Microrchidia family CW-type zinc finger 2 (MORC2) is a ubiquitously expressed protein that contributes to chromatin remodeling, DNA repair, and lipogenesis. However, its role in cholangiocarcinoma (CCA) remains largely unknown. The aim of this study was to investigate the expression profile of MORC2 and its potential functions in CCA progression. The results showed that MORC2 was upregulated in human CCA specimens and cell lines. MORC2 expression was significantly associated with serum CA19-9 levels (P = 0.009), TNM stage (P = 0.003) and lymph node invasion (P = 0.004). Furthermore, high MORC2 expression was associated with poor 5-year survival (P = 0.016). Functional experiments revealed that MORC2 knockdown could suppress CCA cell proliferation, migration, and invasion both in vivo and in vitro. Mechanically, we found that MORC2 promoted CCA cell metastasis through the EMT process and enhanced proliferation via the Akt signaling pathway. Moreover, MORC2 was negatively regulated by miR-186-5p. MiR-186-5p could influence CCA cell proliferation, migration and metastasis by regulating MORC2. Taken together, the findings of this study demonstrated the oncogenic role of MORC2 in CCA tumorigenesis and metastasis, and clarified an underlying regulatory mechanism mediating MORC2 upregulation, which may provide a novel therapeutic target in CCA treatment.

To test the hypothesis that multicenter automatic defibrillator implantation trial (MADIT) - implantable cardioverter-defibrillator (ICD) scores predict replacement requirement and appropriate shock in a mixed population including both primary and secondary prevention and long-term adverse cardiovascular events.

The increasing incidence of obesity in children is a significant risk factor for nonalcoholic fatty liver disease and obesity-associated morbidity. In the present study, we aimed to explore the correlation between Vitamin D level and hepatosteatosis in obese children.

Common fragile sites (CFSs) are conserved genomic regions prone to break under conditions of replication stress (RS). Thus, CFSs are hotspots for rearrangements in cancer and contribute to its chromosomal instability. Here, we have performed a global analysis of proteins that recruit to CFSs upon mild RS to identify novel players in CFS stability. To this end, we performed Chromatin Immunoprecipitation (ChIP) of FANCD2, a protein that localizes specifically to CFSs in G2/M, coupled to mass spectrometry to acquire a CFS interactome. Our strategy was validated by the enrichment of many known regulators of CFS maintenance, including Fanconi Anemia, DNA repair and replication proteins. Among the proteins identified with unknown functions at CFSs was the chromatin remodeler ATRX. Here we demonstrate that ATRX forms foci at a fraction of CFSs upon RS, and that ATRX depletion increases the occurrence of chromosomal breaks, a phenotype further exacerbated under mild RS conditions. Accordingly, ATRX depletion increases the number of 53BP1 bodies and micronuclei, overall indicating that ATRX is required for CFS stability. Overall, our study provides the first proteomic characterization of CFSs as a valuable resource for the identification of novel regulators of CFS stability.

The abnormal aggregation of α‑synuclein (α‑syn), which is an important pathological feature of Parkinson's disease (PD), is cytotoxic to dopaminergic neurons and causes cellular damage and apoptosis. Salidroside (SAL) is the main active component of the traditional Chinese medicine Rhodiola rosea. Previous research has demonstrated that SAL exerts cellular protection against cell senescence and neurodegeneration. However, the role and mechanism of action of SAL in PD remain unclear. The present study used overexpression of the wild‑type and the A53T mutation of α‑syn to induce a neuronal model of PD in SH‑SY5Y cells, which led to neuronal toxicity and a reduced cell proliferation index. SAL increased the cell proliferation index of both PD model groups in a dose‑dependent manner. Additionally, SAL alleviated pathogenic phosphorylated (Ser129) α‑syn expression as well as the ratio of microtubule‑associated proteins 1A/1B light chain 3 (LC3)‑I to LC3‑II expression, which is related to autophagic function. Furthermore, the results suggested that the underlying mechanism for the SAL‑induced protection of PD model neurons may involve the preservation of autophagy, which attenuates the phosphorylation of α‑syn in neurons predominantly via mTOR/p70S6K, and is independent of the PI3K/Akt signaling pathway.

