bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural substrates of word category information as the basis of syntactic processing
Authors: Chen Luyao , Wu Junjie , Fu Yongben , Kang Huntae , Feng Liping
Published: September 2018

The ability to use word category information (WCI) for syntactic structure building has been hypothesized to be the essence of human language faculty. The neural substrate of the ability of using the WCI for the complex syntactic hierarchical structure processing, however, is yet unknown. Therefore, we directly conducted an fMRI experiment by using a pseudo‐Chinese artificial language with syntactic structures containing a center‐embedded relative clause. Thirty non‐Chinese native (Korean) speakers were randomly divided into two groups: one acquired WCI and WCI‐based syntactic rules (the WCI group) before the scanning session, and the other did not (the non‐WCI group). Both groups were required to judge the grammaticality of the testing sentences, with critical long‐distance dependencies between two elements (the main verb and the relativizer). Behaviorally, the WCI group's accuracy was significantly higher and its reaction time was shorter. The scanning results showed that the left superior temporal gyrus (STG) and Broca's area were more strongly activated for the WCI group, and the dynamic causal modeling analyses revealed a distinct effective connectivity pattern for this group. Therefore, the present research, for the first time, reveals that the activation of and the functional connectivity between Broca's area and the left STG play a critical role in the ability of the rule‐based use of the WCI which is crucial for complex hierarchical structure building, and might be substantially corresponding to the “labeling competence” within the linguistic framework.
The role of diversity in data‐driven analysis of multi‐subject fMRI data: Comparison of approaches based on independence and sparsity using global performance metrics
Authors: Long Qunfang , Bhinge Suchita , Levin‐Schwartz Yuri , Boukouvalas Zois , Calhoun Vince D. , Adalı Tülay
Published: September 2018

Data‐driven methods have been widely used in functional magnetic resonance imaging (fMRI) data analysis. They extract latent factors, generally, through the use of a simple generative model. Independent component analysis (ICA) and dictionary learning (DL) are two popular data‐driven methods that are based on two different forms of diversity—statistical properties of the data—statistical independence for ICA and sparsity for DL. Despite their popularity, the comparative advantage of emphasizing one property over another in the decomposition of fMRI data is not well understood. Such a comparison is made harder due to the differences in the modeling assumptions between ICA and DL, as well as within different ICA algorithms where each algorithm exploits a different form of diversity. In this paper, we propose the use of objective global measures, such as time course frequency power ratio, network connection summary, and graph theoretical metrics, to gain insight into the role that different types of diversity have on the analysis of fMRI data. Four ICA algorithms that account for different types of diversity and one DL algorithm are studied. We apply these algorithms to real fMRI data collected from patients with schizophrenia and healthy controls. Our results suggest that no one particular method has the best performance using all metrics, implying that the optimal method will change depending on the goal of the analysis. However, we note that in none of the scenarios we test the highly popular Infomax provides the best performance, demonstrating the cost of exploiting limited form of diversity.
The neurophysiological basis of developmental changes during sequential cognitive flexibility between adolescents and adults
Authors: Giller Franziska , Zhang Rui , Roessner Veit , Beste Christian
Published: September 2018

Cognitive flexibility is a major facet of executive functions and often refers to sequential task control; that is, it is very likely that one may re‐encounter a task that has previously been abandoned to carry out a different task. In the context of sequential cognitive flexibility, the “backward inhibition (BI) effect” has been studied quite extensively. Here we ask whether there are age‐related differences between adolescents and adults to overcome BI and what system‐neurophysiological mechanisms underlie these modulations. This was examined using a system neurophysiological study procedure combining event‐related potentials data with source localization and EEG signal decomposition methods. We show that sequential cognitive flexibility, and the ability overcome backward inhibition, is inferior in adolescents compared with adults. Accounting for intra‐individual variability in the neurophysiological data, this data suggest that two partly inter‐related processes underlie the differences between adolescents than adults to overcome backward inhibition: One process refers to the suppression of the inhibitory effect of the n‐1 trial on the n‐2 trial during perceptual categorization of incoming information that is associated with right inferior frontal regions. The other process refers to immature response selection and conflict monitoring mechanisms associated with regions in the medial frontal cortex.
How much does birth weight matter for child health in developing countries? Estimates from siblings and twins
Authors: McGovern Mark E.
Published: September 2018

About 200 million children globally are not meeting their growth potential, and as a result will suffer the consequences in terms of future outcomes. I examine the effects of birth weight on child health and growth using information from 66 countries. I account for missing data and measurement error using instrumental variables and adopt an identification strategy based on siblings and twins. I find a consistent effect of birth weight on mortality risk, stunting, wasting, and coughing, with some evidence for fever, diarrhoea, and anaemia. Bounds analysis indicates that coefficients may be substantially underestimated due to mortality selection. Improving the pre‐natal environment is likely to be important for helping children reach their full potential.
The effect of weight on labor market outcomes: An application of genetic instrumental variables
Authors: Böckerman Petri , Cawley John , Viinikainen Jutta , Lehtimäki Terho , Rovio Suvi , Seppälä Ilkka , Pehkonen Jaakko , Raitakari Olli
Published: September 2018

