bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of Latent Class Analysis to Identify Metabolic Syndrome Components Patterns in adults: Tehran Lipid and Glucose study
Authors: Ahanchi Noushin Sadat , Hadaegh Farzad , Alipour Abbas , Ghanbarian Arash , Azizi Fereidoun , Khalili Davood 
Published: February 2019

AbstractIn this study, using latent class analysis (LCA), we investigated whether there are any homogeneous subclasses of individuals exhibiting different profiles of metabolic syndrome (MetS) components. The current study was conducted within the framework of the Tehran Lipid and Glucose Study (TLGS), a population-based cohort including 6448 subjects, aged 20–50 years. We carried out a LCA on MetS components and assessed the association of some demographic and behavioral variables with membership of latent subclasses using multinomial logistic regression. Four latent classes were identified:(1) Low riskclass, with the lowest probabilities for all MetS components (its prevalence rate in men: 29%, women: 64.7%), (2) MetS with diabetes medication (men: 1%, women: 2.3%), (3) Mets without diabetes medication (men: 32%, women: 13.4%), (4) dyslipidemia (men: 38%, women: 19.6%). In men the forth subclass was more significantly associated with being smoker (odds ratio: 4.49; 95% CI: 1.89–9.97). Our study showed that subjects with MetS could be classified in sub-classes with different origins for their metabolic disorders including drug treated diabetes, those with central obesity and dyslipidemia associated with smoking.
Voluntary running rescues the defective hippocampal neurogenesis and behaviour observed in lipocalin 2-null mice
Authors: Ferreira Ana Catarina , Novais Ashley , Sousa Nuno , Sousa João Carlos , Marques Fernanda 
Published: February 2019

AbstractThe continuous generation of new neurons in the adult mammalian hippocampus is a form of neural plasticity that modulates learning and memory functions, and also emotion (anxiety and depression). Among the factors known to modulate adult hippocampal neurogenesis and brain function, lipocalin-2 (LCN2) was recently described as a key regulator of neural stem cells (NSCs) proliferation and commitment, with impact on several dimensions of behaviour. Herein, we evaluated whether voluntary running, a well-known regulator of cell genesis, rescue the deficient adult hippocampal neurogenesis observed in mice lacking LCN2. We observed that running, by counteracting oxidative stress in NSCs, reverses LCN2-null mice defective hippocampal neurogenesis, as it promotes NSCs cell cycle progression and maturation, resulting in a partial reduction in anxiety and improved contextual behaviour. Together, these findings demonstrate that running is a positive modulator of adult hippocampal neurogenesis and behaviour in mice lacking LCN2, by impacting on the antioxidant kinetics of NSCs.
Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types
Authors: van de Stolpe Anja , Holtzer Laurent , van Ooijen Henk , Inda Marcia Alves de , Verhaegh Wim 
Published: February 2019

AbstractSignal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enabling quantitative measurement of functional pathway activity based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the pathway-associated transcription factor. Oestrogen receptor, Wnt, and PI3K-FOXO pathway assays have been described previously. Here, we report model development for androgen receptor, Hedgehog, TGFβ, and NFκB pathway assays, biological validation on multiple cell types, and analysis of data from published clinical studies (multiple sclerosis, amyotrophic lateral sclerosis, contact dermatitis, Ewing sarcoma, lymphoma, medulloblastoma, ependymoma, skin and prostate cancer). Multiple pathway analysis of clinical prostate cancer (PCa) studies showed increased AR activity in hyperplasia and primary PCa but variable AR activity in castrate resistant (CR) PCa, loss of TGFβ activity in PCa, increased Wnt activity in TMPRSS2:ERG fusion protein-positive PCa, active PI3K pathway in advanced PCa, and active PI3K and NFκB as potential hormonal resistance pathways. Potential value for future clinical practice includes disease subtyping and prediction and targeted therapy response prediction and monitoring.
In vitro culture with gemcitabine augments death receptor and NKG2D ligand expression on tumour cells
Authors: Gravett Andrew M. , Dalgleish Angus G. , Copier John 
Published: February 2019

