bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generating quantitative binding landscapes through fractional binding selections, deep sequencing and data normalization
Authors: Heyne Michael , Papo Niv , Shifman Julia 
Published: January 2019

AbstractQuantifying the effects of various mutations on binding free energy is crucial for understanding the evolution of protein-protein interactions and would greatly facilitate protein engineering studies. Yet, measuring changes in binding free energy (ΔΔGbind) remains a tedious task that requires expression of each mutant, its purification, and affinity measurements. We developed a new approach that allows us to quantify ΔΔGbindfor thousands of protein mutants in one experiment. Our protocol combines protein randomization, Yeast Surface Display technology, Next Generation Sequencing, and a few experimental ΔΔGbinddata points on purified proteins to generate ΔΔGbindvalues for the remaining numerous mutants of the same protein complex. Using this methodology, we comprehensively map the single-mutant binding landscape of one of the highest-affinity interaction between BPTI and Bovine Trypsin. We show that ΔΔGbindfor this interaction could be quantified with high accuracy over the range of 12 kcal/mol displayed by various BPTI single mutants.
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint
Authors: Bigot Nicolas , Day Matthew , Baldock Robert A. , Watts Felicity Z. , Oliver Antony W. , Pearl Laurence H. 
Published: January 2019

SUMMARYCoordination of the cellular response to DNA damage is organised by multi-domain ‘scaffold’ proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ubiquitylation on other proteins, and are themselves carriers of such regulatory signals. Here we show that the DNA damage checkpoint regulating S-phase entry is controlled by a phosphorylation-dependent interaction of 53BP1 and TOPBP1. BRCT domains of TOPBP1 selectively bind conserved phosphorylation sites in the N-terminus of 53BP1. Mutation of these sites does not affect formation of 53BP1 or ATM foci following DNA damage, but abolishes recruitment of TOPBP1, ATR and CHK1 to 53BP1 damage foci, abrogating cell cycle arrest and permitting progression into S-phase. TOPBP1 interaction with 53BP1 is structurally complimentary to its interaction with RAD9-RAD1-HUS1, allowing these damage recognition factors to bind simultaneously to the same TOPBP1 molecule and cooperate in ATR activation in the G1 DNA damage checkpoint.
Novel, non-nitrocatechol COMT inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility
Authors: Byers Spencer , Buchler Ingrid P. , DePasquale Michael , Rowley Helen L. , Kulkarni Rajiv S. , Pinder Lucy , Kolobova Anna , Li Cailian , Au Vinh , Akuma Daniel , Zhang Gongliang , Wei Huijun , Cheetham Sharon C. , Barrow James C. , Carr Gregory V. 
Published: January 2019

AbstractCognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel COMT inhibitors in a set of preclinicalin vivoefficacy assays to determine their viability as potential clinical candidates. We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two dopamine metabolites, in cerebrospinal fluid (CSF) and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in a rat attentional set-shifting assay (ASST), an effect previously seen with the COMT inhibitor tolcapone. These results demonstrate that LIBD-1 is a novel COMT inhibitor with promisingin vivoactivity and the potential to serve as a new therapy for cognitive impairment.
WheatVRN1,FUL2andFUL3play critical and redundant roles in spikelet development and spike determinacy
Authors: Li Chengxia , Lin Huiqiong , Chen Andrew , Lau Meiyee , Jernstedt Judy , Dubcovsky Jorge 
Published: January 2019

ABSTRACTThe spikelet is the basic unit of the grass inflorescence. In this study, we show that wheat MADS-box genesVRN1,FUL2andFUL3play critical and redundant roles in spikelet and spike development, and also affect flowering time and plant height. In thevrn1ful2ful3-null triple mutant, the inflorescence meristem formed a normal double-ridge structure, but then the lateral meristems generated vegetative tillers subtended by leaves instead of spikelets. These results suggest an essential role of these three genes in the determination of spikelet meristem identity and the suppression of the lower ridge. Inflorescence meristems ofvrn1ful2ful3-null andvrn1ful2-null remained indeterminate and singlevrn1-null andful2-null mutants showed delayed formation of the terminal spikelet and increased number of spikelets per spike. Moreover, theful2-null mutant showed more florets per spikelet, which together with a higher number of spikelets, resulted in a significant increase in the number of grains per spike in the field. Our results suggest that a better understanding of the mechanisms underlying wheat spikelet and spike development can inform future strategies to improve grain yield in wheat.SUMMARY STATEMENTThe wheat MADS-box proteins VRN1, FUL2 and FUL3 play critical and overlapping roles in the development of spikelets, which are the basic unit of all grass inflorescences.
Faster Cognitive Decline in Dementia due to Alzheimer Disease with Clinically Undiagnosed Lewy Body Disease
Authors: Beach TG , Malek-Ahmadi M , Zamrini E , Adler CH , Sabbagh MN , Shill HA , Jacobson SA , Belden CM , Caselli RJ , Woodruff BK , Rapscak SZ , Ahern GL , Shi J , Caviness JN , Driver-Dunckley E , Mehta SH , Shprecher DR , Spann BM , Tariot P , Davis KJ , Long KE , Nicholson LR , Intorcia A , Glass MJ , Walker JE , Callan M , Curry J , Cutler B , Oliver J , Arce R , Walker DG , Lue L-F , Serrano GE , Sue LI , Chen K , Reiman EM 
Published: January 2019

AbstractNeuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer’s disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer’s disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. Subjects with dementia included those with “pure” ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (β = −0.69, 95% CI: −1.05, −0.33, p<0.001) while the AD-DLB group did not (β = −0.30, 95% CI: −0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.
Computational Intractability Law Molds the Topology of Biological Networks
Authors: Atiia Ali A , Hopper Corbin , Inoue Katsumi , Vidal Silvia , Waldispühl Jérôme 
Published: January 2019

AbstractVirtually all molecular interaction networks (MINs), irrespective of organism or physiological context, have a majority of loosely-connected ‘leaf’ genes interacting with at most 1-3 genes, and a minority of highly-connected ‘hub’ genes interacting with at least 10 or more other genes. Previous reports proposed adaptive and non-adaptive hypotheses describing sufficient but not necessary conditions for the origin of this majority-leaves minority-hubs (mLmH) topology. We modeled the evolution of MINs as a computational optimization problem which describes the cost of conserving, deleting or mutating existing genes so as to maximize (minimize) the overall number of beneficial (damaging) interactions network-wide. The model 1) provides sufficient and, assuming , necessary conditions for the emergence of mLmH as a software adaptation to circumvent computational intractability, 2) predicts the percentage number of genes having d interacting partners, and 3) when employed as a fitness function in an evolutionary algorithm, produces mLmH-possessing synthetic networks whose degree distributions match those of equal-size MINs.SummaryOur results indicate that the topology of molecular interaction networks is a selected-for software adaptation that minimizes the evolutionary cost of re-wiring the network in response to an evolutionary pressure to conserve, delete or mutate existing genes and interactions.
General visual and contingent thermal cues interact to elicit attraction in female Aedes aegypti mosquitoes
Authors: Liu Molly Z , Vosshall Leslie B. 
Published: January 2019

ABSTRACTFemale Aedes aegypti mosquitoes use multiple sensory modalities to hunt human hosts to obtain a blood-meal for egg production. Attractive cues include carbon dioxide (CO2), a major component of exhaled breath [1, 2]; heat elevated above ambient temperature, signifying warm-blooded skin [3, 4]; and dark visual contrast [5, 6], proposed to bridge long-range olfactory and short-range thermal cues [7]. Any of these sensory cues in isolation is an incomplete signal of a human host, and so a mosquito must integrate multi-modal sensory information before committing to approaching and biting a person [8]. Here, we study the interaction of visual cues, heat, and CO2 to investigate the contributions of human-associated stimuli to host-seeking decisions. We show that tethered flying mosquitoes strongly orient toward dark visual contrast regardless of CO2 stimulation and internal host-seeking status. This suggests that attraction to visual contrast is general, and not contingent on other host cues. In free-flight experiments with CO2, adding a dark contrasting visual cue to a warmed surface enhanced host-seeking. Moderate warmth became more attractive to mosquitoes, and mosquitoes aggregated on the cue at all non-noxious temperatures. Gr3 mutants, unable to detect CO2, were lured to the visual cue at ambient temperatures, but fled and did not return when the surface was warmed to host-like temperatures. This suggests that attraction to thermal cues is contingent on the presence of the additional human sensory cue CO2. Our results illustrate that mosquitoes integrate general attractive visual stimuli with the context-dependent thermal stimuli to seek promising sites for blood-feeding.GRAPHICAL ABSTRACT
Reduced structural connectivity in Insomnia Disorder
Authors: Jespersen Kira V. , Stevner Angus , Fernandes Henrique , Sørensen Stine D. , Van Someren Eus , Kringelbach Morten , Vuust Peter 
Published: January 2019