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children, which has complex molecular mechanisms. Increasing evidence has suggested that long noncoding RNAs (lncRNAs) account for NB pathogenesis. However, the function of small nucleolar RNA host gene 16 (SNHG16) in NB is currently unclear. In the present study, publically available data and clinical specimens were employed to verify the expression of SNHG16 in NB. Colony formation, real‑time cell proliferation and migration assays were performed to demonstrate the status of cellular proliferation and migration. Flow cytometry was used to examine cell cycle progression in SH‑SY5Y cells, and acridine orange/ethidium bromide staining and caspase‑3/7 activity measurements were applied to study cell apoptosis. To explore the underlying mechanism of SNHG16 function, an online database was used to identify potential RNA‑binding proteins that bind SNHG16. The expression of SNHG16 was revealed to be in line with the clinical staging of NB, and high SNHG16 expression was positively associated with poor clinical outcome. Furthermore, SNHG16 silencing inhibited cell proliferation, repressed migration, and induced cell cycle arrest at the G0/G1 phase in SH‑SY5Y cells. Additionally, apoptosis was undetectable in SH‑SY5Y cells following SNHG16 silencing. Bioinformatics analysis revealed that SNHG16 regulated cell proliferation in NB through transcriptional and translational pathways. These results suggested that SNHG16 may serve important roles in the development and progression of NB, and could represent a potential target for NB therapy.

The developmental pluripotency‑associated 4 (Dppa4) gene serves critical roles in cell self‑renewal, as well as in cancer development and progression. However, the regulatory role of Dppa4 in non‑small‑cell lung cancer (NSCLC) and its underlying mechanisms remain elusive. The aim of the present study was to investigate the biological function of Dppa4 in NSCLC and its underlying mechanism of action. Dppa4 expression was measured in NSCLC tissue samples and cell lines, and its effect on cell proliferation and the expression of glycolytic enzymes was determined. In addition, the underlying mechanisms of Dppa4‑induced alterations in glycolysis were analyzed. Univariate and multivariate analyses were also performed to analyze the prognostic significance of clinicopathological characteristics. Dppa4 was found to be highly expressed in NSCLC tissues and cell lines. Furthermore, it was observed that Dppa4 was correlated with the degree of tumor differentiation and TNM stage. Univariate and multivariate analyses identified Dppa4 expression and clinical stage as prognostic factors for NSCLC patients. Kaplan‑Meier analysis further revealed that patients with lower Dppa4 expression exhibited a better prognosis. In NSCLC cells, Dppa4 knockdown inhibited cell proliferation, while Dppa4 overexpression enhanced cell proliferation, which was likely mediated by glycolysis promotion. Dppa4 knockdown had no evident effect on the majority of enzymes examined; however, glucose transporter type 4 (GLUT‑4) and pyruvate kinase isozyme M2 were significantly upregulated, and hexokinase II (HK‑II) and lactate dehydrogenase B (LDHB) were downregulated following Dppa4 knockdown. By contrast, Dppa4 overexpression resulted in downregulation of GLUT‑4, and upregulation of HK‑II, enolase and LDHB, whereas it had no effect on other enzymes. Since the most evident effect was observed on LDHB, further functional experiments demonstrated that this enzyme reversed the promoting effects of Dppa4 in NSCLC. In conclusion, Dppa4 promotes NSCLC progression, partly through glycolysis by LDHB. Thus, the Dppa4‑LDHB axis critically contributes to glycolysis in NSCLC cells, thereby promoting NSCLC development and progression.

Acute lung injury (ALI) is a major cause of morbidity and mortality globally, and is characterized by widespread inflammation in the lungs. Increased production of reactive oxygen species is hypothesized to be associated with ALI. Matrine and lycopene are active products present in traditional Chinese medicine. Matrine is an effective inhibitor of inflammation, whereas lycopene decreases lipid peroxidation. Therefore, it was hypothesized that combinatorial treatment with matrine and lycopene may provide synergistic protection against ALI. In the present study, mice were treated with dexamethasone (DEX; 5 mg/kg), matrine (25 mg/kg), lycopene (100 mg/kg), and matrine (25 mg/kg) + lycopene (100 mg/kg) for 7 days prior to injury induction using lipopolysaccharide (LPS; 5 mg/kg) for 6 h. Lung tissues were collected following the sacrifice of the mice and hematoxylin and eosin staining was used for histological analysis. Malondialdehyde (MDA), glutathione (GSH) and myeloperoxidas (MPO) levels were examined by respective kits. The expressions of interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) were evaluated by ELISA. The expressions of IκBα and NF‑κB p65 were examined by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results indicated that the combined treatment exhibited a similar effect to DEX, both of which attenuated lung structural injuries, downregulated the expressions of IL‑6, TNF‑α, MPO and MDA, and upregulated that of GSH. Furthermore, the combined treatment and DEX inhibited NF‑κB p65 activation. The present study revealed that combined treatment with matrine and lycopene exhibited protective effects on an LPS‑induced mouse model of ALI, suggesting that they may serve as a potential alternative to glucocorticoid therapy for ALI.