AbstractMuch effort has been made to try to understand the relationship between chemotherapeutic treatment of cancer and the immune system. Whereas much of that focus has been on the direct effect of chemotherapy drugs on immune cells and the release of antigens and danger signals by malignant cells killed by chemotherapy, the effect of chemotherapy on cells surviving treatment has often been overlooked. In the present study, tumour cell lines: A549 (lung), HCT116 (colon) and MCF-7 (breast), were treated with various concentrations of the chemotherapeutic drugs cyclophosphamide, gemcitabine (GEM) and oxaliplatin (OXP) for 24 hours in vitro. In line with other reports, GEM and OXP upregulated expression of the death receptor CD95 (fas) on live cells even at sub-cytotoxic concentrations. Further investigation revealed that the increase in CD95 in response to GEM sensitised the cells to fas ligand treatment, was associated with increased phosphorylation of stress activated protein kinase/c-Jun N-terminal kinase and that other death receptors and activatory immune receptors were co-ordinately upregulated with CD95 in certain cell lines. The upregulation of death receptors and NKG2D ligands together on cells after chemotherapy suggest that although the cells have survived preliminary treatment with chemotherapy they may now be more susceptible to immune cell-mediated challenge. This re-enforces the idea that chemotherapy-immunotherapy combinations may be useful clinically and has implications for the make-up and scheduling of such treatments.
Functional random forest with applications in dose-response predictions
Authors: Rahman Raziur , Dhruba Saugato Rahman , Ghosh Souparno , Pal Ranadip 
Published: February 2019

AbstractDrug sensitivity prediction for individual tumors is a significant challenge in personalized medicine. Current modeling approaches consider prediction of a single metric of the drug response curve such asAUCorIC50. However, the single summary metric of a dose-response curve fails to provide the entire drug sensitivity profile which can be used to design the optimal dose for a patient. In this article, we assess the problem of predicting the complete dose-response curve based on genetic characterizations. We propose an enhancement to the popular ensemble-based Random Forests approach that can directly predict the entire functional profile of a dose-response curve rather than a single summary metric. We design functional regression trees with node costs modified based on dose/response region dependence methodologies and response distribution based approaches. Our results relative to large pharmacological databases such as CCLE and GDSC show a higher accuracy in predicting dose-response curves of the proposed functional framework in contrast to univariate or multivariate Random Forest predicting sensitivities at different dose levels. Furthermore, we also considered the problem of predicting functional responses from functional predictorsi.e., estimating the dose-response curves with a model built on dose-dependent expression data. The superior performance of Functional Random Forest using functional data as compared to existing approaches have been shown using the HMS-LINCS dataset. In summary, Functional Random Forest presents an enhanced predictive modeling framework to predict the entire functional response profile considering both static and functional predictors instead of predicting the summary metrics of the response curves.
Spectral-Topological Superefficient Quantum Memory
Authors: Perminov N. S. , Moiseev S. A. 
Published: February 2019

AbstractIn this work, we propose a universal (spectral-topological) approach towards the realization of the quantum memory, consisting of a small number of controlled absorbers, providing a super-high quantum efficiency of more than 99.9% required for practical quantum information science. In this way, we have found a series of spectral-topological matching conditions for the spectroscopic parameters of the absorbers which ensure the maximal efficiency in the broadband spectral range due to controlling the relative position (topology) of the eigenfrequencies in the absorbers spectrum. We also discuss the implementation of the proposed approach using the modern microwave and optical technologies.
Msx1 loss suppresses formation of the ectopic crypts developed in the Apc-deficient small intestinal epithelium
Authors: Horazna Monika , Janeckova Lucie , Svec Jiri , Babosova Olga , Hrckulak Dusan , Vojtechova Martina , Galuskova Katerina , Sloncova Eva , Kolar Michal , Strnad Hynek , Korinek Vladimir 
Published: February 2019

AbstractThe first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by the Apc loss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditional Apc allele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of the Msx1 gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens, MSX1 displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.
Evaluation of site-specific homologous recombination activity of BRCA1 by direct quantitation of gene editing efficiency
Authors: Yoshino Yuki , Endo Shino , Chen Zhenghao , Qi Huicheng , Watanabe Gou , Chiba Natsuko 
Published: February 2019

