bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmission pathways and spillover of an erythrocytic bacterial pathogen from domestic cats to wild felids
Authors: Kellner Annie , Carver Scott , Scorza Valeria , McKee Clifton D. , Lappin Michael , Crooks Kevin R. , VandeWoude Sue , Antolin Michael F.
Published: September 2018

Many pathogens infect multiple hosts, and spillover from domestic to wild species poses a significant risk of spread of diseases that threaten wildlife and humans. Documentation of cross‐species transmission, and unraveling the mechanisms that drive it, remains a challenge. Focusing on co‐occurring domestic and wild felids, we evaluate possible transmission mechanisms and evidence of spillover of“Candidatus Mycoplasma haemominutum” (CMhm), an erythrocytic bacterial parasite of cats. We examine transmission and possibility of spillover by analyzingCMhmprevalence, modeling possible transmission pathways, deducing genotypes ofCMhmpathogens infecting felid hosts based on sequences of the bacterial 16SrRNAgene, and conducting phylogenetic analyses with ancestral state reconstruction to identify likely cross‐species transmission events. Model selection analyses suggest both indirect (i.e., spread via vectors) and direct (i.e., via interspecific predation) pathways may play a role inCMhmtransmission. Phylogenetic analyses indicate that transmission ofCMhmappears to predominate within host species, with occasional spillover, at unknown frequency, between species. These analyses are consistent with transmission by predation of smaller cats by larger species, with subsequent within‐species persistence after spillover. Our results implicate domestic cats as a source of global dispersal and spillover to wild felids via predation. We contribute to the emerging documentation of predation as a common means of pathogen spillover from domestic to wild cats, including pathogens of global conservation significance. These findings suggest risks for top predators as bioaccumulators of pathogens from subordinate species.
Forest management for novelty, persistence, and restoration influenced by policy and society
Authors: Rissman Adena R , Burke Kevin D , Kramer Heather Anuhea Canfield , Radeloff Volker C , Schilke Paul R , Selles Owen A , Toczydlowski Rachel H , Wardropper Chloe B , Barrow Lori A , Chandler Jennifer L , Geleynse Katelyn , L'Roe Andrew W , Laushman Katherine M , Schomaker A Lisa
Published: September 2018

The ecological literature offers many conflicting recommendations for how managers should respond to ecosystem change and novelty. We propose a framework in which forest managers may achieve desired forest characteristics by combining strategies for (1) restoring historical conditions, (2) maintaining current conditions, and (3) transitioning toward novel conditions. Drawing on policy studies and the ecological and social sciences, we synthesize research on factors that shape forest management responses to ecosystem novelty and change. Although the ecological literature often suggests the likelihood of transitions to novelty, we found that a management focus on restoration and persistence strategies was supported by landowners, private and public lands policy, and forest manager capacity and culture. In this era of unprecedented change, managers and policy makers must address ecosystem novelty to achieve desired forest futures without eroding support for forest conservation and management.
Nutrient retention during ecosystem succession: a revised conceptual model
Authors: Lovett Gary M , Goodale Christine L , Ollinger Scott V , Fuss Colin B , Ouimette Andrew P , Likens Gene E
Published: September 2018

We propose an important revision to a previously published conceptual model of nutrient retention during terrestrial ecosystem succession, which predicted that ecosystem losses of limiting nutrients such as nitrogen (N) should increase as rates of biomass accumulation slow during late stages of succession. This revision explicitly recognizes that mineral soil horizons (the layers of subsoil beneath the organic‐rich surface layers) can behave as an “N bank”, serving as a source of N for growing forests early in secondary succession and as a sink for N later in succession as plant biomass accumulation slows. If this soil N sink were present, mature forests would continue to retain N for decades following the cessation of biomass accumulation. This conceptual model is consistent with long‐term data collected from the Hubbard Brook Experimental Forest in the US state of New Hampshire, where existing N budgets that exclude the mineral soil horizon indicate both a missing source early in succession and a missing sink as the forest has matured.
Nonfat milk attenuates acute hyperglycemia in individuals with android obesity: A randomized control trial
Authors: Leary Miriam P. , Roy Stephen J. , Lim Jisok , Park Wonil , Ferrari Rodrigo , Eaves Jared , Machin Daniel R. , Tanaka Hirofumi
Published: September 2018

Background

Elevated android body fat increases the risk of developing cardiometabolic diseases. Postprandial hyperglycemia contributes to the proatherogenic metabolic state evident in android adiposity. Due to the insulinotropic effect of milk‐derived proteins, postprandial hyperglycemia has been shown to be reduced with the addition of dairy products. The purpose of this study was to determine whether one serving of nonfat milk added to an oral glucose tolerance test (OGTT) could attenuate postprandial hyperglycemia in individuals with elevated android adiposity and whether these improvements would be associated with metabolic and/or peripheral hemodynamic effects.

Methods

In this placebo‐controlled, randomized, crossover experimental study, 29 overweight/obese adults (26 ± 1 year) consumed an OGTT beverage (75 g glucose) combined with either nonfat milk (227 g) or a placebo control (12 g lactose + 8 g protein + 207 g water) that was matched for both carbohydrate and protein quantities.

Results

In the whole sample, blood glucose and insulin concentrations increased over time in both trials with no significant differences between trials. Relative increases in peak blood glucose response were significantly related to android body fat (p < 0.05). The subjects in the highest tertiles of android body fat displayed attenuated hyperglycemic responses as well as improvements in flow‐mediated dilation (FMD) after milk intake.

