bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Rare Conformation of Oligosaccharide by Binding to Calcium-dependent Bacterial Lectin: X-ray Crystallography and Modelling Study
Authors: Lepsik Martin , Sommer Roman , Kuhaudomlarp Sakonwan , Lelimousin Mickaёl , Paci Emanuele , Varrot Annabelle , Titz Alexander , Imberty Anne 
Published: April 2019

ABSTRACTPathogenic micro-organisms utilize protein receptors in adhesion to host tissues, a process that in some cases relies on the interaction between lectin and human glycoconjugates. Oligosaccharide epitopes are recognized through their three-dimensional structure and their flexibility is a key issue in specificity. In this paper, we analyse by X-ray crystallography the structures of the lectin LecB from two strains of Pseudomonas aeruginosa in complex with Lewis x oligosaccharide present on cell surfaces of human tissues. An unusual conformation of the glycan was observed in all binding sites with a non-canonical syn orientation of the N-acetyl group of N-acetyl-glucosamine. A PDB-wide search revealed that such an orientation occurs only in 2% of protein/carbohydrate complexes. Theoretical chemistry calculations showed that the observed conformation is unstable in solution but stabilised by the lectin. A reliable description of LecB/Lewis x complex by force field-based methods had proven as especially challenging due to the special feature of the binding site, two closely apposed Ca2+ ions which induce strong charge delocalisation. By comparing various force-field parametrisations, we design general protocols which will be useful in near future for designing carbohydrate-based ligands (glycodrugs) against other calcium-dependent protein receptors.
K-FIT: An accelerated kinetic parameterization algorithm using steady-state fluxomic data
Authors: Gopalakrishnan Saratram , Dash Satyakam , Maranas Costas 
Published: April 2019

AbstractKinetic models predict the metabolic flows by directly linking metabolite concentrations and enzyme levels to reaction fluxes. Robust parameterization of organism-level kinetic models that faithfully reproduce the effect of different genetic or environmental perturbations remains an open challenge due to the intractability of existing algorithms. This paper introduces K-FIT, an accelerated kinetic parameterization workflow that leverages a novel decomposition approach to identify steady-state fluxes in response to genetic perturbations followed by a gradient-based update of kinetic parameters until predictions simultaneously agree with the fluxomic data in all perturbed metabolic networks. The applicability of K-FIT to large-scale models is demonstrated by parameterizing an expanded kinetic model forE. coli(307 reactions and 258 metabolites) using fluxomic data from six mutants. The achieved thousand-fold speed-up afforded by K-FIT over meta-heuristic approaches is transformational enabling follow-up robustness of inference analyses and optimal design of experiments to inform metabolic engineering strategies.
Legofit: Estimating Population History from Genetic Data
Authors: Rogers Alan R. 
Published: April 2019

AbstractBackgroundOur current understanding of archaic admixture in humans relies on statistical methods with large biases, whose magnitudes depend on the sizes and separation times of ancestral populations. To avoid these biases, it is necessary to estimate these parameters simultaneously with those describing admixture. Genetic estimates of population histories also confront problems of statistical identifiability: different models or different combinations of parameter values may fit the data equally well. To deal with this problem, we need methods of model selection and model averaging, which are lacking from most existing software.ResultsThe Legofit software package allows simultaneous estimation of parameters describing admixture and other aspects of population history. It includes facilities for data manipulation, estimation, model selection, and model averaging. It outperforms several statistical methods that have been widely used to study archaic admixture in humans.
GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons
Authors: Bryson Alexander , Hatch Robert , Zandt Bas-Jan , Rossert Christian , Berkovic Samuel , Reid Christopher A , Grayden David B , Hill Sean , Petrou Steven 
Published: April 2019

ABSTRACTThe binding of GABA to extra-synaptic GABAAreceptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present at low levels throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes through variation in chloride gradient. Here, we introduce a distinct mechanism through which extracellular GABA can differentially modulate the excitability of neuron subtypes through variation in neuronal electrophysiological properties. Using biophysically-detailed computational models, we found that tonic inhibition enhanced the responsiveness (or gain) of models with electrophysiological features typically observed in somatostatin (Sst) interneurons and reduced gain in models with features typical for parvalbumin (Pv) interneurons. These predictions were experimentally verified using patch-clamp recordings. Further analysis revealed that differential gain modulation is also dependent upon the extent of outward rectification of the GABAAreceptor-mediated tonic current. Our detailed neuron models demonstrate two subcellular consequences of tonic inhibition. First, tonic inhibition enhances somatic action potential repolarisation by increasing current flow into the dendritic compartment. This enhanced repolarisation then reduces voltage-dependent potassium currents at the soma during the afterhyperpolarisation. Finally, we show that reductions of potassium current selectively increase gain within neurons exhibiting action potential dynamics typical for Sst interneurons. Potassium currents in Pv-type interneurons are not sensitive to this mechanism as they deactivate rapidly and are unavailable for further modulation. These findings introduce a neuromodulatory paradigm in which GABA can induce a state of differential interneuron excitability through differences in intrinsic electrophysiological properties.
Automated analysis of whole brain vasculature using machine learning
Authors: Todorov Mihail Ivilinov , Paetzold Johannes C. , Schoppe Oliver , Tetteh Giles , Efremov Velizar , Völgyi Katalin , Düring Marco , Dichgans Martin , Piraud Marie , Menze Bjoern , Ertürk Ali 
Published: April 2019

