bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the human kinome and phosphatome reveals diseased signaling networks induced by overexpression
Authors: Lun Xiao-Kang , Szklarczyk Damian , Gábor Attila , Dobberstein Nadine , Zanotelli Vito RT , Saez-Rodriguez Julio , von Mering Christian , Bodenmiller Bernd 
Published: May 2018

AbstractKinase and phosphatase overexpression drives tumorigenesis and drug resistance in many cancer types. Signaling networks reprogrammed by protein overexpression remain largely uncharacterized, hindering discovery of paths to therapeutic intervention. We previously developed a single cell proteomics approach based on mass cytometry that enables quantitative assessment of overexpression effects on the signaling network. Here we applied this approach in a human kinome- and phosphatome-wide study to assess how 649 individually overexpressed proteins modulate the cancer-related signaling network in HEK293T cells. Based on these data we expanded the functional classification of human kinases and phosphatases and detected 208 novel signaling relationships. In the signaling dynamics analysis, we showed that increased ERK-specific phosphatases sustained proliferative signaling, and using a novel combinatorial overexpression approach, we confirmed this phosphatase-driven mechanism of cancer progression. Finally, we identified 54 proteins that caused ligand-independent ERK activation with potential as biomarkers for drug resistance in cells carrying BRAF mutations.
Stability-normalised walking speed: a new approach for human gait perturbation research
Authors: McCrum Christopher , Willems Paul , Karamanidis Kiros , Meijer Kenneth 
Published: May 2018

AbstractIn gait stability research, neither self-selected walking speeds, nor the same prescribed walking speed for all participants, guarantee equivalent gait stability among participants. Furthermore, these options may differentially affect the response to different gait perturbations, which is problematic when comparing groups with different capacities. We present a method for decreasing inter-individual differences in gait stability by adjusting walking speed to equivalent margins of stability (MoS). Eighteen healthy adults walked on a split-belt treadmill for two-minute bouts at 0.4m/s up to 1.8m/s in 0.2m/s intervals. The stability-normalised walking speed (MoS=0.05m) was calculated using the mean MoS at touchdown of the final 10 steps of each speed. Participants then walked for three minutes at this speed and were subsequently exposed to a treadmill belt acceleration perturbation. A further 12 healthy adults were exposed to the same perturbation while walking at 1.3m/s: the average of the previous group. Large ranges in MoS were observed during the prescribed speeds (6-10cm across speeds) and walking speed significantly (P<0.001) affected MoS. The stability-normalised walking speeds resulted in MoS equal or very close to the desired 0.05m and reduced between-participant variability in MoS. The second group of participants walking at 1.3m/s had greater inter-individual variation in MoS during both unperturbed and perturbed walking compared to 12 sex, height and leg length-matched participants from the stability-normalised walking speed group. The current method decreases inter-individual differences in gait stability which may be beneficial for gait perturbation and stability research, in particular for studies on populations with different locomotor capacities.
Distinct temporal requirements for Sonic hedgehog signaling in development of the tuberal hypothalamus
Authors: Corman Tanya S. , Zevallos Solsire E. , Epstein Douglas J. 
Published: May 2018

ABSTRACTSonic hedgehog (Shh) plays well characterized roles in the development of several regions of the brain and spinal cord, but its functions in the hypothalamus have been more difficult to elucidate due to the complex neuroanatomy of this brain area. Here, we utilize fate-mapping and conditional deletion models in mice to define requirements for dynamic Shh activity at distinct stages of tuberal hypothalamic development, a brain region with important homeostatic functions. At early time points, Shh signaling regulates dorsoventral patterning, neurogenesis, and the size of the ventral midline. Fate mapping experiments demonstrate that Shh expressing and responsive progenitors contribute to distinct neuronal subtypes, accounting for some of the cellular heterogeneity in tuberal hypothalamic nuclei. Conditional deletion of the Hedgehog transducer Smoothened (Smo), after dorsoventral patterning has been established, reveals that Shh signaling is necessary to maintain proliferation and progenitor identity during peak periods of hypothalamic neurogenesis. We also find that mosaic disruption ofSmocauses a non-cell autonomous gain in Shh signaling activity in neighboring wild type cells, suggesting a mechanism for the pathogenesis of hypothalamic hamartomas, a benign tumor that forms during hypothalamic development.SUMMARY STATEMENTRequirements for dynamic Sonic hedgehog activity at distinct stages of tuberal hypothalamic development are defined using fate-mapping and conditional deletion models in mice.
Safety of transcranial focused ultrasound for human neuromodulation
Authors: Legon Wynn , Bansal Priya , Ai Leo , Mueller Jerel K. , Meekins Gregg , Gillick Bernadette 
Published: May 2018