Conclusions

A single serving of nonfat milk may attenuate acute hyperglycemia in individuals with elevated android body fat offering a simple and convenient option for managing elevations in blood glucose.
Genome‐wide interaction studies identify sex‐specific risk alleles for nonsyndromic orofacial clefts
Authors: Carlson Jenna C. , Nidey Nichole L. , Butali Azeez , Buxo Carmen J. , Christensen Kaare , Deleyiannis Frederic W.‐D. , Hecht Jacqueline T. , Field L. Leigh , Moreno‐Uribe Lina M. , Orioli Ieda M. , Poletta Fernando A. , Padilla Carmencita , Vieira Alexandre R. , Weinberg Seth M. , Wehby George L. , Feingold Eleanor , Murray Jeffrey C. , Marazita Mary L. , Leslie Elizabeth J.
Published: September 2018

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene‐by‐sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome‐wide joint tests of the genetic (G) and G × S effects genome‐wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test (
p < 1.00 × 10
−5) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results (
p < 1.00 × 10
−5) for the joint test, we observed one genome‐wide significant G × S effect in the 10q21 locus (rs72804706;
p = 6.69 × 10
−9; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.
A parametric analysis of capillary pressure effects during geologic carbon sequestration in a sandstone reservoir
Authors: Wu Hao , Jayne Richard S. , Pollyea Ryan M.
Published: September 2018

During carbon capture and sequestration, capillary forces and buoyancy effects strongly influence CO2 migration and plume geometry. To understand interactions between these processes, we implement a numerical modeling experiment of CO2 injections in a sandstone reservoir to understand how parametric variability reported in the literature affects numerical predictions of CO2 migration. We simulate ten years of supercritical CO2 (scCO2) injections for 189 unique parameter combinations (entry pressure, Po, and van Genuchten fitting parameter, λ) that control the van Genuchten capillary pressure model. Results are analyzed on the basis of a dimensionless ratio, ω, which is a modified Bond number that defines the relationship between buoyancy pressure and capillary pressure. When ω > 1, buoyancy governs the system and CO2 plume geometry is governed by upward flow. In contrast, when ω < 1, then buoyancy is smaller than capillary force and lateral flow governs CO2 plume geometry. We show that the ω ratio is an easily implemented screening tool for qualitative assessment of CO2 distribution characteristics. We also show how parametric variability affects the relationship between buoyancy and capillary force, and thus controls CO2 plume geometry: (1) small entry pressure Po encourages vertical flow and large entry pressure Po inhibits vertical flow; and (2) the van Genuchten fitting parameter λ exhibits minimal control on the spatial distribution of CO2, as evidenced by the 2 × difference between the ∂ω/∂Po and ∂ω/∂λ gradients quantified using response surface analysis of the ω ratio. © 2018 Society of Chemical Industry and John Wiley & Sons, Ltd.
The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system
Authors: Blades Farrah , Aprico Andrea , Akkermann Rainer , Ellis Sarah , Binder Michele D. , Kilpatrick Trevor J.
Published: September 2018

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Major deficits arise in MS patients due to an inability to repair damaged myelin sheaths following CNS insult, resulting in prolonged axonal exposure and neurodegeneration. The TAM receptors (Tyro3, Axl, and Mertk) have been implicated in MS susceptibility, demyelination and remyelination. Previously, we have shown that Tyro3 regulates developmental myelination and myelin thickness within the optic nerve and rostral region of the corpus callosum (CC) of adult mice. In this study we have verified and extended our previous findings via a comprehensive analysis of axonal ensheathment and myelin thickness in the CC of unchallenged mice, following demyelination and during myelin repair. We show that the loss of the Tyro3 receptor correlates with significantly thinner myelin sheaths in both unchallenged mice and during remyelination, particularly in larger caliber axons. The hypomyelinated phenotype observed in the absence of Tyro3 occurs independently of any influence upon oligodendrocyte precursor cell (OPC) maturation, or density of oligodendrocytes (OLs) or microglia. Rather, the primary effect of Tyro3 is upon the radial expansion of myelin. The loss of Tyro3 leads to a reduction in the number of myelin lamellae on axons, and is therefore most likely a key component of the regulatory mechanism by which oligodendrocytes match myelin production to axonal diameter.
Cognitive functioning transitions, health expectancies, and inequalities among elderly people in China: A nationwide longitudinal study
Authors: Hou Chengbei , Lin Yinan , Ren Ming , Liu Mengyang , Ma Yuan , Li Haibin , Tao Lixin , Wang Wei , Li Xia , Fang Xianghua , Guo Xiuhua
Published: September 2018

Objective

In China, cognitive impairment has become a huge challenge owing to the rapid aging process. We investigate cognitive health expectancy and potential factors leading to inequalities of cognitive health for Chinese older people.

Methods

The study included 19 943 participants aged 65 to 95 at the first observation in Chinese Longitudinal Healthy Longevity Survey collected during 2002‐2014. Cognitive impairment was categorized into none, mild, and severe by the score of cMMSE. Multistate models based on continuous‐time Markov process were applied to calculate cognitive health expectancies and estimate hazard ratio from no impairment to impairment for potential factors.

