range (0.02 to 1000 pg·mL−1 of MPT64) and a 10 fg·mL−1 detection limit at a working potential of around −96 mV (vs Ag/AgCl). The results show this biosensor to be a viable tool for detection of tuberculosis at an early stage.

Doxorubicin (Dox) is one of the most widely used chemotherapeutic agents for many types of cancer, including hepatocellular carcinoma. However, clinical applications of Dox are limited due to its non-selective cytotoxicity that results in severe adverse effects. To tackle this problem targeted delivery of Dox exclusively to tumour milieu has become clinically prioritised. In this study, we first synthesized and validated Dextran coated GoldMag Nanoparticles (DGMNs) as a potential delivery vehicle for Dox. We then evaluated the cytotoxicity of Dox-DGMNs, the drug and carrier composites, under guidance of external magnetic field (EMF) in hepatocellular carcinoma cell lines and in tumour grafts. Intriguingly, DGMNs exhibited the capacity to prolong Dox release in vitro; hence, Dox-DGMNs significantly enhanced the therapeutic efficiency of the drug in vitro and in vivo, especially under EMF. However, DGMNs were able to significantly decrease systemic adverse effects and inhibit tumour growth compared to the intravenous application of free Dox. Molecular analysis revealed that tumour cells were more affected by Dox-DGMNs with EMF than Dox-DGMNs or Dox alone in terms of apoptosis and DNA damage marker expression. Overall, DGMNs exhibited a substantial potential to serve as a promising drug delivery carrier for magnetically targeted cancer therapy.

To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.

Background To identify aberrant promoter methylation of genomic loci encoding microRNA (mgmiR) in head and neck squamous cell carcinoma (HNSCC) and to evaluate a biomarker panel of mgmiRs to improve the diagnostic accuracy of HNSCC in tissues and saliva. Methods Methylation of promoter regions of mgmiR candidates was initially screened using HNSCC and control cell lines and further selected using HNSCC and control tissues by quantitative methylation-specific PCR (qMS-PCR). We then examined a panel of seven mgmiRs for validation in an expanded cohort including 189 HNSCC and 92 non-HNSCC controls. Saliva from 86 pre-treatment HNSCC patients and 108 non-HNSCC controls was also examined using this panel of seven mgmiRs to assess the potentials of clinical utilization. Results Among the 315 screened mgmiRs, 12 mgmiRs were significantly increased in HNSCC cell lines compared to control cell lines. Seven out of the 12 mgmiRs, i.e., mgmiR9-1, mgmiR124-1, mgmiR124-2, mgmiR124-3, mgmiR129-2, mgmiR137, and mgmiR148a, were further found to significantly increase in HNSCC tumor tissues compared to control tissues. Using multivariable logistic regression with dichotomized variables, a combination of the seven mgmiRs had sensitivity and specificity of 92.6 and 92.4% in tissues and 76.7 and 86.1% in saliva, respectively. Area under the receiver operating curve for this panel was 0.97 in tissue and 0.93 in saliva. This model was validated by independent bootstrap validation and random forest analysis. Conclusions mgmiR biomarkers represent a novel and promising screening tool, and the seven-mgmiR panel is able to robustly detect HNSCC in both patient tissue and saliva. Electronic supplementary material The online version of this article (10.1186/s13148-018-0470-7) contains supplementary material, which is available to authorized users.

Gliomas with isocitrate dehydrogenases gene mutations (IDHMT) were found to be less aggressive than their wildtype (IDHWT) counterparts. However, the mechanism remains unclear. The current study aims to investigate the role of silenced oncogenic microRNAs in IDHMT gliomas, which were largely ignored and may contribute to the less aggressive behavior of IDHMT gliomas. Microarrays, bioinformatics analysis of the data from TCGA and qPCR analysis of samples from our experimental cohort (LGG: IDHWT = 10, IDHMT = 31; GBM: IDHWT = 34, IDHMT = 9) were performed. The results show that miR-155 was consistently down-regulated in IDHMT gliomas. Establishment of IDH1R132H overexpressing glioma cell line and bisulfite sequencing PCR suggested that miR-155 down-regulation was associated with IDH1R132H mutation induced promoter CpG islands methylation. The cancer testis antigen FAM133A is a direct downstream target of miR-155 and is a negative regulator of glioma invasion and migration possibly by regulating matrix metallopeptidase 14 (MMP14). Together, we found that methylation-regulated miR-155-FAM133A axis may contribute to the attenuated invasion and migration of IDHMT gliomas by targeting MMP14.