Mesenchymal stem cells (MSCs) are derived from the mesoderm and have the self‑renewal capacity and multi‑directional differentiation potential of adult stem cells. Stem cells from different sources have different molecular and growth characteristics; therefore, the mechanisms and effects of stem cell‑mediated repair and tissue regeneration may be different. The aim of the present study was to compare the biological characteristics of MSCs derived from the umbilical cord (UC‑MSCs) and MSCs derived from the decidua parietalis (DP‑MSCs), and to provide new evidence for the selection of seed cells in regenerative medicine. Growth curves, cell doubling times, colony formation rates, immunophenotypes, differentiation capacities and secretion‑factor levels of MSCs derived from the two sources were analysed. UC‑MSCs and DP‑MSCs exhibited similar properties with regards to morphology, spiral growth, immunophenotype, and potential to differentiate into osteoblasts and adipocytes. For each cell type, the positive rates of the cell surface markers CD73, CD90 and CD105 were >95%, whereas CD34 and CD45 positive rates were <1%. Analyses of in vitro growth kinetics revealed shorter cell‑doubling times, and higher proliferative rates and colony formation rates of UC‑MSCs compared with DP‑MSCs (P<0.05). The concentration of basic fibroblast growth factor in the supernatant from UC‑MSCs was higher compared with that from DP‑MSCs (P<0.05). However, UC‑MSC supernatants exhibited lower levels of of keratinocyte growth factor, vascular endothelial growth factor and stem cell factor compared with DP‑MSCs (P<0.05). In conclusion, in vitro characterization of MSCs from these tissue sources revealed a number of common biological properties. However, the results also demonstrated clear biological distinctions and suggested that UC‑MSCs may have more effective application prospects.

CD24 can regulate angiogenesis, drug sensitivity and the progression of colorectal cancer (CRC). However, whether CD24 regulates autophagy and apoptosis in CRC cells remains to be fully elucidated. The present study investigated the functional role of the altered expression of CD24 in the autophagy and apoptosis of HCT116 and HT29 human CRC cells. The results revealed lower expression levels of CD24 in HCT116 cells but higher levels in HT29 cells. Inducing the overexpression or the knockdown of CD24 did not affect the viability or spontaneous apoptosis of HCT116 and HT29 cells, respectively. Induction of the overexpression of CD24 significantly decreased the relative expression levels of Beclin‑1, autophagy‑related (Atg)3 and Atg5, and the numbers of microtubule‑associated protein‑1 light chain‑3 (LC3)‑positive puncta, but increased the expression of p62 in HCT116 cells. By contrast, CD24 silencing increased the expression of Beclin‑1, Atg3 and Atg5, and the numbers of LC3‑positive puncta, but decreased the expression of p62 in HT29 cells. Treatment with 3‑methyladenine, or the knockdown of Atg5 by specific small interfering RNA to attenuate autophagy significantly enhanced the viability of CD24‑overexpressing HCT116 cells, but reduced the viability of CD24‑silenced HT29 cells, relative to their controls. As a result, the attenuation of autophagy significantly decreased the frequency of apoptotic CD24‑overexpressing HCT116 cells, but increased the percentages of apoptotic CD24‑silenced HT29 cells. The overexpression of CD24 promoted the activation of nuclear factor (NF)‑κBp65, whereas CD24 silencing attenuated its activation in CRC cells. Inhibition of the activation of NF‑κB enhanced the CD24 overexpression‑induced decrease in autophagy, but attenuated the CD24 silencing‑induced increase in autophagy in CRC cells. Therefore, CD24 inhibited the autophagy of CRC cells, and the combination of targeting CD24 and inhibiting autophagy promoted the apoptosis of CRC cells. Conceivably, these findings may aid in the design of novel therapies for the intervention of CRC.