Results

Urban women and men aged 65 were expected to spend 31.18% and 19.82% of their remaining 17.46 and 15.45 years with cognitive impairment; meanwhile, rural women and men aged 65 were expected to spend 35.31% and 21.39% of their remaining 16.73 and 14.87 years with cognitive impairment. Women achieving lower educational attainment (HR1‐6 years = 0.78, 95% CI, 0.71‐0.87; HR7+ years = 0.59, 95% CI, 0.49‐0.70) than men and rural residents having less access to medical service (HR = 0.79, 95% CI, 0.68‐0.92) and doing less regular exercise (HR = 0.87, 95% CI, 0.80‐0.96) than urban people caused the differences of cognitive health for genders and regions.

Conclusions

Women and rural people experience less cognitive health expectancies compared with their counterparts, respectively. Chinese government should pay more attention to rural women and make efforts to reduce the inequalities of cognitive health by increasing opportunities of education for women and improving access to medical service and healthy lifestyle for rural people.
The role of the arcuate and middle longitudinal fasciculi in speech perception in noise in adulthood
Authors: Tremblay Pascale , Perron Maxime , Deschamps Isabelle , Kennedy‐Higgins Dan , Houde Jean‐Christophe , Dick Anthony Steven , Descoteaux Maxime
Published: September 2018

In this article, we used High Angular Resolution Diffusion Imaging (HARDI) with advanced anatomically constrained particle filtering tractography to investigate the role of the arcuate fasciculus (AF) and the middle longitudinal fasciculus (MdLF) in speech perception in noise in younger and older adults. Fourteen young and 15 elderly adults completed a syllable discrimination task in the presence of broadband masking noise. Mediation analyses revealed few effects of age on white matter (WM) in these fascicles but broad effects of WM on speech perception, independently of age, especially in terms of sensitivity and criterion (response bias), after controlling for individual differences in hearing sensitivity and head size. Indirect (mediated) effects of age on speech perception through WM microstructure were also found, after controlling for individual differences in hearing sensitivity and head size, with AF microstructure related to sensitivity, response bias and phonological priming, and MdLF microstructure more strongly related to response bias. These findings suggest that pathways of the perisylvian region contribute to speech processing abilities, with relatively distinct contributions for the AF (sensitivity) and MdLF (response bias), indicative of a complex contribution of both phonological and cognitive processes to age‐related speech perception decline. These results provide new and important insights into the roles of these pathways as well as the factors that may contribute to elderly speech perception deficits. They also highlight the need for a greater focus to be placed on studying the role of WM microstructure to understand cognitive aging.
Isotopic response of run‐off to forest disturbance in small mountain catchments
Authors: Vystavna Yuliya , Holko Ladislav , Hejzlar Josef , Perșoiu Aurel , Graham Neil D. , Juras Roman , Huneau Frederic , Gibson John
Published: September 2018

Stable water isotopes were applied to trace hydrological processes in an undisturbed (mature spruce forest) and a nearby disturbed (deforested from a bark beetle outbreak) lake catchments in the Czech Republic. Both catchments are situated above 1,000 m a.s.l. within the Šumava National Park and have similar environmental conditions. The isotopic compositions of precipitation, creeks, springs, and lakes were sampled at 3‐week intervals over one hydrological year. Water inputs to catchments were derived from isotopically similar local precipitation, whereas run‐off was found to have different isotopic signatures. Creeks in the undisturbed catchment had ~1‰ and ~7‰ higher δ18O and δ2H with ~2‰ lower d‐excess than in the disturbed catchment. The d‐excess in creeks of the undisturbed catchment was more pronounced, particularly during snowmelt, and highly heterogeneous as compared with the disturbed catchment. Creeks in the undisturbed catchment were mainly fed by precipitation during the warm period (May–October), whereas creeks in the disturbed catchment were mostly fed by precipitation during the cold period (November–April). Estimated mean transit times of creeks and springs were ~6 months, except for two creeks in the undisturbed catchment, which had residence times of ~1 year. Although evaporation and transpiration fluxes were apparently reduced in the disturbed catchment, transpiration ratios were similar for both catchments. The difference in isotope signatures between catchments was attributed to the altered role of the forest canopy in temporal water distribution, which produced changes in the water cycle, potentially influencing important biogeochemical processes.
Knockdown of USP28 enhances the radiosensitivity of esophageal cancer cells via the c‐Myc/hypoxia‐inducible factor‐1 alpha pathway
Authors: Weili Zhang , Zhikun Liu , Jianmin Wang , Qingbao Tian
Published: September 2018

Acquired radioresistance is a major clinical obstacle in the treatment of esophageal cancer (EC). Ubiquitin‐specific protease 28 (USP28) has been implicated in tumor growth in various cancer types. However, the role of USP28 and its underlying mechanisms of radioresistance in EC remain unknown. In the current study, we found that USP28 and c‐Myc levels were upregulated in EC tissues and EC cell lines. The mRNA expression levels of USP28 and c‐Myc were increased in the radioresistant human EC cell line (ECA109R) compared with those in ECA109 cells. In addition, the expression levels of USP28 and c‐Myc were increased with increase in culture time after irradiation. Meanwhile, overexpression of USP28 decreased the radiosensitivity of ECA109 cells. In contrast, USP28 knockdown enhanced the radiosensitivity of ECA109R cells. Moreover, USP28 positively regulated the protein level of c‐Myc, and c‐Myc negatively regulated the radiosensitivity of ECA109 and ECA109R cells. Furthermore, c‐Myc reversed the inhibitory effect of USP28 on the radiosensitivity of EC cells. Additionally, c‐Myc enhanced the accumulation of hypoxia‐inducible factor‐1 alpha (HIF‐1α) at the posttranscriptional level, and the reinforcing effect of c‐Myc silencing on the radiosensitivity of EC cells could be reversed by HIF‐1α overexpression. Besides, knockdown of USP28 blocked the effect of c‐Myc on activation of ataxia telangiectasia‐mutated/ataxia telangiectasia and Rad3‐related DNA damage checkpoint after irradiation. In conclusion, knockdown of USP28 enhanced the radiosensitivity of EC cells by destabilizing c‐Myc and enhancing the accumulation of HIF‐1α. Therefore, USP28 may serve as a novel therapeutic target to overcome EC radioresistance.
A novel seven‐lncRNA signature for prognosis prediction in hepatocellular carcinoma
Authors: Yan Junhao , Zhou Chao , Guo Kuiyuan , Li Qian , Wang Zheng
Published: September 2018