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is commonly used for weed control. The ubiquity of 2,4-D has gained increasing environmental concerns. Biodegradation is an attractive way to clean up 2,4-D in contaminated soil. However, information on the bioaugmentation trial for remediating contaminated soil is still very limited. The impact of bioaugmentation using 2,4-D-degraders on soil microbial community remains unknown. The present study investigated the bioremediation potential of a novel degrader (strain DY4) for heavily 2,4-D-polluted soil and its bioaugmentation impact on microbial community structure. The strain DY4 was classified as a Novosphingobium species within class Alphaproteobacteria and harbored 2,4-D-degrading TfdAα gene. More than 50 and 95 % of the herbicide could be dissipated in bioaugmented soil (amended with 200 mg/kg 2,4-D) respectively in 3-4 and 5-7 days after inoculation of Novosphingobium strain DY4. A significant growth of the strain DY4 was observed in bioaugmented soil with the biodegradation of 2,4-D. Moreover, herbicide application significantly altered soil bacterial community structure but bioaumentation using the strain DY4 showed a relatively weak impact.

Previous studies suggest that the MDM2 gene is one of the most important candidate genes for influencing the risk of osteosarcoma. This study aims to investigate the potential association of MDM2 c.346GA genetic variant with the risk of osteosarcoma in Chinese. A total of 738 subjects were recruited in this study. The genotypes of MDM2 c.346GA genetic variant were detected by the created restriction site-polymerase chain reaction. Our data suggest that the MDM2 c.346GA genetic variant is associated with the increased risk of osteosarcoma in the homozygote comparison (AA vs. GG: odds ratio [OR]=2.36, 95% confidence interval [CI] 1.30-4.28, χ2=8.35, p=0.004), recessive model (AA vs.OR=2.32, 95% CI 1.30-4.13, χ2=8.50, p=0.004), and allele comparison (A vs. G: OR=1.27, 95% CI 1.01-1.60, χ2=4.34, p=0.037). Results from this study indicated that the allele-A and genotype-AA of MDM2 c.346GA genetic variant could be an increased risk factor for the susceptibility to osteosarcoma and might be used as a potential molecular marker for evaluating the risk of osteosarcoma.

Anti-Müller hormone (AMH) plays an important role in reproductive development and has a wide potential clinical application value. Phthalates have been widely found in human living environment and have negative effects on human reproduction. This study aimed to explore the relationship between urinary phthalate metabolites and serum AMH level in the general male population. Cross-sectional analyses were performed with a population of 489 men aged more than 12 years who participated in National Health and Nutrition Examination Survey (NHANES) 2003–2004 by Centers for Disease Control and Prevention, the United States. NHANES public data (demographic and socioeconomic information, examinations, and laboratory tests) were analyzed using Kruskal-Wallis test, Wilcoxon test and multivariable regression. Results showed that the urine concentration of mono (3-carboxypropyl) phthalate (MCPP) of 12–20 age group was significantly positively correlated with serum AMH concentration in the model without any covariates (p < 0.05). In the 60-year-old group, the monomethyl phthalate (MEP), mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) concentrations were significantly correlated with serum AMH concentrations in models both with and without covariates (all p < 0.05). It could be concluded that exposure to phthalates might have negative effects on AMH level, especially in seniors. AMH could be used as a marker of exposure to phthalates in aged males. How exposure to phthalates affected AMH level and what the potential long-term health consequences of their relationship are needs more investigation.

Genotyping of single nucleotide polymorphisms (SNPs) in point-of-care (POC) settings could be further improved through simplifying the treatment of samples. In this study, we devised an accurate, rapid and easy-to-use SNP detection system based on direct loop-mediated isothermal amplification (LAMP) without DNA extraction, known as Direct-LAMP. Samples from various sources (including whole blood, dried blood spot, buccal swab and saliva), treated with NaOH, can be used directly in amplification. The turnaround time was about 30 min from sample collection to provision of results. The accuracy was evaluated by assessing the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and aldehyde dehydrogenase-2 (ALDH2) Glu504Lys, which are better known for their critical role in folate and ethanol metabolism, respectively. Completely consistent genotyping results reveal that Direct-LAMP is generally concordant with sequencing. This system can serve as a very promising platform in the fields of disease predisposition, drug metabolism and personalized medicine., Graphical abstract fx1, Highlights • Devised a SNP detection system combining DNA amplification directly with LAMP without DNA purification. • Biological samples for the Direct-LAMP system are various. • The genotyping result can be provided within 30 min. • The Direct-LAMP system can serve as a promising POCT for genotyping.