Head and neck squamous cell carcinoma (HNSCC) remains one of the most common malignancies associated with poor prognosis. DNA methylation has emerged as an important mechanism underlying the radio‑resistance of tumors. Prognostic biomarkers based on radiotherapy‑related aberrant DNA methylation are limited. Methylation profiles of 388 patients with HNSCC were acquired from The Cancer Genome Atlas (TCGA) portal. Genes with differentially methylated CpG sites (DMGs) were screened between patients with a favorable and poor prognosis with or without radiotherapy. A weight gene co‑methylation network was constructed using a Weighted Gene Co‑expression Network Analysis (WGCNA) package. A lasso Cox‑PH model was used to identify the optimal panel of genes with the ability to predict survival in these patients. Prognostic performance of the multi‑gene methylation signature was assessed in a training set and confirmed in a validation set. A total of 976 DMGs were observed between favorable and poor prognostic samples. Four DMG‑enriched co‑methylation modules were identified. A four‑gene methylation signature was determined by the lasso Cox‑PH model that consisted of ZNF10, TMPRSS12, ERGIC2, and RNF215. The risk score based on the four‑gene signature was able to divide the training or validation set into two risk groups with significantly different overall survival. Thus, the present study revealed a radiotherapy‑related four‑gene methylation signature to predict survival outcomes of patients with HNSCC, providing candidate therapeutic targets for novel therapy against HNSCC. However, substantial validation experiments are required.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of autoimmune etiopathogenesis, and is characterized by various neurological symptoms. Glatiramer acetate and interferon‑β are administered as first‑line treatments for this disease. In non‑responsive patients, several second‑line therapies are available, including natalizumab; however, a percentage of MS patients does not respond, or respond partially. Therefore, it is of the utmost importance to develop a diagnostic test for the prediction of drug response in patients suffering from complex diseases, such as MS, where several therapeutic options are already available. By a machine learning approach, the UnCorrelated Shrunken Centroid algorithm was applied to identify a subset of genes of CD4+ T cells that may predict the pharmacological response of relapsing‑remitting MS patients to natalizumab, before the initiation of therapy. The results from the present study may provide a basis for the design of personalized therapeutic strategies for patients with MS.

Compare the efficacy and safety of the 2-drug antiretroviral therapy regimen dolutegravir + lamivudine (DTG + 3TC) with traditional 3-drug regimens in treatment-naive patients with HIV-1.

African trypanosomosis, primarily transmitted by tsetse flies, remains a serious public health and economic challenge in sub-Saharan Africa. Interventions employing natural repellents from non-preferred hosts of tsetse flies represent a promising management approach. Although zebras have been identified as non-preferred hosts of tsetse flies, the basis for this repellency is poorly understood. We hypothesized that zebra skin odors contribute to their avoidance by tsetse flies.

Despite the broad-spectrum antimicrobial activities of silver, its internal usage is restricted, owing to the toxicity. Strategies to enhance its efficacy are highly desirable but rely heavily on the understanding of its molecular mechanism of action. However, up to now, no direct silver-targeting proteins have been mined at a proteome-wide scale, which hinders systemic studies on the biological pathways interrupted by silver. Herein, we build up a unique system, namely liquid chromatography gel electrophoresis inductively coupled plasma mass spectrometry (LC-GE-ICP-MS), allowing 34 proteins directly bound by silver ions to be identified in Escherichia coli. By using integrated omic approaches, including metalloproteomics, metabolomics, bioinformatics, and systemic biology, we delineated the first dynamic antimicrobial actions of silver (Ag+) in E. coli, i.e., it primarily damages multiple enzymes in glycolysis and tricarboxylic acid (TCA) cycle, leading to the stalling of the oxidative branch of the TCA cycle and an adaptive metabolic divergence to the reductive glyoxylate pathway. It then further damages the adaptive glyoxylate pathway and suppresses the cellular oxidative stress responses, causing systemic damages and death of the bacterium. To harness these novel findings, we coadministrated metabolites involved in the Krebs cycles with Ag+ and found that they can significantly potentiate the efficacy of silver both in vitro and in an animal model. Our study reveals the comprehensive and dynamic mechanisms of Ag+ toxicity in E. coli cells and offers a novel and general approach for deciphering molecular mechanisms of metallodrugs in various pathogens and cells to facilitate the development of new therapeutics.

