bluuebunny/crossref_metadata_2025_split huggingface dataset:
LIN28A activates the transcription of NANOG in dairy goat male germline stem cells
Authors: Ma Fanglin , Du Xiaomin , Wei Yudong , Zhou Zhe , Clotaire Daguia Zambe John , Li Na , Peng Sha , Li Guangpeng , Hua Jinlian 
Published: October 2018

AbstractLIN28A serves as a crucial marker of dairy goat male germline stem cells (GmGSCs). In our previous study, we demonstrated that
LIN28A promotes proliferation, self‐renewal, and maintains the stemness of GmGSCs. Here, we found that
LIN28A could activate the transcription of
NANOG in a
let‐7g independent manner. We cloned the 5′ upstream of two
NANOG genes which were located on chromosome 15 (
NANOG‐ch15) and chromosome 5 (
NANOG‐ch5), respectively, and then examined their promoter activities and promoter methylation levels. Results showed that
NANOG‐ch15 is a pseudogene whereas
NANOG‐ch5 is active in
Capra hircus. Bioinformatics analysis indicated that the 5′ upstream region of
NANOG‐ch5 does not have typical CpG islands but contains several CG enrichment regions and several
LIN28A binding sites. Deletion analysis suggested that
NANOG‐ch5 promoter can be activated by
LIN28A directly binding to the site ‐210 but not by the indirect effect from the inhibition of
let‐7g, which is known to be downregulated by
LIN28A. Mechanistically,
LIN28A recruits and interacts with 5‐methylcytosine‐dioxygenase Ten‐Eleven translocation 1 (TET1) to
NANOG‐ch5 gene promoter binding sites to orchestrate 5‐methylcytosine and 5‐hydroxymethylcytosine dynamics. These results revealed the role of
LIN28A in
NANOG transcriptional regulation via epigenetic DNA modifications to maintain the stemness of GmGSC.
Physiological and structural changes of the lung tissue in male albino rat exposed to immobilization stress
Authors: Saber Entesar Ali , Abd El Aleem Mohammed Mustafa , Aziz Neven Makram , Ibrahim Randa Ahmed 
Published: October 2018

AbstractIn case of a life‐threatening, stressful event, the body prepares for an emergency. Indeed, the lung is unique in which alveolar cells are constantly exposed to physical and chemical stresses. This study aimed to study the impact of immobilization stress on the blood–air barrier and how it initiate and maintain an inflammatory response, plus determining the resolution of lung inflammation and repair. There was a significant increase in the plasma levels of stress markers “corticosterone and catecholamines” with a decrease in surfactant protein A (a lung‐injury marker). Chronic stress produced a significant increase in the pulmonary oxidative and inflammatory markers malondialdehyde, tumor necrosis factor α, and induced nitric oxide synthase when compared with that of acute stress. Both stresses provoked marked pulmonary morphological and ultrastructural changes with a significant increase in caspase‐3 immunoexpression. There was increasing evidence of lung’s capacity for repair. This process involved edema resolution, cell proliferation, and tissue remodeling in improving the lung‐injury, oxidative, and inflammatory markers.
Genome‐wide CRISPR‐Cas9 viability screen reveals genes involved in TNF‐α‐induced apoptosis of human umbilical vein endothelial cells
Authors: Cai Meng , Li Sitao , Shuai Yunfei , Li Jie , Tan Jieqiong , Zeng Qiyi 
Published: October 2018

AbstractTumor necrosis factor α (TNF‐α), a pivotal cytokine in sepsis, protects the host against pathogens by promoting an inflammatory response while simultaneously inducing apoptosis of the vascular endothelium. Unfortunately, inhibitors targeting certain components of the TNF‐α signaling pathway to reduce cellular apoptosis have failed to translate into clinical applications, partly due to the adverse effects of excessive immunosuppression. In an attempt to discover potential targets in the TNF‐α signaling pathway to modulate moderate inflammation and apoptosis during the development of sepsis, we performed a pooled genome‐wide CRISPR/Cas9 knockout screen in human umbilical vein endothelial cells (HUVECs). Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), B‐cell lymphoma 2 (BCL2), Bcl2‐associated death promoter (BAD), and NLR family member X1 (NLRX1) deficiencies were identified as the effective genetic suppressors of TNF‐α cytotoxicity on a list of candidate regulators. CRISPR‐mediated
NLRX1 knockout conferred cellular resistance to challenge with TNF‐α, and NLRX1 could be induced to colocalize with mitochondria following TNF‐α stimulation. Thus, our work demonstrates the advantage of genome‐scale screening with Cas9 and validates NLRX1 as a potential modulator of TNF‐α‐induced vascular endothelial apoptosis during sepsis.
Insulin resistance: Review of the underlying molecular mechanisms
Authors: Yaribeygi Habib , Farrokhi Farin Rashid , Butler Alexandra E. , Sahebkar Amirhossein 
Published: October 2018