AbstractBackgroundLow intensity transcranial focused ultrasound (tFUS) is a new method of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. tFUS offers high spatial resolution and adjustable focal lengths for precise neuromodulation of discrete regions in the human brain. Before the full potential of low intensity ultrasound for research and clinical application can be investigated, data on the safety of this technique is indicated.Objective/HypothesisTo provide an initial evaluation of the safety of tFUS for human neuromodulation through participant report and neurological assessment surrounding pilot investigation of tFUS for neuromodulation.MethodsParticipants (N = 120) that were enrolled in one of seven human ultrasound neuromodulation studies at the University of Minnesota (2015 – 2017) were queried to complete a follow-up Participant Report of Symptoms questionnaire assessing their self-reported experience and tolerance to participation in tFUS research and the perceived relation of symptoms to tFUS.ResultsA total of 64/120 participant (53%) responded to follow-up requests to complete the Participant Report of Symptoms questionnaire. During the conduct of the seven studies in this report, none of the participants experienced serious adverse effects. From the post-hoc assessment of safety using the questionnaire, 7/64 reported mild to moderate symptoms, that were perceived as ‘possibly’ or ‘probably’ related to participation in tFUS experiments. These reports included neck pain, problems with attention, muscle twitches and anxiety. The most common unrelated symptoms included sleepiness and neck pain. There were initial transient reports of mild neck pain, scalp tingling and headache that were extinguished upon follow-up. No new symptoms were reported upon follow up out to 1 month.Conclusions(s)To date, in the literature and including this report, no serious adverse events have been reported as a result of low intensity tFUS for human neuromodulation. Here, we report new data on minor transient events. As currently employed with the parameters used in the studies in this report, tFUS looks to be a safe form of transient neuromodulation in humans.
Increased DNA methylation variability in rheumatoid arthritis discordant monozygotic twins
Authors: Webster Amy P. , Plant Darren , Ecker Simone , Zufferey Flore , Bell Jordana T. , Feber Andrew , Paul Dirk S. , Beck Stephan , Barton Anne , Williams Frances M.K. , Worthington Jane 
Published: May 2018

ABSTRACTBackgroundRheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease discordant monozygotic twin pairs.MethodsGenome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between RA and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population.ResultsWe have identified a differentially variable DNA methylation signature, that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention.ConclusionsThrough genome-wide analysis of DNA methylation in disease discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.
Uncovering indirect interactions in bipartite ecological networks
Authors: Simmons Benno I. , Cirtwill Alyssa R. , Baker Nick J. , Dicks Lynn V. , Stouffer Daniel B. , Sutherland William J. 
Published: May 2018

AbstractIndirect interactions play an essential role in governing population, community and coevolutionary dynamics across a diverse range of ecological communities. Such communities are widely represented as bipartite networks: graphs depicting interactions between two groups of species, such as plants and pollinators or hosts and parasites. For over thirty years, studies have used indices, such as connectance and species degree, to characterise the structure of these networks and the roles of their constituent species. However, compressing a complex network into a single metric necessarily discards large amounts of information about indirect interactions. Given the large literature demonstrating the importance and ubiquity of indirect effects, many studies of network structure are likely missing a substantial piece of the ecological puzzle. Here we use the emerging concept of bipartite motifs to outline a new framework for bipartite networks that incorporates indirect interactions. While this framework is a significant departure from the current way of thinking about networks, we show that this shift is supported by quantitative analyses of simulated and empirical data. We use simulations to show how consideration of indirect interactions can highlight ecologically important differences missed by the current index paradigm. We extend this finding to empirical plant-pollinator communities, showing how two bee species, with similar direct interactions, differ in how specialised their competitors are. These examples underscore the need for a new paradigm for bipartite ecological networks: one incorporating indirect interactions.
Multisite phosphorylation regulates phenotypic variability in antibiotic tolerance
Authors: Libby Elizabeth A. , Reuveni Shlomi , Dworkin Jonathan 
Published: May 2018