Liver cancer is still one of the leading causes of cancer‐related death worldwide. This study is dedicated to developing a multi–long noncoding RNA (lncRNA) model for risk stratification and prognosis prediction on patients with hepatocellular carcinoma (HCC). We first downloaded lncRNA expression profiles and corresponding clinical information of patients with liver cancer from The Cancer Genome Atlas database. Differentially expressed (DE) lncRNAs between HCC samples and normal samples were identified. In total, 308 patients with HCC were randomly divided into a training group (n = 154) and a testing group (n = 154). Univariate Cox regression and least absolute shrinkage and selection operator Cox regression analyses were performed to select the best survival‐related candidates from these DE lncRNAs in the training set. Seven lncRNAs (AC009005.2, RP11‐363N22.3, RP11‐932O9.10, RP11‐572O6.1, RP11‐190C22.8, RP11‐388C12.8, and ZFPM2‐AS1) were finally identified and used to construct a seven‐lncRNA signature. The signature could classify patients into high‐risk and low‐risk groups with significantly different overall survival. The area under the curve of receiver operating characteristic curve for the signature to predict 5‐year survival reached more than 0.75. Besides, the prognostic value of the seven‐lncRNA signature was independent of conventional clinical factors. The predictive performance of the signature was further validated in the testing set and the whole set. Functional enrichment analysis indicated that the seven prognostic lncRNAs may be involved in several essential biological processes and pathways. The current study demonstrated the potential clinical implications of the seven‐lncRNA signature for survival prediction of patients with HCC.
Liver kinase B1 overexpression controls mycobacterial infection in macrophages via FOXO1/Wnt5a signaling
Authors: Cui Junwei , Li Mingying , Liu Weiguo , Zhang Bianfang , Sun Bing , Niu Wenyi , Wang Yongliang
Published: September 2018

Mycobacterium tuberculosis (Mtb) is a primary cause of tuberculosis (TB), which has infected more than one‐third of the world’s population. Mtb survival and subsequent inflammation in macrophages are important components of TB. Liver kinase B1 (LKB1) has demonstrated anti‐inflammation effects, but its function and underlying mechanism in mycobacteria‐infected macrophages remains unknown. In the current study, we discovered that LKB1 was markedly decreased in Mtb‐infected THP‐1 and U937 macrophages. Moreover, LKB1 overexpression inhibited Mtb survival in macrophages. Mtb infection increased expression of nitric oxide, inducible nitric oxide synthase, and inflammation‐related cytokines interleukin (IL)‐6, tumor necrosis factor‐α, and IL‐1β, whereas pcDNA3‐LKB1 transfection inhibited the release of these cytokines in THP‐1 and U937 cells. Furthermore, LKB1 overexpression significantly decreased protein expression of Wnt5a, which is dependent on the elevation of forkhead box protein O1 (FOXO1). Generally, we show that interruption of FOXO1 or overexpression of Wnt5a can reverse the effects of LKB1 on mycobacterial intracellular survival, nitric oxide, inducible nitric oxide synthase expression, and inflammatory cytokine release. These findings indicate important roles for LKB1, FOXO1, and Wnt5a in controlling mycobacteria and cell inflammation.
Retracted: KDM6B promotes ovarian cancer cell migration and invasion by induced transforming growth factor‐β1 expression
Authors: Liang Shumei , Yao Qingmin , Wei Deying , Liu Ming , Geng Feng , Wang Qin , Wang Yun‐shan
Published: September 2018

KDM6B, also known as JMJD3, is a member of the family of histone lysine demethylase (KDMs), which is closely related to many types of cancers. However, its role and the underlying mechanisms in ovarian cancer remain unknown. Here we show that KDM6B is elevated in epithelial ovarian cancer and its expression level is closely related with metastasis and invasion. In addition, survival analysis showed that high expression of KDM6B was associated with low overall survival in ovarian cancer patients. Overexpression of KDM6B in epithelial ovarian cancer cells promoted proliferation, epithelial‐mesenchymal transition (EMT), migration and invasion in vitro, and enhanced metastatic capacities in vivo. On the contrary, silencing KDM6B in invasive and metastatic ovarian cancer cells inhibited these processes. Mechanistically, we found that KDM6B exerts its function by modulating the transforming growth factor‐β1 (TGF‐β1) expression, and TGF‐β1 signal pathway inhibitor LY2157299 significantly inhibited KDM6B‐induced proliferation, migration, metastasis, and EMT in ovarian cancer cells. Our findings, for the first time, reveal the pivotal role of KDM6B in the invasion and metastatic behavior of epithelial ovarian cancer. Thus, targeting KDM6B may be a useful strategy to interfere with these behaviors of epithelial ovarian cancer.
MiR‐490‐5p inhibits the stemness of hepatocellular carcinoma cells by targeting ECT2
Authors: Yu Yuanjie , Cai Ou , Wu Pengbo , Tan Shiyun
Published: September 2018