AbstractInsomnia Disorder is the most prevalent sleep disorder and it involves both sleep difficulties and daytime complaints. The neural underpinnings of Insomnia Disorder are poorly understood. Existing neuroimaging studies are limited by their focus on local measures and specific regions of interests. To address this shortcoming, we applied a data-driven approach to assess differences in whole-brain structural connectivity between adults with Insomnia Disorder and matched controls without sleep complaints. We used diffusion tensor imaging and probabilistic tractography to assess whole-brain structural connectivity and examined group differences using Network-Based Statistics. The results revealed a significant difference in the structural connectivity of the two groups. Participants with Insomnia Disorder showed reduced connectivity in a subnetwork that was largely left lateralized, including mainly fronto-subcortical connections with the insula as a key region. By taking a whole-brain network perspective, our study succeeds at integrating previous inconsistent findings, and our results reveal that reduced structural connectivity of the left insula and the connections between frontal and subcortical regions are central neurobiological features of Insomnia Disorder. The importance of these areas for interoception, emotional processing, stress responses and the generation of slow wave sleep may help guide the development of neurobiology-based models of the highly prevalent condition of Insomnia Disorder.
The evolution of life history theory: Bibliometric analysis of an interdisciplinary research area
Authors: Nettle Daniel , Frankenhuis Willem E. 
Published: January 2019

AbstractLife history theory developed as a branch of formal evolutionary theory concerned with the fitness consequences of allocating energy to reproduction, growth and self-maintenance across the life course. More recently, researchers have advocated its relevance to many psychological and social-science questions. As a scientific paradigm expands its range, its parts can become conceptually isolated from one another, so that in the end it is no longer held together by a common core of shared ideas. Here, we investigate the life history theory literature using quantitative bibliometric methods based on patterns of citation. We found that the literature up to and including 2010 was relatively coherent: it drew on a shared body of core references, and had only weak cluster divisions running along taxonomic lines. The post-2010 literature is more fragmented: it has more marked cluster boundaries, including boundaries within the literature on humans. Specifically, there are two clusters of human literature based around the idea of a fast-slow continuum of individual differences in behaviour that are bibliometrically isolated from the rest of the literature. We also find some evidence suggesting a relative decline in formal mathematical modelling. We point out that the human fast-slow continuum literature is conceptually closer to the non-human ‘pace of life’ literature than to the non-human literature usually referred to as ‘life history theory’.
Influence of Vocal Feedback on Emotions Provides Causal Evidence for the Self-Perception Theory
Authors: Goupil Louise , Johansson Petter , Hall Lars , Aucouturier Jean-Julien 
Published: January 2019

AbstractEmotional reactions are usually accompanied by vocalizations whose acoustic features are largely impacted by the physiological state of the body. While many theoretical frameworks emphasize the role played by the perception of bodily changes in the emergence of emotional feelings, few attempts have been made to assess the impact of vocal self-perception in this process. Here, we address this question by asking participants to deliberate out loud about how they would feel in various imaginary situations while we covertly manipulate their voices in order to make them sound emotional. Perceiving these artificial expressive cues in their own voice altered participants’ inferences about how they would feel. Crucially, this effect of vocal self-perception on felt emotions was abolished when participants detected our manipulation either explicitly or implicitly. Beyond demonstrating that vocal self-perception plays a role in the emergence of emotions, these results provide causal evidence for self-perception theories.
Variation in reported human head tissue electrical conductivity values
Authors: McCann Hannah , Pisano Giampaolo , Beltrachini Leandro 
Published: January 2019

ABSTRACTElectromagnetic source characterisation requires accurate volume conductor models representing head geometry and the electrical conductivity field. Head tissue conductivity is often assumed from previous literature, however, despite extensive research, measurements are inconsistent. A meta-analysis of reported human head electrical conductivity values was therefore conducted to determine significant variation and subsequent influential factors. Of 3,121 identified publications spanning three databases, 56 papers were included in data extraction. Conductivity values were categorised according to tissue type, and recorded alongside methodology, measurement condition, current frequency, tissue temperature, participant pathology and age. We found variation in electrical conductivity of the whole-skull, the spongiform layer of the skull, isotropic, perpendicularly- and parallelly-oriented white matter (WM) and the brain-to-skull-conductivity ratio (BSCR) could be significantly attributed to a combination of differences in methodology and demographics. This large variation should be acknowledged, and care should be taken when creating volume conductor models, ideally constructing them on an individual basis, rather than assuming them from the literature. When personalised models are unavailable, it is suggested weighted average means from the current meta-analysis are used. Assigning conductivity as: 0.41 S/m for the scalp, 0.02 S/m for the whole skull, or when better modelled as a 3-layer skull 0.048 S/m for the spongiform layer, 0.007 S/m for the inner compact and 0.005 S/m for the outer compact, as well as 1.71 S/m for the CSF, 0.47 S/m for the grey matter, 0.22 S/m for WM and 50.4 for the BSCR.
OGRE: Overlap Graph-based metagenomic Read clustEring
Authors: Balvert Marleen , Hauptfeld Tina , Schönhuth Alexander , Dutilh Bas E. 
Published: January 2019