This paper contributes to the literature on the labor market consequences of obesity by using a novel instrument: genetic risk score, which reflects the predisposition to higher body mass index (BMI) across many genetic loci. We estimate instrumental variable models of the effect of BMI on labor market outcomes using Finnish data that have many strengths, for example, BMI that is measured rather than self‐reported, and data on earnings and social income transfers that are from administrative tax records and are thus free of the problems associated with nonresponse, reporting error or top coding. The empirical results are sensitive to whether we use a narrower or broader genetic risk score, and to model specification. For example, models using the narrower genetic risk score as an instrument imply that a one‐unit increase in BMI is associated with 6.9% lower wages, 1.8% fewer years employed, and a 3 percentage point higher probability of receiving any social income transfers. However, when we use a newer, broader genetic risk score, we cannot reject the null hypothesis of no effect. Future research using genetic risk scores should examine the sensitivity of their results to the risk score used.
Prevalence of Undetectable Vaccine‐Induced Immunity Against Hepatitis B Virus in US Adults at High Risk for Infection
Authors: Yeo Yee Hui , Le Michael H. , Chang Ellen T. , Henry Linda , Nguyen Mindie H.
Published: September 2018

In 2015, the Centers for Disease Control and Prevention reported a substantial increase in the number of acute hepatitis B virus (HBV) infections in the United States. Although national guidelines recommend vaccination of adults at high risk for HBV infection, the prevalence of undetectable immunity (i.e., susceptibility) in this population remains unknown. In this study, we analyzed a nationally representative sample using the National Health and Nutrition Examination Survey to evaluate the prevalence, trend, and predictors of undetectable vaccine‐induced antibodies against HBV surface antigen (<10 mIU/mL) among high‐risk adults from 2003‐2014. Among adults at high risk for HBV infection, the prevalence of undetectable immunity decreased from 83.2% in 2003‐2004 (95% confidence interval [CI]: 81.3‐85.0) to 69.4% (about 64 million) in 2013‐2014 (95% CI: 66.0‐72.6). The prevalence decreased significantly in individuals with multiple sex partners or sexually transmitted disease and in pregnant women. However, there were no significant changes in men who have sex with men (MSMs), intravenous drug users (IDUs), hepatitis C virus (HCV)‐infected and patients with diabetes, and those with elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT). Mexican Americans had the highest prevalence of undetectable immunity (77.6%, 95% CI: 72.6‐81.9), followed by non‐Hispanic whites (70.1%, 95% CI: 66.9‐73.1). Older age, lower socioeconomic status, and having at least 1 high‐risk factor were associated with a higher risk of undetectable immunity, whereas an increased risk among the foreign‐born disappeared after multivariable adjustment. Conclusion: Approximately 64 million high‐risk adults in the United States remain susceptible to HBV infection, especially MSMs, IDUs, diabetics, HCV patients, and populations with elevated AST/ALT. To eliminate HBV, efforts should be made to increase screening and vaccination in high‐risk adults.
Tillage‐induced surface roughness and topographic conditions for rill initiation in Angereb watershed, Ethiopia
Authors: Gessesse Gizaw Desta
Published: September 2018

Rill erosion makes up one source of sediment detachment and transport on agricultural fields in the Ethiopia highlands. It is so important to understand the conditions for rill initiation and demarcating rill prone areas for management planning. In this paper, we estimated rill incision considering tillage‐induced surface roughness, upslope contributing area, and slope gradient. Field experiments were installed on two fresh‐tilled smallholder agricultural plots of 3.2 m wide and 14.4 m long in the Angereb watershed of the upper Lake Tana subbasin in Ethiopia. The plots mainly represent clay and sandy clay loam soils. Time series digital elevation models generated by digital photogrammetry were used to derive topographic and surface roughness variables corresponding to 46, 116, 174, and 410‐mm cumulative rainfall. A non‐linear regression model was fitted on the slope gradient, upslope contributing area, and surface random roughness of individual rills to predict threshold area for rill initiation. Subsequent rainfall events have resulted in rough surfaces later. The change in random roughness in each rainfall event compared with the first stage amounts to 1.81, 1.62, 1.68, and 1.74 cm on clay soil and −0.05, 0.86, 1.55, and 2.06 cm on sandy clay loam soil. Prediction of the threshold area for rill initiation has improved when considering random roughness and its temporal changes. The average prediction parameter of the unit contributing area was 0.03 ± 0.05 and 0.04 ± 0.04, and of the random roughness was −0.08 ± 0.13 and −0.13 ± 0.05 on clay and sandy clay loam soils, respectively. The prediction resulted in a threshold area between 0.20 and 0.47 (average of 0.36 ± 0.11) on clay soil and 0.28 and 0.39 (average of 0.34 ± 0.05) on sandy clay loam soil. The significant variation of threshold area (p < 0.05) over the subsequent rainfall events ensures the role of incorporating surface roughness in predicting rill initiation. The result demonstrates the need to consider the variable threshold area over rainfall periods for rill incision modelling and indirectly improves the slope–length factor of erosion models.
Flow alteration impacts on Hudson Bay river discharge
Authors: Déry Stephen J. , Stadnyk Tricia A. , MacDonald Matthew K. , Koenig Kristina A. , Guay Catherine
Published: September 2018