AbstractHomologous recombination (HR) contributes to the repair of DNA double-strand breaks (DSBs) and inter-strand crosslinks. The HR activity in cancer cells can be used to predict their sensitivity to DNA-damaging agents that cause these damages. To evaluate HR activity, we developed a system called Assay for Site-specific HR Activity (ASHRA), in which cells are transiently transfected with an expression vector for CRISPR/Cas9 and a HR donor sequence containing a marker gene. DSBs are created by Cas9 and then repaired by HR using donor vector sequences homologous to the target gene. The level of genomic integration of the marker gene is quantified by Western blotting, flowcytometry, or quantitative PCR (qPCR). ASHRA detected HR deficiency caused by BRCA1, BARD1, or RAD51 knockdown or introduction of BRCA1 variants. The influence of BRCA1 variants on HR, as determined by qPCR, was consistent with the chemosensitivities of the transfected cells. The qPCR format of ASHRA could measure HR activity in both transcribed and un-transcribed regions. Knockdown of BRCA1 nor BARD1 did not affect HR activity in a transcriptionally inactive site. ASHRA can evaluate HR activity and will be useful for predicting sensitivity to chemotherapy, screening drugs that affect HR, and investigating the mechanisms of HR.
Non-invasive in vivo fluorescence imaging of apoptotic retinal photoreceptors
Authors: Mazzoni Francesca , Müller Claudia , DeAssis Jonathan , Lew Deborah , Leevy W. Matthew , Finnemann Silvia C. 
Published: February 2019

AbstractPhosphatidylserine externalization is an early molecular signature for apoptosis. In many retinal degenerative diseases, photoreceptor neurons die by apoptosis. Here, we report utility of the phosphatidylserine-binding conjugate of Bis(zinc(II)-dipicolylamine (Zn-DPA) with Texas-red (PSVue-550) in transiently labeling apoptotic photoreceptors in living pigmented or albino rats and mice with retinal degeneration. Applying PSVue-550 as eyedrop is non-toxic and eliminates need for intraocular injection. PSVue-550 fluorescence specifically and transiently labeling dying retinal photoreceptors is detectable in anesthetized animals using standard retinal or whole small animal imaging systems. Importantly, prior PSVue-550 eyedrop administration and imaging does not affect repeat testing. Altogether, our results establish PSVue-550 imaging as a completely non-invasive method that provides the opportunity to longitudinally monitor retinal photoreceptor cell death in preclinical studies.
Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults
Authors: Yi Sang-Wook , Yi Jee-Jeon , Ohrr Heechoul 
Published: February 2019

AbstractIt is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age. 12,815,006 Korean adults underwent routine health examinations during 2001–2004, and were followed until 2013. During follow-up, 694,423 individuals died. U-curve associations were found. In the TC ranges of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group). TC had U-curve associations with mortality in each age-sex group. TC levels associated with lowest mortality were 210–249 mg/dL, except for men aged 18–34 years (180–219 mg/dL) and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). The inverse associations for TC < 200 mg/dL were stronger than the positive associations in the upper range.
Machine learning for MEG during speech tasks
Authors: Kostas Demetres , Pang Elizabeth W. , Rudzicz Frank 
Published: February 2019

AbstractWe consider whether a deep neural network trained with raw MEG data can be used to predict the age of children performing a verb-generation task, a monosyllable speech-elicitation task, and a multi-syllabic speech-elicitation task. Furthermore, we argue that the network makes predictions on the grounds of differences in speech development. Previous work has explored taking ‘deep’ neural networks (DNNs) designed for, or trained with, images to classify encephalographic recordings with some success, but this does little to acknowledge the structure of these data. Simple neural networks have been used extensively to classify data expressed as features, but require extensive feature engineering and pre-processing. We present novel DNNs trained using raw magnetoencephalography (MEG) and electroencephalography (EEG) recordings that mimic the feature-engineering pipeline. We highlight criteria the networks use, including relative weighting of channels and preferred spectro-temporal characteristics of re-weighted channels. Our data feature 92 subjects aged 4–18, recorded using a 151-channel MEG system. Our proposed model scores over 95% mean cross-validation accuracy distinguishing above and below 10 years of age in single trials of un-seen subjects, and can classify publicly available EEG with state-of-the-art accuracy.
Holocene El Niño–Southern Oscillation variability reflected in subtropical Australian precipitation
Authors: Barr C. , Tibby J. , Leng M. J. , Tyler J. J. , Henderson A. C. G. , Overpeck J. T. , Simpson G. L. , Cole J. E. , Phipps S. J. , Marshall J. C. , McGregor G. B. , Hua Q. , McRobie F. H. 
Published: February 2019