SUMMARYTissue clearing methods enable imaging of intact biological specimens without sectioning. However, reliable and scalable analysis of such large imaging data in 3D remains a challenge. Towards this goal, we developed a deep learning-based framework to quantify and analyze the brain vasculature, named Vessel Segmentation & Analysis Pipeline (VesSAP). Our pipeline uses a fully convolutional network with a transfer learning approach for segmentation. We systematically analyzed vascular features of the whole brains including their length, bifurcation points and radius at the micrometer scale by registering them to the Allen mouse brain atlas. We reported the first evidence of secondary intracranial collateral vascularization in CD1-Elite mice and found reduced vascularization in the brainstem as compared to the cerebrum. VesSAP thus enables unbiased and scalable quantifications for the angioarchitecture of the cleared intact mouse brain and yields new biological insights related to the vascular brain function.GRAPHICAL ABSTRACTSupporting material of VesSAP is available athttp://DISCOtechnologies.org/VesSAP
Power, positive predictive value, and sample size calculations for random field theory-based fMRI inference
Authors: Ostwald Dirk , Schneider Sebastian , Bruckner Rasmus , Horvath Lilla 
Published: April 2019

AbstractRecent discussions on the reproducibility of task-related functional magnetic resonance imaging (fMRI) studies have emphasized the importance of power and sample size calculations in fMRI study planning. In general, statistical power and sample size calculations are dependent on the statistical inference framework that is used to test hypotheses. Bibliometric analyses suggest that random field theory (RFT)-based voxel- and cluster-level fMRI inference are the most commonly used approaches for the statistical evaluation of task-related fMRI data. However, general power and sample size calculations for these inference approaches remain elusive. Based on the mathematical theory of RFT-based inference, we here develop power and positive predictive value (PPV) functions for voxel- and cluster-level inference in both uncorrected single test and corrected multiple testing scenarios. Moreover, we apply the theoretical results to evaluate the sample size necessary to achieve desired power and PPV levels based on an fMRI pilot study.
Cross-modal integration of reward value during oculomotor planning
Authors: Cheng Felicia Pei-Hsin , Saglam Adem , André Selina , Pooresmaeili Arezoo 
Published: April 2019

AbstractReward value guides goal-directed behavior and modulates early sensory processing. Rewarding stimuli are often multisensory but it is not known how reward value is combined across sensory modalities. Here we show that the integration of reward value critically depends on whether the distinct sensory inputs are perceived to emanate from the same multisensory object. We systematically manipulated the congruency in monetary reward values and the relative spatial positions of co-occurring auditory and visual stimuli that served as bimodal distractors during an oculomotor task. The amount of interference induced by the distractors was used as an indicator of their perceptual salience. Our results across two experiments show that when reward value is linked to each modality separately, the value congruence between vision and audition determines the combined salience of the bimodal distractors. However, reward value of vision wins over the value of audition if visual and auditory stimuli have been experienced as belonging to the same audiovisual object prior to the learning of the reward values. The perceived spatial alignment of auditory and visual stimuli is a prerequisite for the integration of their reward values, as no effect of reward value was observed when the two modalities were perceived to be misaligned. These results show that in a task that highly relies on the processing of visual spatial information, the reward values from multiple sensory modalities are integrated with each other, each with their respective weights. This weighting depends on the congruency in reward values, exposure history, and spatial co-localization.
Use of latent class analysis to identify multimorbidity patterns and associated factors in Korean adults aged 50 years and older
Authors: Park Bomi , Lee Hye Ah , Park Hyesook 
Published: April 2019