This study explores flow regulation controls on daily river discharge variations and trends into Hudson Bay from four highly regulated and 17 moderately regulated/unregulated systems over 1960–2016. These 21 rivers contribute ~70% of the total annual riverine freshwater export to Hudson Bay, with highly regulated and moderately regulated/unregulated rivers accounting for 47% and 53% of the discharge, respectively. Daily observed streamflow data from the Water Survey of Canada, Manitoba Hydro, Ontario Power Generation, and Hydro‐Québec are used. Decadal hydrographs of the mean and coefficient of variation of daily river discharge are developed to assess the changing hydrological regimes in both systems. Decadal spectral analyses reveal the dominant controls on daily river discharge input to Hudson Bay from the regulated and unregulated systems. Apart from expected peaks in spectral power on annual timescales arising from the nival regimes in both systems, a strong secondary peak emerges at weekly timescales from flow regulation due to hydropower production. Hydrographs that consider the day of the week reveal distinct weekly cycles in regulated rivers with ~10% declines in daily river discharge during weekends and statutory holidays relative to weekday averages, demonstrating the importance of regulation on the timing of freshwater into Hudson Bay.
Second primary cancers in non‐Hodgkin lymphoma: Bidirectional analyses suggesting role for immune dysfunction
Authors: Chattopadhyay Subhayan , Sud Amit , Zheng Guoqiao , Yu Hongyao , Sundquist Kristina , Sundquist Jan , Försti Asta , Houlston Richard , Hemminki Akseli , Hemminki Kari
Published: September 2018

Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non‐Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family‐Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi‐directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy‐related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population‐level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients.
Thyroid cancer “epidemic” also occurs in low‐ and middle‐income countries
Authors: Lortet‐Tieulent Joannie , Franceschi Silvia , Dal Maso Luigino , Vaccarella Salvatore
Published: September 2018

Thyroid cancer incidence varies greatly between and within high‐income countries (HICs), and overdiagnosis likely plays a major role in these differences. Yet, little is known about the situation in low‐ and middle‐income countries (LMICs). We compare up‐to‐date thyroid cancer incidence and mortality at national and subnational levels. 599,851 thyroid cancer cases in subjects aged 20–74 reported in Cancer Incidence in Five Continents volume XI from 55 countries with at least 0.5 million population, aged 20–74 years, covered by population‐based cancer registration, and 22,179 deaths from the WHO Mortality Database for 36 of the selected countries, over 2008–2012, were included. Age‐standardized rates were computed. National incidence rates varied 50‐fold. Rates were 4 times higher among women than men, with similar patterns between countries. The highest rates (>25 cases per 100,000 women) were observed in the Republic of Korea, Israel, Canada, the United States, Italy, France, and LMICs such as Turkey, Costa Rica, Brazil, and Ecuador. Incidence rates were low (<8) in a few HICs (the Netherlands, the United Kingdom, and Denmark) and lowest (3–4) in some LMICs (such as Uganda and India). Within‐country incidence rates varied up to 45‐fold, with the largest differences recorded between rural and urban areas in Canada (HIC) and Brazil, India, and China (LMICs). National mortality rates were very low (<2) in all countries and in both sexes, and highest in LMICs. The very high thyroid cancer incidence and low mortality rates in some LMICs also strongly suggest a major role of overdiagnosis in these countries.
Inhibition of Ca2+‐activated chloride channel ANO1 suppresses ovarian cancer through inactivating PI3K/Akt signaling
Authors: Liu Zongtao , Zhang Sushan , Hou Feng , Zhang Congxiao , Gao Jianjun , Wang KeWei
Published: September 2018

Most common ovarian cancers are epithelial carcinoma in which the etiology for carcinogenesis remains elusive. ANO1/TMEM16A, a member of Ca2+‐activated Cl− channels (CaCCs), has been demonstrated to promote epithelium‐originated cancers and whether it plays a role in the pathogenesis of ovarian cancer is unknown. In our study we found that ANO1 proteins were overexpressed in human epithelial ovarian cancer cells and tissue samples. ANO1 protein upregulation was correlated with the clinical FIGO (International Federation of Gynecology and Obstetrics) staging and poor grade in ovarian cancer tissues. Interestingly, the upregulation of ANO1 gene expression was also detected in the peripheral blood mononuclear cells (PBMCs) from preoperative patients with ovarian tumors, and the down‐regulation of ANO1 in the PBMCs from postoperative patients. Silencing of ANO1 inhibited proliferation and invasion of ovarian cancer cells. Mechanistically, ANO1 knockdown attenuated phosphorylation of PI3K/Akt, and inhibition of PI3K/Akt signaling by specific inhibitor LY294002 resulted in suppression of ovarian cancer cells growth promoted by ANO1 expression. Furthermore, intratumoral injection of ANO1 siRNA suppressed subcutaneous xenograft tumor growth in nude mice implanted with ovarian cancer SKOV3 cells. Taken together, our findings demonstrate that ANO1 overexpression is involved in the pathogenesis of human epithelial ovarian cancer. Inhibition of ANO1 upregulation or inactivating PI3K/Akt signaling may have therapeutic potential for epithelial ovarian cancer, and the detection of ANO1 expression level in PBMCs from patients may also serve as a biomarker for diagnosis and prognosis of epithelial ovarian cancers.
Acute inhalation co‐exposure to 1,2‐dichloropropane and dichloromethane cause liver damage by inhibiting mitochondrial respiration and defense ability in mice
Authors: Wang Hufei , Chen Jiamin , Suda Megumi , Yanagiba Yukie , Weng Zuquan , Wang Rui‐Sheng
Published: September 2018