AbstractThe La Niña and El Niño phases of the El Niño-Southern Oscillation (ENSO) have major impacts on regional rainfall patterns around the globe, with substantial environmental, societal and economic implications. Long-term perspectives on ENSO behaviour, under changing background conditions, are essential to anticipating how ENSO phases may respond under future climate scenarios. Here, we derive a 7700-year, quantitative precipitation record using carbon isotope ratios from a single species of leaf preserved in lake sediments from subtropical eastern Australia. We find a generally wet (more La Niña-like) mid-Holocene that shifted towards drier and more variable climates after 3200 cal. yr BP, primarily driven by increasing frequency and strength of the El Niño phase. Climate model simulations implicate a progressive orbitally-driven weakening of the Pacific Walker Circulation as contributing to this change. At centennial scales, high rainfall characterised the Little Ice Age (~1450–1850 CE) in subtropical eastern Australia, contrasting with oceanic proxies that suggest El Niño-like conditions prevail during this period. Our data provide a new western Pacific perspective on Holocene ENSO variability and highlight the need to address ENSO reconstruction with a geographically diverse network of sites to characterise how both ENSO, and its impacts, vary in a changing climate.
Drosophila Hcf regulates the Hippo signaling pathway via association with the histone H3K4 methyltransferase Trr
Authors: Nan Zi , Yang Weiwei , Lyu Jialan , Wang Fang , Deng Qiannan , Xi Yongmei , Yang Xiaohang , Ge Wanzhong 
Published: February 2019

Abstract
Control of organ size is a fundamental aspect in biology and plays important roles in development. The Hippo pathway is a conserved signaling cascade that controls tissue and organ size through the regulation of cell proliferation and apoptosis. Here, we report on the roles of Hcf (host cell factor), the Drosophila homolog of Host cell factor 1, in regulating the Hippo signaling pathway. Loss-of-Hcf function causes tissue undergrowth and the down-regulation of Hippo target gene expression. Genetic analysis reveals that Hcf is required for Hippo pathway-mediated overgrowth. Mechanistically, we show that Hcf associates with the histone H3 lysine-4 methyltransferase Trithorax-related (Trr) to maintain H3K4 mono- and trimethylation. Thus, we conclude that Hcf positively regulates Hippo pathway activity through forming a complex with Trr and controlling H3K4 methylation.
The role of chromosome segregation and nuclear organisation in human subfertility
Authors: Fowler Katie E. , Mandawala Anjali A. , Griffin Darren K. 
Published: February 2019

Abstract
Spermatogenesis is central to successful sexual reproduction, producing large numbers of haploid motile male gametes. Throughout this process, a series of equational and reductional chromosome segregation precedes radical repackaging of the haploid genome. Faithful chromosome segregation is thus crucial, as is an ordered spatio-temporal ‘dance’ of packing a large amount of chromatin into a very small space. Ergo, when the process goes wrong, this is associated with an improper chromosome number, nuclear position and/or chromatin damage in the sperm head. Generally, screening for overall DNA damage is relatively commonplace in clinics, but aneuploidy assessment is less so and nuclear organisation studies form the basis of academic research. Several studies have focussed on the role of chromosome segregation, nuclear organisation and analysis of sperm morphometry in human subfertility observing significant alterations in some cases, especially of the sex chromosomes. Importantly, sperm DNA damage has been associated with infertility and both extrinsic (e.g. lifestyle) and intrinsic (e.g. reactive oxygen species levels) factors, and while some DNA-strand breaks are repaired, unexpected breaks can cause differential chromatin packaging and further breakage. A ‘healthy’ sperm nucleus (with the right number of chromosomes, nuclear organisation and minimal DNA damage) is thus an essential part of reproduction. The purpose of this review is to summarise state of the art in the fields of sperm aneuploidy assessment, nuclear organisation and DNA damage studies.
Twenty years of Mediator complex structural studies
Authors: Verger Alexis , Monté Didier , Villeret Vincent 
Published: February 2019

Abstract
Mediator is a large multiprotein complex conserved in all eukaryotes that plays an essential role in transcriptional regulation. Mediator comprises 25 subunits in yeast and 30 subunits in humans that form three main modules and a separable four-subunit kinase module. For nearly 20 years, because of its size and complexity, Mediator has posed a formidable challenge to structural biologists. The first two-dimensional electron microscopy (EM) projection map of Mediator leading to the canonical view of its division in three topological modules named Head, Middle and Tail, was published in 1999. Within the last few years, optimization of Mediator purification combined with technical and methodological advances in cryo-electron microscopy (cryo-EM) have revealed unprecedented details of Mediator subunit organization, interactions with RNA polymerase II and parts of its core structure at high resolution. To celebrate the twentieth anniversary of the first Mediator EM reconstruction, we look back on the structural studies of Mediator complex from a historical perspective and discuss them in the light of our current understanding of its role in transcriptional regulation.