To explore the targeting relationship between miR‐490‐5p and ECT2 in hepatocellular carcinoma (HCC) and the influences of miR‐490‐5p and
ECT2 on the stemness of HCC cells. The expressions of miR‐490‐5p and
ECT2 in HCC tissues and adjacent tissues were identified by quantitative real‐time polymerase chain reaction (qRT‐PCR). The relationships between the expression levels of miR‐490‐5p/
ECT2 and the overall/disease‐free survival (OS/DFS) of patients with HCC were evaluated using correlative curves. In addition, the targeting relationship between miR‐490‐5p and
ECT2 was predicted by TargetScan and verified by dual‐luciferase reporter assay. Plasmid transfection was used for overexpression of
ECT2 in HepG2 cells, and transfection efficiency was verified by qRT‐PCR. Cell Counting Kit‐8 assay and cell sphere‐formation assay were conducted to detect the proliferation and sphere‐formation ability of HCC cells, respectively. Cell populations with different cell transfections were sorted using flow cytometry. The expression levels of proteins in the stem cell signaling pathway were determined using Western blot analysis. MiR‐490‐5p was remarkably downregulated, yet
ECT2 was upregulated in HCC tissues compared with adjacent tissues. MiR‐490‐5p expression was positively correlated with OS and DFS of patients with HCC, which were otherwise negatively correlated with
ECT2 expression.
ECT2 was validated to be the downstream target of miR‐490‐5p. Overexpression of miR‐490‐5p restrained the sphere formation ability, stemness, and proliferation of HCC cells. MiR‐490‐5p repressed the stemness of HCC cells through inhibiting the expression of
ECT2. MiR‐490‐5p may be an underlying therapeutic target in HCC treatment.
A unified mitochondria mechanistic target of rapamycin acyl‐coenzyme A dehydrogenase 10 signal relay modulation for metformin growth inhibition in human immortalized keratinocytes cells
Authors: Wu Jiawen , Xiao Shengxiang , Ren Jianwen , Zhang Dingwei
Published: September 2018

Metformin exhibits antiproliferative and proapoptotic effects in a variety of diseases, characterized by malignant and nonmalignant hyperplastic cells; however, the underlying molecular mechanism of metformin in psoriasis has not been elucidated. In the current study, we found that after metformin treatment the proliferation of human immortalized keratinocytes (HaCaT) was significantly inhibited, while cell apoptosis was increased in a dose‐dependent manner, accompanied with enhanced protein expression of acyl‐coenzyme A dehydrogenase 10 (ACAD10). Furthermore, mechanism analysis revealed that ACAD10 expression is induced by downregulated activities of mechanistic target of rapamycin 1 (mTORC1) signaling rather than AMP‐activated protein kinase signaling. The inactivation of mTORC1 by rapamycin pretreatment or rotenone‐induced mitochondrial complex inhibition showed a similar effect because of the metformin treatment on the proliferation and apoptosis of HaCaT keratinocytes. Overexpression of mTORC1 almost reversed the antiproliferation and proapoptosis effects induced by metformin. This study showed that the metformin treatment inhibited HaCaT cells proliferation and promoted apoptosis by affecting the mitochondrial‐mTORC1 signaling and elevated the ACAD10 expression. Hence, metformin can be used as a potential therapeutic agent for psoriasis.
miR‐214‐5p targets KLF5 and suppresses proliferation of human hepatocellular carcinoma cells
Authors: Pang Jinzhong , Li Zheng , Wang Guangjun , Li Ningbo , Gao Yan , Wang Shuhui
Published: September 2018

MicroRNAs (miRNAs) are small endogenous conserved RNAs regulating genes expression through base pairing with the 3′‐untranslated region (3′‐UTR) of target messenger RNAs. MiR‐214‐5p is a newly identified miRNA with its biological role largely unknown. In this study, we explored miR‐214‐5p expression status in 78 paired tumor and nontumor tissues obtained from patients with hepatocellular carcinoma (HCC) by RT‐qPCR. The effects of miR‐214‐5p expression on HCC cell proliferation, cell cycle progression, and cell migration were measured by CCK‐8 assay, flow cytometry, and wound‐healing assay. A dual‐luciferase activity assay was performed to identify whether KLF5 was a target of miR‐214‐5p. Kaplan‐Meier curve and log‐rank test were used to investigate the effects of miR‐214‐5p and KLF5 on overall survival and disease‐free survival of patients with HCC. We found miR‐214‐5p expression was sharply reduced in HCC tissues and cell lines compared with the normal tissues and cell lines. Functional assay revealed that miR‐214‐5p overexpression could downregulate cell proliferation, cell migration, and arrested cell cycle at G0/G1 phase. Further, we validated Krüppel‐like factor 5 (KLF5) as a direct target of miR‐214‐5p, and was upregulated in HCC and inversely correlated with the expression of miR‐214‐5p. Moreover, we found the low expression of miR‐214‐5p and high expression of KLF5 were correlated with tumor size, tumor stage, and poorer 5‐year overall survival and disease‐free survival of patients with HCC. In conclusion, our results suggested miR‐214‐5p functions as a tumor suppressor through targeting KLF5 in HCC. Also, miR‐214‐5p and KLF5 were identified as potential prognostic markers and might be therapeutic targets in HCC.
Structural and energetic understanding of novel natural inhibitors of Mycobacterium tuberculosis malate synthase
Authors: Shukla Rohit , Shukla Harish , Tripathi Timir
Published: September 2018