1,2‐Dichloropropane (1,2‐DCP) is used as an industrial solvent, insecticide fumigant and household dry cleaning product. Carcinogenicity caused by long‐term exposure to 1,2‐DCP is well established. However, the possible liver damage and related toxic mechanisms associated with acute inhalation exposure to 1,2‐DCP are rarely reported. In this study, we investigated the effects of individual and combined exposure to 1,2‐DCP and dichloromethane (DCM) on mice liver. The results showed that 1,2‐DCP significantly caused liver necrosis, possibly due to 1,2‐DCP‐induced inhibition of the mitochondrial respiratory chain complex I‐IV activities, resulting in mitochondrial dysfunction and extreme ATP consumption. Moreover, 1,2‐DCP also decreased mitochondrial defense ability by inhibiting the mitochondrial glutathione S‐transferase 1 (MGST1) activity, further aggravating liver damage. Additionally, we found that DCM co‐exposure potentially enhanced 1,2‐DCP toxicity. Our findings suggest that inhibition of mitochondrial function and MGST1 activity play critical roles in modulating 1,2‐DCP‐induced liver damage. Furthermore, our results contribute to study the new mechanism of mitochondria‐dominated signaling pathways underlying liver injury induced by 1,2‐DCP and DCM.
Cardiomyogenic differentiation of human bone marrow‐derived mesenchymal stem cell spheroids within electrospun collagen nanofiber mats
Authors: Joshi Jyotsna , Brennan David , Beachley Vince , Kothapalli Chandrasekhar R.
Published: September 2018

Collagen is the major structural protein in myocardium and contributes to tissue strength and integrity, cellular orientation, and cell–cell and cell‐matrix interactions. Significant post‐myocardial infarction related loss of cardiomyocytes and cardiac tissue, and their subsequent replacement with fibrous scar tissue, negatively impacts endogenous tissue repair and regeneration capabilities. To overcome such limitations, tissue engineers are working toward developing a 3D cardiac patch which not only mimics the structural, functional, and biological hierarchy of the native cardiac tissue, but also could deliver autologous stem cells and encourage their homing and differentiation. In this study, we examined the utility of electrospun, randomly‐oriented, type‐I collagen nanofiber (dia = 789 ± 162 nm) mats on the cardiomyogenic differentiation of human bone marrow‐derived mesenchymal stem cells (BM‐MSC) spheroids, in the presence or absence of 10 μM 5‐azacytidine (aza). Results showed that these scaffolds are biocompatible and enable time‐dependent evolution of early (GATA binding protein 4: GATA4), late (cardiac troponin I: cTnI), and mature (myosin heavy chain: MHC) cardiomyogenic markers, with a simultaneous reduction in CD90 (stemness) expression, independent of aza‐treatment. Aza‐exposure improved connexin‐4 expression and sustained sarcomeric α‐actin expression, but provided only transient improvement in cardiac troponin T (cTnT) expression. Cell orientation and alignment significantly improved in these nanofiber scaffolds over time and with aza‐exposure. Although further quantitative in vitro and in vivo studies are needed to establish the clinical applicability of such stem‐cell laden collagen nanofiber mats as cardiac patches for cardiac tissue regeneration, our results underscore the benefits of 3D milieu provided by electrospun collagen nanofiber mats, aza, and spheroids on the survival, cardiac differentiation and maturation of human BM‐MSCs. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3303–3312, 2018.
Retracted: CRNDE promotes cell tongue squamous cell carcinoma cell growth and invasion through suppressing miR‐384
Authors: Ren Yixiong , He Wenting , Chen Wenge , Ma Chao , Li Yun , Zhao Zhenyan , Gao Tao , Ni Qianwei , Chai Juan , Sun Moyi
Published: September 2018

Tongue squamous cell carcinoma (TSCC) is the most common type of oral cancer and is an aggressive head and neck malignancy. Increasing studies have demonstrated that long noncoding RNAs (lncRNAs) play important roles in diverse biological cell processes, such as cell development, fate decisions, cell differentiation, cell migration, and invasion. In our study, we showed that long noncoding RNA colorectal neoplasia differentially expressed (CRNDE) expression was upregulated in TSCC cell lines and tissues. Overexpression of CRNDE increased the TSCC cell proliferation, cell cycle, and cell invasion. Moreover, ectopic expression of CRNDE inhibited the miR‐384 expression in the SCC1 cell and increased the Kirsten Ras (KRAS), cell division cycle 42, and insulin receptor substrate 1 expression, which were the direct target genes of miR‐384. We demonstrated that the miR‐384 expression was downregulated in the TSCC samples compared with the paired adjacent nontumor samples. The expression of CRNDE was negatively correlated with the expression of miR‐384 in the TSCC samples. Overexpression of miR‐384 suppressed TSCC cell proliferation, cell cycle, and invasion. Furthermore, we demonstrated that CRNDE promoted TSCC cell proliferation and invasion through inhibiting miR‐384 expression. These results suggested that CRNDE acts as an oncogene in the development of TSCC, which partially occurs through inhibiting miR‐384 expression.
Minor allele of rs1057317 polymorphism in TLR4 is associated with increased risk of Helicobacter pylori ‐induced gastric cancer
Authors: Wang Yi‐Wei , Zhang Cai‐Hong , He Xiang
Published: September 2018

Background

Helicobacter pylori (HP) plays a significant role in the carcinogenesis of gastric cancer (GC), the second leading cause of cancer‐related death worldwide. The aim of this study was to investigate the effect of rs1057317 polymorphism on the interaction between microRNA‐034a (miR‐034a) and toll‐like receptor 4 (TLR4), and their involvement in the HP‐associated GC.