AbstractMost human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes and metabolic syndrome, impairments in insulin signaling disrupting entry of glucose into the adipocytes, and skeletal muscle cells. Although the exact underlying cause of IR has not been fully elucidated, a number of major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. In this review, we consider the role these cellular mechanisms play in the development of IR.
Estradiol‐17β stimulates H2S biosynthesis by ER‐dependent CBS and CSE transcription in uterine artery smooth muscle cells in vitro
Authors: Lechuga Thomas J. , Bilg Amanpreet K. , Patel Bansari A. , Nguyen Nicole A. , Qi Qian‐rong , Chen Dong‐bao 
Published: October 2018

AbstractEndogenous hydrogen sulfide (H2S), synthesized by cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE), is a potent vasodilator that can be stimulated by estradiol‐17β (E
2β) in uterine artery (UA) smooth muscle (UASMC) in vivo; however, the underlying mechanisms are unknown. This study tested a hypothesis that E
2β stimulates H
2S biosynthesis by upregulating CBS expression via specific estrogen receptor (ER). Treatment with E
2β stimulated time‐ and concentration‐ dependent CBS and CSE messenger RNA (mRNA) and protein expressions, and H
2S production in cultured primary UASMC isolated from late pregnant ewes, which were blocked by ICI 182,780. Treatment with specific ERα or ERβ agonist mimicked these E
2β‐stimulated responses, which were blocked by specific ERα or ERβ antagonist. Moreover, E
2β activated both
CBS and
CSE promoters and ICI 182,780 blocked the E
2β‐stimulated responses. Thus, E
2β stimulates H
2S production by upregulating CBS and CSE expression via specific ER‐dependent transcription in UASMC in vitro.
X‐box binding protein l splicing attenuates brain microvascular endothelial cell damage induced by oxygen‐glucose deprivation through the activation of phosphoinositide 3‐kinase/protein kinase B, extracellular signal‐regulated kinases, and hypoxia‐inducible factor‐1α/vascular endothelial growth factor signaling pathways
Authors: Shi Shupeng , Tang Mimi , Li Honglei , Ding Hui , Lu Yangfan , Gao Lijuan , Wu Qian , Zhou Luo , Fu Yujiao , Xiao Bo , Zhang Mengqi 
Published: October 2018

AbstractAngiogenesis is positively correlated with the survival rate of stroke patients. Therefore, studying factors that initiate and promote angiogenesis after ischemic stroke is crucial for finding novel and effective treatment targets that improve the prognosis of stroke. X‐box binding protein l splicing (XBP1s) plays a positive regulatory role in cell proliferation and angiogenesis. However, the role and mechanism of XBP1s on the proliferation of brain microvascular endothelial cells (BMECs) and angiogenesis after cerebral ischemia remains unclear. In the current study, we investigated the role XBP1s plays in BMEC proliferation and angiogenesis following cerebral ischemia. In this study, the roles of XBP1s on cell survival, apoptosis, cycle migration, and angiogenesis were determined in oxygen‐glucose deprivation (OGD) treated BMECs. The expression of XBP1s in BMECs, which were exposed to OGD at 0, 2, 4, and 6 hr, increased in a time‐dependent manner. The overexpression of XBP1s promoted cell survival, cell cycle, migration, and angiogenesis of BMECs, and inhibited the apoptosis in OGD‐treated BMECs. In addition, the overexpression of XBP1s promoted the expression of cyclin D1, matrix metalloproteinase (MMP‐2), and MMP‐9, but inhibited cleaved Caspase‐3 and cleaved Caspase‐9 expression in OGD‐treated BMECs. The overexpression of XBP1s also promoted the expression of hypoxia‐inducible factor 1‐alpha, vascular endothelial growth factor, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, p‐AKT, p‐mTOR, p‐GSK3β, and p‐extracellular signal‐regulated kinase1/2 in OGD‐treated BMECs. The effect of XBP1s silencing was opposite to that of XBP1s overexpression. In conclusion, using an in vitro OGD model, we demonstrated that XBP1s may be a promising target for ischemic stroke therapy to maintain BMECs survival and induce angiogenesis.
Proinsulin C‐peptide as an alternative or combined treatment with insulin for management of testicular dysfunction and fertility impairments in streptozotocin‐induced type 1 diabetic male rats
Authors: Nazmy Walaa Hassan , Elbassuoni Eman Abdelmonem , Ali Fatma Farrag , Rifaai Rehab Ahmed 
Published: October 2018