Persistent infection by Mycobacterium tuberculosis requires the glyoxylate shunt. This is a bypass to the tricarboxylic acid cycle in which isocitrate lyase (ICL) and malate synthase (MS) catalyze the net incorporation of carbon during mycobacterial growth on acetate or fatty acids as the primary carbon source. To identify a potential antitubercular compound, we performed a structure‐based screening of natural compounds from the ZINC database (n = 1 67 740) against the M tuberculosis MS (MtbMS) structure. The ligands were screened against MtbMS, and 354 ligands were found to have better docking score. These compounds were assessed for Lipinski and absorption, distribution, metabolism, excretion, and toxicity prediction where 15 compounds were found to fit well for redocking studies. After refinement by molecular docking and drug‐likeness analysis, four potential inhibitors (ZINC1483899, ZINC1754310, ZINC2269664, and ZINC15729522) were identified. These four ligands with phenyl‐diketo acid were further subjected to molecular dynamics simulation to compare the dynamics and stability of the protein structure after ligand binding. The binding energy analysis was calculated to determine the intermolecular interactions. Our results suggested that the four compounds had a binding free energy of −201.96, −242.02, −187.03, and −169.02 kJ·mol−1, for compounds with IDs ZINC1483899, ZINC1754310, ZINC2269664, and ZINC15729522, respectively. We concluded that two compounds (ZINC1483899 and ZINC1754310) displayed considerable structural and pharmacological properties and could be probable drug candidates to fight against M tuberculosis parasites.
Forkhead box protein A1 confers resistance to transforming growth factor‐β‐induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation
Authors: Hirata Kensuke , Takakura Yuki , Shibazaki Misato , Morii Mariko , Honda Takuya , Oshima Motohiko , Aoyama Kazumasa , Iwama Atsushi , Nakayama Yuji , Takano Hiroyuki , Yamaguchi Naoto , Yamaguchi Noritaka
Published: September 2018

Transforming growth factor‐β (TGF‐β) induces apoptosis of normal epithelial cells, such as mammary epithelium. Although breast cancer progression associates with acquisition of resistance to TGF‐β‐induced apoptosis, the molecular mechanisms underlying this resistance are largely unknown. Here, we show that forkhead box protein A1 (FOXA1), which is known as a pioneer transcription factor, suppresses TGF‐β‐induced apoptosis of estrogen receptor–positive breast cancer cells. FOXA1 is found to inhibit nuclear translocation of Smad3, a key transcription factor downstream of TGF‐β signaling, through suppression of the binding of Smad3 to the nuclear import receptor importin7. Furthermore, RNA sequencing analyses show that knockdown of FOXA1 upregulates Smad3‐mediated proapoptotic gene expression. These results demonstrate that FOXA1 as a potent survival factor that suppresses TGF‐β‐induced apoptosis by inhibiting Smad3 signaling in estrogen receptor–positive breast cancer cells. Thus, we provide evidence for the first time that FOXA1 localizing to the cytoplasm negatively regulates Smad3‐induced apoptosis in TGF‐β‐mediated signal transduction.
Daphnetin inhibits RANKL‐induced osteoclastogenesis in vitro
Authors: Liu Xifang , Gao Xiaohang , Liu Yuanxin , Liang Dongsheng , Fu Ting , Song Yixin , Zhao Congzhe , Dong Bo , Han Weihua
Published: September 2018

Osteoporosis is a common orthopedic disease which is associated with hyper‐activated osteoclastogenesis. Daphnetin is a natural coumarin derivative isolated from Genus Daphne, which possesses antiarthritis effect. However, the role of daphnetin in osteoclastogenesis has not been illustrated. This study aimed to investigate the effects of daphnetin on receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis in vitro. Our results showed that the osteoclast formation was significantly suppressed by daphnetin treatment in bone marrow‐derived macrophages (BMMs), which was illustrated by reduced number of tartrate‐resistant acid phosphatase positive multinucleated osteoclasts and decreased expression levels of tumor necrosis factor receptor‐associated factors (TRAF6), c‐Fos, nuclear factor of activated T cells c1, and cathepsin K. RANKL caused significant induction effects in reactive oxygen species (ROS) generation and nicotinamide adenine dinucleotide phosphate oxidase activity, whereas the induction was dramatically reduced after pretreatment with daphnetin. In addition, daphnetin prevented the RANKL‐induced activation of NF‐κB and Akt/GSK‐3β pathways in BMMs. These findings indicated that daphnetin exhibited an inhibitory effect on RANKL‐induced osteoclastogenesis in vitro. The effect of daphnetin might be mediated by inhibiting ROS signal transduction, as well as preventing the activation of NF‐κB and Akt/GSK‐3β signaling pathways. These findings indicated that daphnetin might be considered as a new therapeutic approach for the osteoporosis treatment.
Coexpression network analysis identified Krüppel‐like factor 6 (KLF6) association with chemosensitivity in ovarian cancer
Authors: Chen Ying , Bi Fangfang , An Yuanyuan , Yang Qing
Published: September 2018