Methods

Computation analyses, real‐time polymerase chain reaction, enzyme‐linked immunosorbent assay, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide, and luciferase assays were performed to identify potential miRNAs involved in the carcinogenesis of HP‐induced GC. Subsequently, the effect of miR‐34a and recombinant TNFα‐interacting protein α (rTip‐α) on the expression of TLR4, interleukin (IL)‐6, and tumor necrosis factor α (TNF‐α) was measured.

Results

Three hundred and twelve HP‐positive GC patients (HP+ GC) and 380 HP‐negative GC patients (HP− GC) were enrolled into this study. It was found that, in HP‐positive patient, the AA genotype of the rs1057317 polymorphism was closely associated with the risk of GC (95% confidence interval, 1.12 to 2.70; odds ratio, 1.74; P = 0.0129). Furthermore, between the HP+ GC and HP− GC groups, miR‐34a was the only miRNA showing a significantly different expression. Subsequently, TLR4 was identified as a target gene of miR‐34a. Interestingly, miR‐34a evidently reduced the expression of TLR4 3′‐untranslated region (3′‐UTR) containing the C allele of the rs1057317 polymorphism, but the TLR4 3′‐UTR containing the A allele in the rs1057317 was not affected by miR‐34a. In addition, the expression of IL‐6 and TNF‐α was significantly downregulated by miR‐34a, but increased by rTip‐α. Both miR‐34a and rTip‐α could enhance the viability of cells, although the effect of rTip‐α was stronger.

Conclusion

The data of this study suggested that the rs1057317 polymorphism in the miR‐34a binding site of TLR4 may predict the risk of HP‐induced GC.
Retracted: Curcumin derivative L6H4 inhibits proliferation and invasion of gastric cancer cell line BGC‐823
Authors: Mu Jianfeng , Wang Xiaodong , Dong Lihua , Sun Pengda
Published: September 2018

Curcumin and its chalcone derivatives have well‐known, explicit biological antitumor properties, such as instance antiproliferative and apoptotic effects via multiple molecular targets. In this study, we investigated the anticancer activity of curcumin derivative L6H4 (curcumin L6H4) on gastric cancer cells. Inhibitory effects of curcumin L6H4 on gastric cancer cells (BGC‐823) were studied by the diphenyltetrazolium (MTT) assay, and cell apoptosis was detected by Annexin‐V/propidium iodide (PI) staining and then analyzed by flow cytometry. A mouse xenotransplant gastric tumor model was established to detect the role of curcumin L6H4 in vivo. The apoptosis‐related proteins p53, p21, Bax, and Bcl‐2 in BGC‐823 cells and mouse xenotransplant models treated with curcumin L6H4 were determined by Western blot analysis. Curcumin L6H4 can significantly inhibit the proliferation and induce the apoptosis of BGC‐823 cells, thus enhancing the expression levels of p53, p21, Bax, and Bcl‐2 noticeably in vivo and in vitro. Meanwhile, curcumin L6H4 can remarkably suppress the growth of tumor cells in animal models. These results suggest that curcumin derivative L6H4 has potent of antitumor properties in vitro or in vivo.
Ulinastatin protects rats from sepsis‐induced acute lung injury by suppressing the JAK‐STAT3 pathway
Authors: Wu Jian , Yan Xin , Jin Guoqiang
Published: September 2018

Sepsis is usually accompanied by pulmonary inflammations, leading to acute lung injury. During this process, endogenous factors that play a regulatory role could be exploited to therapeutically alleviate such lethal tissue injury. Here, we showed that ulinastatin (UTI) administration could reduce lung tissue necrosis and swelling during sepsis in rats. UTI treatment also decreased the levels of inflammatory mediators both in the lung and in the serum. Mechanistically, we showed that the phosphorylation levels of JAK2 and STAT3 in the lung of UTI‐treated rats were lower than control rats and were correlated with the decreased levels of inflammatory mediators. Taken together, these results demonstrate the protective role of UTI in sepsis‐induced acute lung injury.
Exosomes and their importance in metastasis, diagnosis, and therapy of colorectal cancer
Authors: Cheshomi Hamid , Matin Maryam M.
Published: September 2018

Extracellular vesicles are known as actual intermediaries of intercellular communications, such as biological signals and cargo transfer between different cells. A variety of cells release the exosomes as nanovesicular bodies. Exosomes contain different compounds such as several types of nucleic acids and proteins. In this study, we focused on exosomes in colorectal cancer as good tools that can be involved in various cancer‐related processes. Furthermore, we summarize the advantages and disadvantages of exosome extraction methods and review related studies on the role of exosomes in colorectal cancer. Finally, we focus on reports available on relations between mesenchymal stem cell–derived exosomes and colorectal cancer. Several cancer‐related processes such as cancer progression, metastasis, and drug resistance of colorectal cancer are related to the cargoes of exosomes. A variety of molecules, especially proteins, microRNAs, and long noncoding RNAs, play important roles in these processes. The microenvironment features, such as hypoxia, also have very important effects on the properties of the origin cell–derived exosomes. On the other hand, exosomes derived from colorectal cancer cells also interfere with cancer chemoresistance. Furthermore, today it is known that exosomes and their contents can likely be very effective in noninvasive colorectal cancer diagnosis and therapy. Thus, exosomes, and especially their cargoes, play different key roles in various aspects of basic and clinical research related to both progression and therapy of colorectal cancer.
The lncRNA small nucleolar RNA host gene 5 regulates trophoblast cell proliferation, invasion, and migration via modulating miR‐26a‐5p/N‐cadherin axis
Authors: Yang Yang , Xi Lan , Ma Yuan , Zhu Xiaoming , Chen Rui , Luan Lixia , Yan Jiajia , An Ruifang
Published: September 2018