The incidence and mortality of colorectal cancer (CRC) have been rising rapidly in China. A number of miRNAs have been confirmed to be involved in diverse biological processes of CRC. However, whether miR‑197 plays a role in migration and invasion of CRC has never been explored. In the present study Transwell chambers were used in in vitro migration and invasion assays. Dual-luciferase reporter assay was employed to confirm the target of miR‑197. RT‑PCR and IHC staining were performed to quantify miR‑197 and IGFBP3 expression, respectively. Clinicopathological features were collected for statistical analysis. We observed that the overexpression of miR‑197 significantly promoted migration and invasion in 3 CRC cell lines including HCT8, HCT116 and SW480 (P

A family of six homologous subunits, Mcm2, -3, -4, -5, -6, and -7, each with its own unique features, forms the catalytic core of the eukaryotic replicative helicase. The necessity of six similar but non-identical subunits has been a mystery since its initial discovery. Recent cryo-EM structures of the Mcm2–7 (MCM) double hexamer, its precursors, and the origin recognition complex (ORC)-Cdc6-Cdt1-Mcm2–7 (OCCM) intermediate showed that each of these subunits plays a distinct role in orchestrating the assembly of the pre-replication complex (pre-RC) by ORC-Cdc6 and Cdt1.

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells.

Background Endometriosis is a relatively common condition in women of reproductive age. Malignant transformation of intestinal endometriosis is a very rare event. We report a case in which a patient with a history of endometriosis underwent surgery for malignant intestinal endometriosis. Case presentation A 55-year-old woman complained of rectorrhagia and intermittent abdominal pain. A neoplasm was revealed by colonoscopy, CT scan and F18-FDG PET/CT of the recto-sigmoidal colon. The patient underwent a rectal anterior resection, hysterectomy and bilateral salpingo-oophorectomy for treatment. According to the histological and immunohistochemical presentation, the diagnosis of endometriosis-associated recto-sigmoid cancer was confirmed. The patient was treated with adjuvant chemotherapy for 6 months. During the follow-up appointment 22 months later, there was clinical and radiographic evidence of recurrence in the rectum. The patient received chemotherapy again and will receive another surgery after two more cycles of chemotherapy. Conclusion We report a case of malignant intestinal endometriosis. Although there is no standard therapy for malignant intestinal endometriosis due to the rarity of this disease, surgery and adjuvant chemotherapy seemed to be rational. This case indicates that local recurrence may be a common situation after standard therapy.

Glial damage and immune dysfunction are involved in pathogenesis of schizophrenia. However, interaction between glial damage and immune dysfunction in schizophrenia is undefined. This study aims to compare plasma S100 calcium binding protein (S100B) levels between schizophrenia patients and healthy participants and to determine if immune markers are independently related with concentration of S100B in schizophrenia patients. Forty-one schizophrenia patients and thirty-three healthy volunteers were enrolled. Enzyme-linked immunosorbent assay (ELISA) was used to assess the concentrations of plasma S100B and inflammatory markers. We found that concentrations of S100B were elevated in schizophrenia patients than healthy participants (p p = 0.046). Receiver operating characteristic (ROC) curve analysis showed that different S100B levels between schizophrenia and healthy participants can be used as a clinical diagnostic factor (predictive value: 0.666, p = 0.015). Multiple linear regression analysis found that length of illness (Beta = −0.161), plasma levels of inflammatory regulation factors (including TGF-β1, logIL-23 and logIL-10) (Beta = 0.119, 0.475, 0.514) were independently associated with concentrations of S100B (Adjusted R2 = 0.897, p

Current techniques for single nucleotide polymorphism (SNP) detection require tedious experimental procedures and expensive and sophisticated instruments. In this study, a visual genotyping method has been successfully established via combining ARMS-PCR with gold magnetic nanoparticle (GoldMag)-based lateral flow assay (LFA) and applied to the genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T. C677T substitution of the gene MTHFR leads to an increased risk of diseases. The genotyping result is easily achievable by visual observation within 5 minutes after loading of the PCR products onto the LFA device. The system is able to accurately assess a broad detection range of initial starting genomic DNA amounts from 5 ng to 1200 ng per test sample. The limit of detection reaches 5 ng. Furthermore, our PCR-LFA system was applied to clinical trials for screening 1721 individuals for the C677T genotypes. The concordance rate of the genotyping results detected by PCR-LFA was up to 99.6% when compared with the sequencing results. Collectively, our PCR-LFA has been proven to be rapid, accurate, sensitive, and inexpensive. This new method is highly applicable for C677T SNP screening in laboratories and clinical practices. More promisingly, it could also be extended to the detection of SNPs of other genes.