AbstractThe microbes that live in an environment can be identified from the genomic material that is present, also referred to as the metagenome. Using Next Generation Sequencing techniques this genomic material can be obtained from the environment, resulting in a large set of sequencing reads. A proper assembly of these reads into contigs or even full genomes allows one to identify the microbial species and strains that live in the environment. Assembling a metagenome is a challenging task and can benefit from clustering the reads into species-specific bins prior to assembly. In this paper we propose OGRE, an Overlap-Graph based Read clustEring procedure for metagenomic read data. OGRE is the only method that can successfully cluster reads in species-specific bins for large metagenomic datasets without running into computation time-or memory issues.
A staphylococcal cyclophilin carries a single domain and unfolds via the formation of an intermediate that preserves cyclosporin A binding activity
Authors: Seal Soham , Polley Soumitra , Sau Subrata 
Published: January 2019

AbstractCyclophilin (Cyp), a peptidyl-prolylcis-transisomerase (PPIase), acts as a virulence factor in many bacteria includingStaphylococcus aureus. The enzymatic activity of Cyp is inhibited by cyclosporin A (CsA), an immunosuppressive drug. To precisely determine the unfolding mechanism and the domain structure of Cyp, we have investigated a chimericS. aureusCyp (rCyp) using various probes. Our limited proteolysis and the consequent analysis of the proteolytic fragments indicate that rCyp is composed of one domain with a short flexible tail at the C-terminal end. We also show that the urea-induced unfolding of both rCyp and rCyp-CsA is completely reversible and proceeds via the synthesis of at least one stable intermediate. The secondary structure, tertiary structure, and the hydrophobic surface area of no intermediate are fully identical to those of other intermediate or the related native protein. Further analyses reveal no loss of CsA binding activity in rCyp intermediate. The thermodynamic stability of rCyp was also significantly increased in the presence of CsA, recommending that this protein could be employed to screen new CsA derivatives in future.
Factors Associated with Suicidal Ideation and Suicidal Attempts among Adolescent Students in Nepal: Findings from Global School Based Students Health Survey
Authors: Pandey Achyut Raj , Bista Bihungum , Dhungana Raja Ram , Aryal Krishna Kumar , Chalise Binaya , Dhimal Meghnath 
Published: January 2019

AbstractIntroductionSuicide has been recognized as a public health problem with high burden in low and middle income countries. Suicide has long lasting psychological trauma on friends and relatives in addition to loss of economic productivity. Although the need of high quality evidence is acknowledged for designing suicide prevention program, Nepal lacks evidence from reliable and nationally representative data. In this context, this study aimed to estimate the prevalence of suicidal ideation and attempt and identify the factors associated with them.Materials and MethodsTotal of 6,531 students of grade 7 to 11 from 74 schools representing all three ecological belts and five development regions participated in this cross sectional study. To select the representative sample from study population, we used the two stage cluster sampling method. The respondents filled the self-administed standardized questionnaire. We carried out a Complex survey analysis for adjusting the selection probability of each research participants.ResultsNearly 14% had considered suicide while 10.33% had attempted suicide. Factors associated with suicidal ideation were the food insecurity (OR=2.31, CI=1.64-3.27), anxiety (OR=2.53, CI=1.48-4.30), loneliness (OR=2.50, CI=1.41-4.44) and gender (OR=1.38, CI=1.03, 1.88) as risk factors of suicidal ideation and anxiety (OR=2.99, CI=1.18-7.64), loneliness (OR=2.19, CI=1.28-3.74) truancy(OR= 1.99, CI=1.39-2.87), cigarette use(OR=3.06, CI=1.32-7.09) and gender (OR=1.60, CI=1.07-2.39) as risk factors of suicidal attempt. Having 3 or more close friends was found to have protective effect (OR=0.35, CI=0.16-0.74) against suicidal attempt.ConclusionsStudy reveals the relatively high prevalence of suicidal ideation and suicidal attempt among school-going adolescents in Nepal. Appropriate coping strategies for factors like anxiety, loneliness seem could be useful for preventing both suicidal ideation and attempt.