Pre‐eclampsia (PE) is a pregnancy‐specific disease characterized by the occurrence of hypertension and proteinuria after two weeks of gestation. Long noncoding RNAs (lncRNAs) are emerging as key regulators in PE development. This study aims to investigate the role of lncRNA, small nucleolar RNA host gene 5 (SNHG5), in the pathogenesis of PE. The expression of SNHG5 was significantly downregulated in placental tissues from patients with severe PE compared normal controls. Overexpression of SNHG5 promoted trophoblast (HTR‐8/SVneo) cell proliferation, invasion, and migration, and flow cytometry results showed that SNHG5 overexpression inhibited apoptosis and caused a decrease of cell population at the G
0/G
1 phase and an increase of cell population at the S phase, while knockdown of SNHG5 had the opposite effects. The interaction between SNHG5 and miR‐26a‐5p was predicted by bioinformatics analysis and confirmed by luciferase reporter assay and RNA immunoprecipitation, and miR‐26a‐5p was negatively regulated by SNHG5; miR‐26a‐5p expression was upregulated in PE placental tissues and was inversely correlated with SNHG5 expression. Furthermore, miR‐26a‐5p was predicted to target the 3′ untranslated region of N‐cadherin, which was confirmed by luciferase reporter assay, and miR‐26a‐5p overexpression suppressed N‐cadherin expression in HTR‐8/SVneo cells. N‐cadherin mRNA expression was downregulated in PE placental tissues and was positively correlated with SNHG5 expression. Both overexpression of miR‐26a‐5p and knockdown of N‐cadherin suppressed HTR‐8/SVneo cell invasion and migration, and also attenuated the effects of SNHG5 on the cellular functions of HTR‐8/SVneo cells. In conclusion, our study suggested that SNHG5 promotes trophoblast cell proliferation, invasion, and migration at least partly via regulating the miR‐26a‐5p/N‐cadherin axis.
Improvement of membranous nephropathy by inhibition of miR‐193a to affect podocytosis via targeting WT1
Authors: Li Jiao , Chen Yi , Shen Lianli , Deng Yueyi
Published: September 2018

The objective of this paper was to explore the role and molecular mechanism of miR‐193a in membranous nephropathy (MN). Experimental rats and podocytes were randomly divided into four groups: control, MN, miR‐NC, and miR‐193a inhibitor groups. The relative mRNA level of miR‐193a was determined. The mRNA level and protein expression of PODXL, NPHS1, and Notch1 were determined by real‐time polymerase chain reaction (RT‐PCR) and Western blot analysis, respectively. The mRNA level and protein expression of WT1 in podocytes were also determined by RT‐PCR and Western blot analysis. The relative mRNA level of miR‐193a in the MN group was significantly higher than that in the control group, and inhibition of miR‐193a inhibited the increase successfully. Inhibition of miR‐193a inhibited renal injury, podocyte injury, and tissue cell apoptosis resulting from MN. The expression of PODXL, NPHS1, and Notch1 was decreased in the MN group, while the expression was increased in the miR‐193a inhibitor group. WT1 was verified as a target gene of miR‐193a and the expression of WT1 increased after inhibition of miR‐193a. Inhibition of miR‐193a by targeting WT1 could inhibit renal function injury, renal tissue cell apoptosis, and podocytosis.
Scaffolding role of TcpB in disrupting TLR4‐Mal interactions: Three to tango
Authors: Saqib Uzma , Baig Mirza S
Published: September 2018

Toll/interleukin‐1 like receptors (TLRs) are membrane‐spanning proteins crucially involved in innate immunity. On activation, the cytoplasmic toll/interleukin‐1 receptor (TIR) domains of these receptors undergo homo‐ or heterodimerization.
Brucella sp. are bacterial pathogens that affect the immune system by suppressing the TLR signaling pathway. They enact this by encoding a TIR domain–containing protein, TcpB, which suppresses NF‐κB activation and proinflammatory cytokine secretion mediated by TLR4 receptors. TcpB has been shown to target the Mal‐mediated pathway to suppress TLR signaling. The recent identification of its mechanism of interference with TLR4 signaling involving Mal prompted us to further study the structural aspects of TcpB binding with TLR4 and Mal. Our triprotein model displays the overall scaffolding role of TcpB in anchoring TLR4 and Mal thereby inhibiting their interaction leading to the attenuation of the TLR4 pathway.
mTOR/STAT‐3 pathway mediates mesenchymal stem cell–secreted hepatocyte growth factor protective effects against lipopolysaccharide‐induced vascular endothelial barrier dysfunction and apoptosis
Authors: Meng Shan‐Shan , Guo Feng‐Mei , Zhang Xi‐Wen , Chang Wei , Peng Fei , Qiu Hai‐Bo , Yang Yi
Published: September 2018