AbstractIntroductionMultimorbidity associated with significant disease and economic burdens is common among the aged. We identified chronic disease multimorbidity patterns in Koreans 50 years of age or older, and explored whether such patterns were associated with particular sociodemographic factors and health-related quality-of-life.MethodsThe multimorbidity patterns of 10 chronic diseases (hypertension, dyslipidemia, stroke, osteoarthritis, tuberculosis, asthma, allergic rhinitis, depression, diabetes mellitus, and thyroid disease) were identified via latent class analysis of data on 8,370 Korean adults aged 50+ years who participated in the sixth Korean National Health and Nutrition Examination Survey (2013-2015). The associations between multimorbidity patterns, and sociodemographic factors and health-related quality of life, were subjected to regression analysis.ResultsThree patterns of multimorbidity were identified: 1) a relatively healthy group (60.4% of the population); 2) a ‘cardiometabolic conditions’ group (27.8%); and, 3) an ‘arthritis, asthma, allergic rhinitis, depression, and thyroid disease’ group (11.8%). The female (compared to male) gender was associated with an increased likelihood of membership of thecardiometabolic conditionsgroup (odds ratio [OR]=1.32, 95% confidence interval [CI]=1.15-1.51) and (to a much greater extent) thearthritis, asthma, allergy, depression, and thyroid diseasegroup (OR=4.32, 95% CI=3.30-5.66). Low socioeconomic status was associated with membership of the two multimorbidity classes. Membership of thearthritis, asthma, allergy, depression, and thyroid diseasegroup was associated with a significantly poorer health-related quality-of-life than was membership of the other two groups.ConclusionThe co-occurrence of chronic diseases was not attributable to chance. Multimorbidity patterns were associated with sociodemographic factors and quality-of-life. Our results suggest that targeted, integrated public health and clinical strategies dealing with chronic diseases should be based on an understanding of multimorbidity patterns; this would improve the quality-of-life of vulnerable multimorbid adults.
Determination of clinical risk factors associated with inflammation in hypertensive patients with type-2 diabetes mellitus
Authors: Ellulu Mohammed S. 
Published: April 2019

ABSTRACTBackgroundObesity and chronic diseases associated with the development of inflammation have remained unclear if the observed inflammatory state in diabetic patients is due to excess adipose tissue mass and/or directly associated with the diabetic state. Therefore, this study determined the risk factors associated with inflammation in hypertensive patients with type-2 diabetes mellitus.MethodsA total of 164 hypertensive diabetic patients aged 38 to 60 years were selected from seven primary health care centers in Gaza city, Palestine. Interview and questionnaire were employed to collect data related to age, gender, smoking habits, and physical activity pattern. Besides, the selection of patients depended on objective criteria.ResultsThe study involved 118 (72%) women and 46 (28%) men. The mean of age for all patients was 53.7±0.46 years old. 76 patients (46.3%) were categorized as current smokers, 88 patients (53.7%) categorized as non-smokers. The baseline distribution of patients according to physical activity has displayed that 130 (79.3%) were low physically active patients, 28 (27.1%) were moderate, and 6 (3.7%) were highly physically active patients. A tertile of inflammation feature with high sensitivity C-reactive protein (hs-CRP) was developed. The highest tertile of hs-CRP was significantly associated with women, higher obesity indices, metabolic dysregulation involving lipid profile markers, fasting blood glucose (FBG) and blood pressure, higher interleukin 6 (IL-6), and lower adiponectin. Via ordinal logistic regression analysis, after adjusting for age, gender, smoking habits, and physical activity; the risk factors for hs-CRP were the increased body mass index [OR: 1.17, P=0.018], IL-6 [OR: 2.22, P=0.025] and FBG [OR: 1.01, P=0.007], as well as reduced adiponectin [OR: 0.81, P=0.002].ConclusionThe inflammation state was affected by obesity and had been related to altered adipokines levels of IL-6 and adiponectin, as well as affected by the disease condition of diabetes, as evidenced by higher serum level of FBG.
The prevalence of vitamin D deficiency between Saudis and non-Saudis in Al-Madinah Al-Munawarah a cross-sectional study
Authors: Nasr Muhammed Hassan , Othman Noordin , Hassan Bassam Abdulrasol , Karoppannan Mahmathi , Abdulaziz Noorizan Binti , Alsarani Mohammed Ahmed , Eskembaji Mohammed Husain 
Published: April 2019