AbstractDiabetes mellitus (DM) is closely associated with male infertility and sexual dysfunction. Recent data indicate that the proinsulin C‐peptide (CP) exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. So, this study was done to investigate the effect of C‐peptide with or without insulin treatment on testicular function and architecture in diabetic rats. Rats were divided into the following groups: control, diabetic, and diabetic groups treated with either CP alone or combined with insulin. Tested parameters included, estimation of serum follicle‐stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and glucose levels, testicular samples for histopathology and estimation of malondialdehyde (MDA), total antioxidant capacity (TAC), and B‐cell leukemia/lymphoma‐2 (BCL‐2) levels as well as sperm count and motility. Results showed that DM caused a severe alteration in hormonal profile and reduced sperm parameters along with increased MDA and decrease in both TAC and BCL‐2 levels. CP alone or with insulin treatment efficiently reversed all the negative effects of DM on rat testes, with maximum improvement in the combined regimen. Proposed mechanisms may involve its hypoglycemic, antioxidant, and antiapoptotic properties. Thus, CP could substitute for or better combined with insulin to prevent or retard diabetic‐induced testicular dysfunction.
Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease
Authors: Hu Ziheng , Wang Lirong , Ma Shifan , Kirisci Levent , Feng Zhiwei , Xue Ying , Klunk William E. , Kamboh M. Ilyas , Sweet Robert A. , Becker James , Lv Qianzhou , Lopez Oscar L. , Xie Xiang‐Qun 
Published: October 2018

AbstractIntroductionWe investigated the effect of antihypertensive (aHTN) medications and cholinesterase inhibitors (ChEIs) on the cognitive decline in patients with Alzheimer's disease (AD) and analyzed synergism by chemogenomics systems pharmacology mapping.MethodsWe compared the effect of aHTN drugs on Mini‐Mental State Examination scores in 617 AD patients with hypertension, and studied the synergistic effects.ResultsThe combination of diuretics, calcium channel blockers, and renin‐angiotensin‐aldosterone system blockers showed slower cognitive decline compared with other aHTN groups (Δβ = +1.46, P < .0001). aHTN medications slow down cognitive decline in ChEI users (Δβ = +0.56, P = .006), but not in non‐ChEI users (Δβ = −0.31, P = .53).DiscussionaHTN and ChEI drugs showed synergistic effects. A combination of diuretics, renin‐angiotensin‐aldosterone system blockers, and calcium channel blockers had the slowest cognitive decline. The chemogenomics systems pharmacology–identified molecular targets provide system pharmacology interpretation of the synergism of the drugs in clinics. The results suggest that improving vascular health is essential for AD treatment and provide a novel direction for AD drug development.
Intricate structure of the interphase chromocenter revealed by the analysis of a factor involved in species formation
Authors: Kochanova Natalia Y. , Schauer Tamas , Mathias Grusha Primal , Lukacs Andrea , Schmidt Andreas , Flatley Andrew , Schepers Aloys , Thomae Andreas W. , Imhof Axel 
Published: October 2018