Mesenchymal stem cells (MSCs) protect the endothelial barrier complex and survival, implicated in the pathogenesis of acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF). However, the mechanism of HGF in endothelial regulation remains unclear. Here, we introduced a coculture protocol of pulmonary microvascular endothelial cells (PMVECs) and overexpression of the HGF gene of MSCs (MSC‐HGF). Immunofluorescence and endothelial permeability analysis revealed that MSC‐HGF protected endothelial tight junction protein occludin expression and attenuated cellular permeability as well as endothelial apoptosis. To investigate the novel mechanism mammalian TOR (mTOR)/ signal transducer and activator of transcription 3 (STAT‐3) signaling in HGF protective effects against endothelial barrier and apoptosis, we used recombinant mouse HGF in endothelial cells. In addition, we used mTOR inhibitor rapamycin to inhibit the mTOR pathway. Our study demonstrated that rapamycin decreased the protective effects of HGF on the endothelium by decreasing tight junction protein occludin expression and cell proliferation, and raising lipopolysaccharide (LPS)‐induced endothelial permeability, endothelial cell injury factors ET‐1 and vWF. Similarly, the protective effects of HGF on reducing endothelial barrier and apoptosis were weakened when PMVECs were treated with the STAT‐3 inhibitor S3I‐201. Moreover, mTOR/STAT‐3 were activated by HGF demonstrated as raising mTOR (Ser2448) and STAT3 (Ser727) phosphorylation proteins, leading to endothelial barrier improvement and survival. Reversely, rapamycin or S3I‐201 inhibited mTOR/STAT‐3 activation. Taken together, our findings highlight that the activation of the mTOR/STAT‐3 pathway provides novel mechanistic insights into MSC‐secreted HGF protection against LPS‐induced vascular endothelial permeability dysfunction and apoptosis, which contributes to decreasing microvascular loss and lung injury.
A 4‐microRNA signature for survival prognosis in pediatric and adolescent acute myeloid leukemia
Authors: Zhu Ruiqi , Lin Wenyi , Zhao Weiwei , Fan Fengjuan , Tang Liang , Hu Yu
Published: September 2018

Acute myeloid leukemia (AML) is a hematologic malignancy with significant molecular heterogeneity. MicroRNAs (miRNAs) play a critical role in AML diagnosis, pathogenesis, and prognosis of AML. Little has been done to identify a miRNA signature in pediatric and adolescent patients for predicting overall survival. This study aims to identify a panel of miRNA signature that could predict the prognosis of all younger AML patients with all subtypes of AML by analyzing data from The Cancer Genome Atlas (TCGA). A total of 229 patients under 23 years with miRNA data and corresponding clinical data from TCGA database were enrolled in this study. Through conducting multivariate analysis in the training test, it was identified that the high expression of hsa‐miR‐509 and hsa‐miR‐542 were independent poor prognostic factors, whereas that of hsa‐miR‐146a and hsa‐miR‐3667 had a trend to be favorable factors. A 4‐miRNA signature was constructed by these miRNAs considering the weight of each. In testing group and all 229 patients’ cohort as well as 59 cytogenetically normal AML (CN‐AML) patients’ cohort, higher risk score was associated with shorter overall survival (OS). All results were confidential by using powerful statistical analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were carried out to further develop leukemia‐relevant mechanisms supporting the model. The results indicate that the 4‐miRNA‐based signature is a reliable prognostic biomarker for pediatric and adolescent AML patients.
Blood routine test is a good indicator for predicting premature rupture of membranes
Authors: Zhan Fengxia , Zhu Shuzhen , Liu Haiying , Wang Qian , Zhao Guanghui
Published: September 2018

Objective

To assess the value of blood routine test (blood RT) in order to predict the occurrence of premature rupture of membranes (PROM).

Methods

A retrospective study was conducted to collect blood RT data from 100 cases of preterm premature rupture of membranes (pPROM), 70 cases of full‐term premature rupture of membranes (fPROM), and 100 cases of full‐term pregnancy (Normal). Nonparametric tests were performed for each blood routine parameter, the ROC curve was established for the parameters with significant difference, and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratios (+LR), and negative likelihood ratios (−LR) were further calculated.

Results

The statistical results showed that WBC, NE.%, LY.%, EO.%, BA.%, NE.#, EO.#, RBC, HGB, HCT, and NLR were significantly different between pPROM and fPROM (P < 0.05). There was a significant difference in WBC, NE.%, LY.%, NE.#, MO.#, RBC, HGB, HCT, and NLR between the pPROM and Normal groups (P < 0.05). Between the fPROM and Normal groups, only WBC was statistically significant (P < 0.05). By establishing ROC curve, the results showed that when the cutoff value of WBC was 9.63 and NEU# was 7.12, their combined detection had the best predictive value with a sensitivity of 73% and a specificity of 81%. In addition, Its PPV was 79.3%, NPV was 75%, +LR was 3.84, and ‐LR was 0.33.