Although most patients with ovarian cancer (OC) are initially sensitive to paclitaxel/carboplatin combination chemotherapy, eventually they develop resistance to chemotherapy drugs and experience disease relapse. OC is the most lethal gynecological malignancy, and the five‐year survival rate is extremely low. Thus, research on specific biomarkers and potential targets for chemotherapy‐resistant patients with OC is needed. In our study, genes in the top 10% of variance in data set GSE30161 from chemoresistant and chemosensitive OC tissues were determined to conduct a weighted gene coexpression network analysis (WGCNA). The magenta module was most strongly related to OC chemoresponse. Gene ontology enrichment analysis indicated that the function of the magenta module primarily focused on transcription regulation, cell cycle control, and apoptosis modulation. Integration of the WGCN with the protein‐protein interaction network identified five candidate genes. These five genes were verified using the GSE51373 test set, and Krüppel‐like factor 6 (
KLF6) was identified as tightly linked to OC chemosensitivity. The receiver operating characteristic (ROC) curve showed that
KLF6 differentiated chemoresistant from chemosensitive OC tissues. The Kaplan‐Meier online database indicated that high
KLF6 expression was associated with poor OC prognosis. Gene set enrichment analysis determined that the
KLF6 mechanism was potentially associated with cell cycle, mTOR, and DNA‐damage repair signaling pathways. In conclusion,
KLF6 was identified in association with OC chemoresistance, and the mechanism of
KLF6‐mediated chemoresistance may involve the cell cycle, mTOR, and DNA‐damage repair signaling pathways.
Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway
Authors: Li He , Chen Hongying , Li Ruli , Xin Juanjuan , Wu Sisi , Lan Jie , Xue Kunyue , Li Xue , Zuo Caili , Jiang Wei , Zhu Ling
Published: September 2018

Endoplasmic reticulum stress (ERS) is usually involved in tumor development and progression, and anticancer agents have recently been recognized to induce ERS. Cucurbitacin‐I showed a potent anticancer action by inducing apoptosis through the inhibition of signal transducer and activator of transcription 3 pathway and triggering autophagic cell death. It is not known whether ERS mediates the cancer cell death induced by cucurbitacin‐I. Here, we investigated the role of ERS in cucurbitacin‐I‐treated SKOV3 ovarian cancer cells and PANC‐1 pancreatic cancer cells. We confirmed that cucurbitacin‐I caused cell death and stirred excessive ERS levels by activating inositol requiring enzyme 1α (IRE1α) and protein kinase R‐like endoplasmic reticulum kinase (PERK), as well as PERK downstream factors, including IRE1α and C/EBP homologous protein, but not activating transcription factor 6 (ATF6α) pathway, which was in parallel with the increased Bax and caspase‐12‐dependent ERS‐associated apoptosis, autophagy and autophagy flux levels and caspase‐independent nonapoptotic cell death. Furthermore, 4‐phenylbutyrate, an ERS inhibitor, suppressed cucurbitacin‐I‐induced apoptosis, autophagy, autophagy flux, and autophagic cell death. Simultaneously, there are positive correlations among ERS and cucurbitacin‐I‐induced reactive oxygen species and Ca
2+. Our results suggested that cucurbitacin‐I‐induced cancer cell death through the excessive ERS and CHOP‐Bax and caspase‐12‐dependent ERS‐associated apoptosis, as well as ERS‐dependent autophagy, autophagy flux, and caspase‐independent nonapoptotic cell death. These novel signaling insights may be useful for developing new, effective anticancer strategies in oncotherapy.
In silico analysis and molecular dynamics simulation of human superoxide dismutase 3 (SOD3) genetic variants
Authors: Pereira G. R. C. , Da Silva A. N. R. , Do Nascimento S. S. , De Mesquita J. F.
Published: September 2018

Oxidative stress is a major factor in aging processes. Superoxide dismutase 3 (SOD3) plays a key role in the protection of extracellular oxidative stress. Missense mutations in SOD3 have been described to be associated with the occurrence of pulmonary, cardiovascular, and neoplastic diseases. This study aims to analyze the effects of missense mutations on the SOD3 structure and function by modeling a complete SOD3 structure as well as analyzing the differences between the wild‐types and mutants using computational simulations. Here, ten algorithms were used to predict the structural and functional effects of missense mutations. A complete model of SOD3 protein was made by ab initio and comparative modeling using the Rosetta algorithm and validated by PROCHECK, Verify 3D, QMEAN, and ProSa. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package. The deleterious potential of the A58T and R231G mutants was not predicted by the majority of the used algorithms. The analyzed mutations were predicted as destabilizing by at least one algorithm. The MD analyses indicated that protein flexibility may be increased by all of the analyzed mutations, while the protein‐ligand stability may be decreased. They also suggested that the variants A91T and R231G increase the overall dimensions of SOD3 and decrease its accessible surface area. Our findings, therefore, indicated that the analyzed mutations could affect the protein structure and its ability to interact with other molecules, which may be related to the functional impairment of SOD3 upon A58T and R231G mutations, as well as their involvement in pathologies.
Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications
Authors: Mittal Rahul , Karhu Elisa , Wang Jay‐Shing , Delgado Stefanie , Zukerman Ryan , Mittal Jeenu , Jhaveri Vasanti M.
Published: September 2018