ABSTRACTIn higher eukaryotes centromeres often coalesce into a large intranuclear domain called the chromocenter. Chromocenters are important for the organization of pericentric heterochromatin and a disturbance of their formation results in an upregulation of repetitive elements and causes defects in chromosome segregation. Mutations in the gene encoding for the centromere associated Drosophila speciation factor HMR show very similar phenotypes suggesting a role of HMR in chromocenter architecture and function. We performed confocal and super resolution microscopy as well as proximity based biotinylation experiments of HMR and its associated protein HP1a to generate a molecular map of HMR and HP1a bound chromatin. Our work reveals an intricate internal structure of the centromeric chromatin region, which suggests a role of HMR in separating heterochromatin from centromeric chromatin.
Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs
Authors: Kern David M. , Oh SeCheol , Hite Richard K. , Brohawn Stephen G. 
Published: October 2018

AbstractHypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here we present single-particle cryo-electron microscopy structures of LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.
Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight novel adipocyte biology
Authors: Tanigawa Yosuke , Li Jiehan , Justesen Johanne Marie , Horn Heiko , Aguirre Matthew , DeBoever Christopher , Chang Chris , Narasimhan Balasubramanian , Lage Kasper , Hastie Trevor , Park Chong Yon , Bejerano Gill , Ingelsson Erik , Rivas Manuel A. 
Published: October 2018

AbstractPopulation-based biobanks with genomic and dense phenotype data provide opportunities for generating effective therapeutic hypotheses and understanding the genomic role in disease predisposition. To characterize latent components of genetic associations, we applied truncated singular value decomposition (DeGAs) to matrices of summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured in 337,199 White British individuals in the UK Biobank study. We systematically identified key components of genetic associations and the contributions of variants, genes, and phenotypes to each component. As an illustration of the utility of the approach to inform downstream experiments, we report putative loss of function variants, rs114285050 (GPR151) and rs150090666 (PDE3B), that substantially contribute to obesity-related traits, and experimentally demonstrate the role of these genes in adipocyte biology. Our approach to dissect components of genetic associations across the human phenome will accelerate biomedical hypothesis generation by providing insights on previously unexplored latent structures.
Comparison between QSTand ΦSTindices in an endangeredBoswellia serrataRoxb: Implications for conservation
Authors: Mahesh Shashank , Kumar Pramod , Vaishnav Vivek , Mohammad Naseer , Ansari Shamim Akhtar 
Published: October 2018

AbstractBoswellia serrata, an economically important indigenous tree of dry deciduous forests, provides oleoresin gum of pharmaceutical significance and excellent pulp for paper industries, but faces threat to extinction due to poor natural regeneration and commercial exploitation. 240 individuals of the species representing 12 locations of its natural distribution in central India were investigated to compare the genetic differentiation indices, QSTfor GBH and wood fiber length and ϕSTfor neutral (RAPD+ISSR) markers. The comparison for paired locations was more informative than for metapopulation. The most paired locations were either under the stabilizing selection (QST(L) < ΦST(L)) or in the genetic drift (QST(L) = ΦST(L)) whereas a relatively small number of paired locations was under the divergent selection (QS T(L) > ΦST(L)). The comparison for the metapopulation generating only a single trend of QST(P) > ΦST(P) is, therefore, misleading. For conservation, the genetically deficit locations (QST(L) < ΦST(L) and QST(L) = ΦST(L)) ofB. serratawarrant for reinforcement of their genetic diversity by introduction of genotypes from other genetically divergent locations (QST(L) > ΦST(L)), which would check the fragmentation and genetic drift, resulting in reproductive vigour, natural regeneration and reverse the endangered status of the species.
Measurement of the Topological Dimension of Hippocampal Place Cell Activity
Authors: Fox Steven E. , Ranck James B. 
Published: October 2018

ABSTRACTThe fundamental property of topological dimension of neural activity has never been measured before. We measured the topological dimension of the activity of 89 rat hippocampal place cells recorded during foraging using the neighborhood boundary countdown method. Points were rate vectors forming a manifold in an 89 dimensional rate space Since a boundary has one less dimension than the neighborhood it encloses, reducing the dimension in sequential radial cuts finally arrives at boundary that is two points. The number of cuts required is the topological dimension of the set. Due to sparsity, we used a shell-like boundary with thickness. As expected, we found the large inductive dimension of this set of points to be two. To examine the robustness of the method, we used both real and modeled place cells and varied the number of neurons, duration of the time step and smoothing, radius and thickness for the boundary, decrement of the radius with each cut, requirements for the center point, and number of points in the final cluster. With the exception of shell thickness, the result was insensitive to these variations. Knowing the topological dimension allows application of rigorous topological principles to the activity of neuron populations. The method potentially can be applied to other neural classes and other behaviors, to enumerate firing variables when they are unknown, even count the factors influencing neural activity in sleep.
A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers
Authors: Chang Wai Hoong , Forde Donall , Lai Alvina G. 
Published: October 2018