Conclusion

The patient's blood RT results can be used to predict the risk of premature rupture of membranes, and in order to improve the sensitivity and specificity, multiple parameters can be combined.
Molecular mechanisms involved in the protective effect of pituitary adenylate cyclase‐activating polypeptide in an in vitro model of amyotrophic lateral sclerosis
Authors: Maugeri Grazia , D’Amico Agata G. , Rasà Daniela M. , Federico Concetta , Saccone Salvatore , Morello Giovanna , La Cognata Valentina , Cavallaro Sebastiano , D’Agata Velia
Published: September 2018

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Based on transcriptional profiles of motor cortex samples, in a previous work, we were able to classify two subgroups of sporadic ALS (SALS) patients, named SALS1 and SALS2. A further meta‐analysis study has revealed sixteen drug targets commonly deregulated in SALS2 and superoxide dismutase 1 (SOD1) G93A mice. The identified candidate drug targets included pituitary adenylate cyclase‐activating polypeptide (PACAP), epidermal growth factor receptor (EGFR) and matrix metallopeptidase‐2 (MMP‐2). By using a motor neuron‐like hybrid cell line (NSC‐34) expressing human SOD1 G93A as an in vitro model of ALS, here we investigated the functional correlation among these three genes. Our results have shown that PACAP increases cell viability following serum deprivation. This effect is induced through EGFR transactivation mediated by protein kinase A stimulation. Furthermore, EGFR phosphorylation activates mitogen‐activated protein kinases/extracellular signal‐regulated kinases 1 and 2 survival signaling pathway and increases MMP‐2 expression, significantly reduced by serum starvation. These results suggest that a deeper characterization of mechanisms involved in PACAP/EGFR/MMP‐2 axis activation in G93A SOD1 mutated neurons may allow identifying new targets for ALS therapy.
1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways
Authors: Fan Jiangjiang , Wu Mingsheng , Wang Jian , Ren Dongmei , Zhao Jian , Yang Guotao
Published: September 2018

1,7‐Bis(4‐hydroxyphenyl)‐1,4‐heptadien‐3‐one (EB30) is a diarylheptanoid‐like compound isolated from Viscum coloratum. This curcumin analog exhibits significant cytotoxic activity against HeLa, SGC‐7901, and MCF‐7 cells. However, little is known about the anticancer effects and mechanisms of EB30 in human lung cancer. The current study reports that EB30 significantly reduced the cell viability of A549 and NCI‐H292 human lung cancer cells. Further examination revealed that EB30 not only induced cell cycle arrest and promoted the generation of reactive oxygen species (ROS) but also induced cell apoptosis through the intrinsic and extrinsic signaling pathways. Furthermore, EB30 upregulated the expression levels of p‐ERK1/2 and p‐P90RSK, whereas downregulating the phosphorylation of Akt and P70RSK. Cell viability was further inhibited by the combination of EB30 with LY294002 (a specific PI3K inhibitor) or U0126 (a MEK inhibitor). The current study indicates that EB30 is a potential anticancer agent that induces cell apoptosis via suppression of the PI3K/Akt pathway and activation of the ERK1/2 pathway.
Identification of a novel cell cycle‐related gene signature predicting survival in patients with gastric cancer
Authors: Zhao Lan , Jiang Longyang , He Linxiu , Wei Qian , Bi Jia , Wang Yan , Yu Lifeng , He Miao , Zhao Lin , Wei Minjie
Published: September 2018

Gastric cancer (GC) is one of the most fatal cancers in the world. Thousands of biomarkers have been explored that might be related to survival and prognosis via database mining. However, the prediction effect of single gene biomarkers is not specific enough. Increasing evidence suggests that gene signatures are emerging as a possible better alternative. We aimed to develop a novel gene signature to improve the prognosis prediction of GC. Using the messenger RNA (mRNA)‐mining approach, we performed mRNA expression profiling in a large GC cohort (n = 375) from The Cancer Genome Atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed, and we recovered genes related to the G2/M checkpoint, which we identified with a Cox proportional regression model. We identified a set of five genes (MARCKS, CCNF, MAPK14, INCENP, and CHAF1A), which were significantly associated with overall survival (OS) in the test series. Based on this five‐gene signature, the test series patients could be classified into high‐risk or low‐risk subgroups. Multivariate Cox regression analysis indicated that the prognostic power of this five‐gene signature was independent of clinical features. In conclusion, we developed a five‐gene signature related to the cell cycle that can predict survival for GC. Our findings provide novel insight that is useful for understanding cell cycle mechanisms and for identifying patients with GC with poor prognoses.
Autophagy participates in cyst breakdown and primordial folliculogenesis by reducing reactive oxygen species levels in perinatal mouse ovaries
Authors: Zhihan Tu , Xinyi Mu , Qingying Li , Rufei Gao , Yan Zhang , Xuemei Chen , Yanqing Geng , Yingxiong Wang , Junlin He
Published: September 2018

The reserve of primordial follicles, which serves all oocytes for the female reproductive lifespan, is established a few days after birth in mice. During this process, more than half of the oocytes are primarily eliminated by apoptosis. Autophagy, the conserved intracellular process maintaining cellular homeostasis, serves as a protective mechanism for oocyte survival. In the current study, we speculate a new role for autophagy during primordial folliculogenesis. Active autophagy was observed in perinatal ovaries from 16.5 days post coitus to 3 days post parturition. The inhibition of autophagy by 3‐methyladenine (3‐MA) increased the number of cyst oocytes and delayed follicle formation in vivo and in organ cultures. Furthermore, the reactive oxygen species (ROS) level was elevated in ovaries treated with 3‐MA, while N‐acetylcysteine, an oxidant, alleviated the inhibitory effect of 3‐MA on primordial folliculogenesis. Additionally, the expression of growth differentiation factor 9 and transforming growth factor β1, which regulates follicle activation, was decreased after 3‐MA treatment. These data suggest that the physiological level of autophagy in perinatal ovaries regulates germ cell cyst breakdown and primordial follicle assembly by ROS clearance and exerts extensive effects on further follicular development.