BackgroundVitamin D, or the “sunshine” hormone became an attractable topic that recently captivates many researchers. The increased prevalence of vitamin D deficiency became an alarming health concern despite the accumulative evidence exploring its crucial role not only in bone metabolism, but also in a variety of pleiotropic functions throughout the various body organs. The aim of this study is to compare the prevalence that might influence vitamin D deficiency among Saudi and non-Saudi nationalities in Almadinah Almunawarh, Saudi Arabia, and to study the different factors that may have an influence in the difference of this prevalence like the marital status, occupation, smoking, sunlight exposure, education, and dietary habits.MethodsThe study was a cross sectional study done in the medical care unit in Taiba University Almadina Almunawarah in which, 65 healthy male individuals from different nationalities (Saudis and non-Saudis), aged 18 - 65 years were divided into 2 groups, 33 Saudis and 32 non-Saudis. A sociodemographic questionnaire was filled by the study participants and 25-OH vitamin D3 (25(OH)D3) concentrations were detected by electrochemiluminescence immunoassay.ResultsResults showed a Significant percentage of the participants in the Saudi group (n = 30, 91%) suffered from deficiency in vitamin D levels [25 (OH) D < 20 ng/ml] 12.57 ± 4.82 (mean ± SD), compared to only 47% (n = 15) in the non-Saudi group [21.56 ± 6.82 (mean ± SD)]. Vitamin D deficiency was found to be significantly higher in the Saudi group than the non-Saudi group with P = 0.001.ConclusionResults showed a significant increase in vitamin D deficiency in Saudi population than the non-Saudis P = 0.001. The occupation status was found to be the only factor positively correlated with vitamin D deficiency.
Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease
Authors: Fan Chun Chieh , Banks Sarah J. , Thompson Wesley K. , Chen Chi-Hua , McEvoy Linda K. , Tan Chin Hong , Kukull Walter , Bennett David A. , Farrer Lindsay A. , Mayeux Richard , Schellenberg Gerard D. , Andreassen Ole A. , Desikan Rahul , Dale Anders M. 
Published: April 2019

AbstractSex differences in the manifestations of Alzheimer’s disease (AD) are under intense investigations 1,2. Despite the emerging importance of polygenic predictions for AD 3–8, the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Sex-matched polygenic hazard scores (PHS) have significantly stronger associations with age-at-disease-onset, clinical progressions, amyloid depositions, neurofibrillary tangles, and composite neuropathological scores, than sex-mismatched PHS, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores (PRS), have lower predictive power than PHS and show no evidence for sex differences. Our results indicate revealing sex-dependent genetic architecture requires the consideration of temporal processes of AD. This has strong implications not only for the genetic underpinning of AD but also for how we estimate sex-dependent polygenic effects for clinical use.
The role of diffusion and perivascular spaces in dynamic susceptibility contrast MRI
Authors: Doucette Jonathan , Kames Christian , Hernández-Torres Enedino , Traboulsee Anthony , Rauscher Alexander 
Published: April 2019

AbstractWe investigated the effects of brain tissue orientation, diffusion, and perivascular spaces on dynamic susceptibility contrast MRI. A 3D numerical model of a white matter voxel was created that consists of an isotropic capillary bed and anisotropic vessels that run in parallel with white matter tracts and are surrounded by perivascular spaces. The signal within the voxel was simulated by solving the Bloch-Torrey equation. Experimental perfusion data were acquired with a gradient echo dynamic susceptibility contrast scan. White matter fibre orientation was mapped with diffusion tensor imaging. Our numerical model of the contrast agent induced increase in R2*, as a function of tissue orientation, was fit to dynamic susceptibility contrast MRI data from thirteen subjects by minimizing the bias-corrected Akaike information criterion. White matter blood volume fraction in both the isotropic and the anisotropic vessels was determined as a free parameter, and results were analyzed as a function of diffusivity and perivascular space size. Total white matter blood volume was found to be 2.57%, with one third of the blood residing in blood vessels that run parallel with white matter tracts. Gradient echo dynamic susceptibility contrast MRI strongly depended on white matter tissue orientation and, according to the numerical simulations, this effect is amplified by diffusion and perivascular spaces.
Low Dose Ionizing Radiation Strongly Stimulates Insertional Mutagenesis in a γH2AX Dependent Manner
Authors: Zelensky Alex N. , Schoonakker Mascha , Brandsma Inger , Tijsterman Marcel , van Gent Dik C. , Essers Jeroen , Kanaar Roland 
Published: April 2019

AbstractExtrachromosomal DNA can integrate into the genome with no sequence specificity producing an insertional mutation. This process, which is referred to as random integration (RI), requires a double stranded break (DSB) in the genome. Inducing DSBs by various means, including ionizing radiation, increases the frequency of integration. Here we report that non-lethal physiologically relevant doses of ionizing radiation (10-100 mGy), within the range produced by medical imaging equipment, stimulate RI of transfected and viral episomal DNA in human and mouse cells with an extremely high efficiency. Genetic analysis of stimulated RI (S-RI) revealed that it is distinct from the background RI, requires histone H2AX S139 phosphorylation (γH2AX) and is not reduced by DNA polymerase θ (Polq) inactivation. S-RI efficiency was unaffected by the main DSB repair pathway (homologous recombination and non-homologous end joining) disruptions, but double deficiency in MDC1 and 53BP1 phenocopies γH2AX inactivation. The robust responsiveness of S-RI to physiological amounts of DSBs has implications for radiation risk assessment and can be exploited for extremely sensitive, macroscopic and direct detection of DSB-induced mutations.