AbstractBackgroundDespite much progress in cancer research, it’s incidence and mortality continue to rise. A robust biomarker that would predict tumor behavior is highly desirable and could improve patient treatment and prognosis.MethodsIn a retrospective bioinformatics analysis involving patients with liver cancer (n=839), we developed a prognostic signature consisting of 45 genes associated with tumor-infiltrating lymphocytes and cellular responses to hypoxia. From this gene set, we were able to identify a second prognostic signature comprised of 8 genes. Its performance was further validated in five other cancers: head and neck (n=520), renal papillary cell (n=290), lung (n=515), pancreas (n=178) and endometrial (n=370).FindingsThe 45-gene signature predicted overall survival in three liver cancer cohorts: hazard ratio (HR)=1.82, P=0.006; HR=1.84, P=0.008 and HR=2.67, P=0.003. Additionally, the reduced 8-gene signature was sufficient and effective in predicting survival in liver and five other cancers: liver (HR=2.36, P=0.0003; HR=2.43, P=0.0002 and HR=3.45, P=0.0007), head and neck (HR=1.64, P=0.004), renal papillary cell (HR=2.31, P=0.04), lung (HR=1.45, P=0.03), pancreas (HR=1.96, P=0.006) and endometrial (HR=2.33, P=0.003). Receiver operating characteristic analyses demonstrated both signature’s superior performance over current tumor staging parameters. Multivariate Cox regression analyses revealed that both 45-gene and 8-gene signatures were independent of other clinicopathological features in these cancers. Combining the gene signatures with somatic mutation profiles increased their prognostic ability.ConclusionsThis study, to our knowledge, is the first to identify a gene signature uniting both tumor hypoxia and lymphocytic infiltration as a prognostic determinant in six cancer types (n=2,712). The 8-gene signature can be used for patient risk stratification by incorporating hypoxia information to aid clinical decision making.
Synaptic circuits for irradiance coding by intrinsically photosensitive retinal ganglion cells
Authors: Sabbah Shai , Papendorp Carin , Koplas Elizabeth , Beltoja Marjo , Etebari Cameron , Gunesch Ali Noel , Carrete Luis , Kim Min Tae , Manoff Gabrielle , Bhatia-Lin Ananya , Zhao Tiffany , Schreck Daniel , Dowling Henry , Briggman Kevin L. , Berson David M. 
Published: October 2018

SummaryWe have explored the synaptic networks responsible for the unique capacity of intrinsically photosensitive retinal ganglion cells (ipRGCs) to encode overall light intensity. This luminance signal is crucial for circadian, pupillary and related reflexive responses light. By combined glutamate-sensor imaging and patch recording of postsynaptic RGCs, we show that the capacity for intensity-encoding is widespread among cone bipolar types, including OFF types.Nonetheless, the bipolar cells that drive ipRGCs appear to carry the strongest luminance signal. By serial electron microscopic reconstruction, we show that Type 6 ON cone bipolar cells are the dominant source of such input, with more modest input from Types 7, 8 and 9 and virtually none from Types 5i, 5o, 5t or rod bipolar cells. In conventional RGCs, the excitatory drive from bipolar cells is high-pass temporally filtered more than it is in ipRGCs. Amacrine-to-bipolar cell feedback seems to contribute surprisingly little to this filtering, implicating mostly postsynaptic mechanisms. Most ipRGCs sample from all bipolar terminals costratifying with their dendrites, but M1 cells avoid all OFF bipolar input and accept only ectopic ribbon synapses from ON cone bipolar axonal shafts. These are remarkable monad synapses, equipped with as many as a dozen ribbons and only one postsynaptic process.