We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model's energy function uncovers distinct mechanisms for chromatin folding at various length scales and suggests a need to go beyond simple A/B compartment types to predict specific contacts between regulatory elements using polymer simulations.

In developing countries, the cost of vaccination limits the use of prophylactic rabies vaccination, especially in cattle. Intradermal vaccination delivers antigen directly to an area with higher number of antigen-presenting cells. Therefore, it could produce equivalent or higher antibody titres than conventional intramuscular vaccination even when a lower dose is given. This study aimed to compare the antibody response in cattle vaccinated intramuscularly with 1mL of inactivated rabies vaccine (Raksharab, Indian Immunologicals) against intradermally vaccinated cattle with 0.2mL of the same vaccine. The study was conducted in Haa province of Bhutan where rabies is not endemic. One hundred cattle from 27 farms were selected for the study. Virus neutralising antibody (VNA) response was measured using the fluorescent antibody virus neutralisation test on the day of vaccination (day 0) and 14, 30, 60 and 90 days later. Overall, 71% of intradermally vaccinated cattle and 89% of the intramuscularly vaccinated cattle produced an adequate response (≥0.5IU/mL). On days 14 and 30 post vaccination fewer cattle (P<0.02) in the intradermal group had adequate titres with 36% and 58%, respectively, having titres ≥0.5 IU/mL compared to the equivalent figures of 78% and 77% in the intramuscular group. The mean VNA titres were lower for the intradermal group than intramuscular group (p<0.001) with the mean difference being > 0.6 IU/mL. Although low dose intradermal vaccination did produce a detectable antibody response, it was inferior to intramuscular vaccination. Thus, although intradermal vaccination has the potential to reduce the cost of vaccination by reducing the dose required, this study showed that a single dose of 0.2 mL intradermally was inferior to an intramuscular dose of 1 mL. Further research evaluating dose and dose regimen is needed before intradermal vaccination using the Raksharab rabies vaccine can be recommended in cattle.

Companies need to ensure that customers perceive their brands as intended, with strong and unique associations, when facing a competitive market. Traditionally, brand associations are measured using conventional techniques such as surveys and questionnaires albeit both conscious and unconscious factors can influence the collected data and the outcome of a campaign. Neuromarketing can shed light on how the customer's brain processes marketing stimuli. We report here on an EEG study aimed at gauging mental associations with brands. We focus on the N400 event-related potential, an EEG component most strongly elicited in response to a concept unrelated to a preceding concept. We considered two video on demand brands, Netflix and Rex&Rio, and selected a set of words grouped in 4 categories that were either related (Television, Relaxation, and Price), in varying degrees, or unrelated (Unrelated) to the said brands. The experiment started with both brands' TV commercials, as a common reference for our participants. We then applied a semantic priming paradigm in which a brand logo ("prime") was followed by a word ("target"), and the strength of the N400 response to the word used as an inverted measure of the association strength with the brand logo. We clustered N400 responses to identify, for each brand, natural groups of associated words. As a result, for Netflix the cluster with the smallest N400 responses (i.e., strongest associations) consisted of words related to Television but for Rex&Rio it consisted of words related to Relaxation. We also evaluated the relationship between the two brands and determined which associations they share or which ones not. It turned out that associations related to Relaxation and Television distinguish the two brands. Interestingly, survey data did not show any difference between the two brands as they were equally associated with Television and Relaxation. These findings show that our N400 technique can reveal brand associations, and natural categories thereof, that would otherwise go unnoticed when using conventional surveys.

The objective of this study was to examine whether exposure to Intimate Partner Violence (IPV) is associated with premature termination of Exclusive Breastfeeding (EB). Per WHO recommendations, this was defined as ceasing breastfeeding or supplementing with other foods or liquids before the child was 6 months old.

Gastrointestinal parasites are neglected infections, yet they cause significant burden to animal and human health globally. To date, most studies of gastrointestinal parasites focus on host-parasite systems that involve either a single parasite or a host species. However, when hosts share habitat and resources, they may also cross-transmit generalist gastrointestinal parasites. Here we explore multi-host-parasite interactions in a single ecosystem to understand the infection patterns, especially those linked to livestock-wildlife interfaces and zoonotic risk.