Intercellular communication is essential for the development and maintenance of multicellular organisms. Tunneling nanotubes (TNTs) are a recently recognized means of long and short distance communication between a wide variety of cell types. TNTs are transient filamentous membrane protrusions that connect cytoplasm of neighboring or distant cells. Cytoskeleton fiber‐mediated transport of various cargoes occurs through these tubules. These cargoes range from small ions to whole organelles. TNTs have been shown to contribute not only to embryonic development and maintenance of homeostasis, but also to the spread of infectious particles and resistance to therapies. These functions in the development and progression of cancer and infectious disease have sparked increasing scrutiny of TNTs, as their contribution to disease progression lends them a promising therapeutic target. Herein, we summarize the current knowledge of TNT structure and formation as well as the role of TNTs in pathology, focusing on viral, prion, and malignant disease. We then discuss the therapeutic possibilities of TNTs in light of their varied functions. Despite recent progress in the growing field of TNT research, more studies are needed to precisely understand the role of TNTs in pathological conditions and to develop novel therapeutic strategies.
Cerebroprotective effects of hydrogen sulfide in homocysteine‐induced neurovascular permeability: Involvement of oxidative stress, arginase, and matrix metalloproteinase‐9
Authors: Nath Nibendu , Prasad Himanshu Kishore , Kumar Munish
Published: September 2018

An elevated level of homocysteine (Hcy) leads to hyperhomocysteinemia (HHcy), which results in vascular dysfunction and pathological conditions identical to stroke symptoms. Hcy increases oxidative stress and leads to increase in blood–brain barrier permeability and leakage. Hydrogen sulfide (H2S) production during the metabolism of Hcy has a cerebroprotective effect, although its effectiveness in Hcy‐induced neurodegeneration and neurovascular permeability is less explored. Therefore, the current study was designed to perceive the neuroprotective effect of exogenous H
2S against HHcy, a cause of neurodegeneration. To test this hypothesis, we used four groups of mice: control, Hcy, control + sodium hydrosulfide hydrate (NaHS), and Hcy + NaHS, and an HHcy mice model in Swiss albino mice by giving a dose of 1.8 g of
dl‐Hcy/L in drinking for 8–10 weeks. Mice that have 30 µmol/L Hcy were taken for the study, and a H
2S supplementation of 20 μmol/L was given for 8 weeks to all groups of mice. HHcy results in the rise of the levels of superoxide and nitrite, although a concomitant decrease in the level of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, and arginase in oxidative stress and a concomitant decrease in the endogenous level of H
2S. Although H
2S supplementation ameliorated, the effect of HHcy and the levels of H
2S returned to the average level in HHcy animals supplemented with H
2S. Interestingly, H
2S supplementation ameliorated neurovascular remodeling and neurodegeneration. Thus, our study suggested that H
2S could be a beneficial therapeutic candidate for the treatment of Hcy‐associated neurodegeneration, such as stroke and neurovascular disorders.
Cyclic tensile force stimulates BMP9 synthesis and in vitro mineralization by human periodontal ligament cells
Authors: Tantilertanant Yanee , Niyompanich Jitti , Everts Vincent , Supaphol Pitt , Pavasant Prasit , Sanchavanakit Neeracha
Published: September 2018

Periodontal ligament (PDL) cells are mechanosensitive and have the potential to differentiate into osteoblast‐like cells under the influence of cyclic tensile force (CTF). CTF modulates the expression of regulatory proteins including bone morphogenetic proteins (BMPs), which are essential for the homeostasis of the periodontium. Among the BMPs, BMP9 is one of the most potent osteogenic BMPs. It is yet unknown whether CTF affects the expression of BMP9 and mineralization. Here, we demonstrated that continuously applied CTF for only the first 6 hr stimulated the synthesis of BMP9 and induced mineral deposition within 14 days by human PDL cells. Stimulation of
BMP9 expression depended on ATP and P2Y
1 receptors. Apyrase, an ecto‐ATPase, inhibited CTF‐mediated ATP‐induced
BMP9 expression. The addition of ATP increased the expression of
BMP9. Loss of function experiments using suramin (a broad‐spectrum P2Y antagonist), MRS2179 (a specific P2Y
1 receptor antagonist), MRS 2365 (a specific P2Y
1 agonist), U‐73122 (a phospholipase C [PLC] inhibitor), and thapsigargin (enhancer of intracytosolic calcium) revealed the participation of P2Y
1 in regulating the expression of
BMP9. This was mediated by an increased level of intracellular Ca
2+ through the PLC pathway. A neutralizing anti‐BMP9 antibody decreased mineral deposition, which was stimulated by CTF for almost 45% indicating a role of BMP9 in an in vitro mineralization. Collectively, our findings suggest an essential modulatory role of CTF in the homeostasis and regeneration of the periodontium.
Nerve repair and regeneration: Biological tubulization limits and future perspectives
Authors: Riccio Michele , Marchesini Andrea , Pugliese Pierfrancesco , De Francesco Francesco
Published: September 2018

Peripheral nerve physiology and regeneration has been observed and investigated in literature but surgical applications to reconstruct and restore motor or sensory functions are still in a developmental phase. The peripheral nerve progresses slowly and incompletely compared with other tissues, it may provoke separations of the nerve stumps and the axonal proliferation of the conduits is restricted to 30 mm. Recent surgical attempts to treat proximal nerve injures include direct nerve restoration, transfer, and autografting measures with favorable results. Moreover, studies are suggesting that engineering tissue tubes maybe as effective as nerve grafting to restore separations of more than 4 cm toward optimal nerve repair.