AbstractIsogenic populations of cells exhibit phenotypic variability that has specific physiological consequences. For example, individual bacteria within a population can differ in their sensitivity to an antibiotic, but whether this variability can be regulated or is generally an unavoidable consequence of stochastic fluctuations is unclear. We observed that a bacterial stress response gene, the (p)ppGpp synthetase sasA, exhibits high levels of extrinsic noise in expression, suggestive of a regulatory process. We traced this variability to the convergence of two signaling systems that together control the multisite phosphorylation of a transcription factor, an event largely unexplored in bacteria, This regulatory intersection between a Ser/Thr kinase and a prototypical two component system is crucial for controlling the appearance of outliers, rare cells with unusually high levels of sasA expression. Additionally, by examining the full distributions of gene expression we calculated the contribution of the additional Ser/Thr kinase-dependent phosphorylation in setting the relative abundance of cells with a given a level of SasA. We then created a predictive model for the probability of a given cell surviving antibiotic treatment as a function of sasA expression. Therefore, our data show that multisite phosphorylation can be used to strongly regulate variations in phenotypes across a bacterial population.
Akaike information criteria and predictive geographical accuracy are not related in ecological niche modeling
Authors: Velasco Julián A. , Gonzales-Salazar Constantino 
Published: May 2018

AbstractAimEcological niche modeling (ENM) is an approach used to estimate species‘ presence given its environmental preferences. Model complexity in ENMs has increasingly gained relevance in the last years. In particular, in Maxent algorithm is captured using the Akaike Information Criteria (AIC) based on the number of parameters and likelihoods of continuous raw outputs. However, it is not clear whether best-selected models using AIC are the models with the highest classification rate of correct presences and absences. Here, we test for a link between model complexity and accuracy of geographical predictions of Maxent models.InnovationWe created a set of virtual species and generate true geographical predictions for each one. We build a set of Maxent models using presence data from each virtual species with different regularization and features schemes. We compared AICc values for each model with the scores of standard validation metrics (e.g., Kappa, TSS) and with the number of pixels correctly predicted as presences, absences or both.Main ConclusionsWe found that binary predictions (i.e., presence-absence maps) selected as best models for AIC tend to predict incorrectly sites as presences and absences using independent datasets. We suggest that information criteria as AIC should be avoided when users are interested in binary predictions. Future applications that capture model complexity in ENM applications should be evaluated using standard validation metrics.
Evolution of transmission mode in conditional mutualisms with spatial variation in symbiont quality
Authors: Brown Alexandra , Akçay Erol 
Published: May 2018

AbstractWhile some symbioses are always mutualistic or parasitic, others have costs and benefits that depend on environmental factors. The environmental context may itself vary in space, in some cases causing a symbiont to be a mutualist in one location and a parasite in another. Such spatially conditional mutualisms pose a dilemma for hosts, who might evolve (higher or lower) horizontal or vertical transmission to increase their chances of being infected only where the symbiont is beneficial. To determine how transmission in hosts might evolve, we modeled transmission evolution where the symbiont had a spatially conditional effect on either host lifespan or fecundity. We found that over ecological time, symbionts that affected lifespan but not fecundity led to high frequencies of infected hosts in areas where the symbiont was beneficial and low frequencies elsewhere. In response, hosts evolved increased horizontal transmission only when the symbiont affected lifespan. We also modeled transmission evolution in symbionts, which evolved high horizontal and vertical transmission, indicating a possible host-symbiont conflict over transmission mode. Our results suggest an eco-evolutionary feedback where the component of host fitness that a conditionally mutualistic symbiont influences affects its distribution in the population, and, through this, the transmission mode that evolves.
Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior
Authors: Gokhale Avanti , Freeman Amanda A. H. , Hartwig Cortnie , Bassell Julia L. , Zlatic Stephanie A. , Sapp Christie , Vadlamudi Trishna , Abudulai Farida , Crocker Amanda , Werner Erica , Wen Zhexing , Repetto Gabriela M. , Gogos Joseph A. , Claypool Steven M. , Forsyth Jennifer K. , Bearden Carrie , Gausier Jill , Lewis David A. , Seyfried Nicholas T. , Faundez Victor 
Published: May 2018

AbstractNeurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts and mouse brains carrying a 22q11.2-like defect,Df(16)A+/-. Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of theDrosophilaSLC25A4 orthologue, dSLC25A4-sesB, affected synapse function and impaired sleep patterns in a neuronal-specific manner. These results identify a novel synaptic role of mitochondrial inner membrane solute transporters. We propose that mitochondria are among key organelles affected by genetic defects that increase the risk of neurodevelopmental disorders.
Revisiting public health informatics: patient privacy concerns
Authors: Birnbaum David , Gretsinger Kathryn , Antonio Marcy G. , Loewen Elizabeth , Lacroix Paulette 
Published: May 2018

Purpose
Expanding networks of data portals and repositories linked to electronic patient record systems, along with advances in information technology, have created both new opportunities in improving public health and new challenges in protecting patient privacy. The purpose of this paper is to review stakeholder perspectives and provide a framework for promoting implementation of current privacy protection improvement recommendations.

Design/methodology/approach
This paper summarizes a workshop session discussion stemming from the 2017 Information Technology and Communication in Health (ITCH) biennial international conference in Victoria, British Columbia, Canada. The perspectives within health service research, journalism, informatics and privacy protection were represented.

Findings
Problems underlying gaps in privacy protection in the USA and Canada, along with then-current changes recommended by public health leaders as well as Information and Privacy Commissioners, were identified in a session of the 2015 ITCH conference. During the 2017 conference, a workshop outlined the current situation, identifying ongoing challenges and a lack of significant progress. This paper summarizes that 2017 discussion identifying political climate as the major impediment to progress on this issue. It concludes with a framework to guide the path forward.

Originality/value
This paper provides an international perspective to problems, resources and solution pathways with links useful to readers in all countries.
A novel fuzzy risk matrix based risk assessment approach
Authors: Can Gülin Feryal , Toktas Pelin 
Published: May 2018

Purpose
Traditional risk assessment (RA) methodologies cannot model vagueness in risk and cannot prioritize corrective-preventive measures (CPMs) by considering effectiveness of those on risk types (RTs). These cannot combine and reflect accurately different subjective opinions and cannot be used in a linguistic manner. Risk factors (RFs) are assumed to have the same importance and interrelations between RFs are not considered. This study aims to overcome these disadvantages by combining fuzzy logic with multi-criteria decision-making in a dynamic manner.

Design/methodology/approach
This study proposes a novel three-stage fuzzy risk matrix-based RA integrating fuzzy decision-making trial and evaluation laboratory (F-DEMATEL) and fuzzy multi-attributive border approximation area comparison (F-MABAC). At the first stage, importance weights of RFs are computed by F-DEMATEL. At the second stage, risk degrees of RTs are computed via using fuzzy risk matrix. At the third stage, CPMs are ranked by F-MABAC. Finally, a numerical example for RA in a warehouse is given.

Findings
Results show that developing instructions for material loading or unloading is the most important CPM and severity is the most important RF for the warehouse.

Originality/value
This study has originality in terms of having fuzzy dynamic structure. At first, RFs are assumed to be criteria sets then, RTs are assumed to be criteria set considering their risk degrees to rank CPMs in a fuzzy manner. Risk degrees of RTs are used for weights of RTs and effectiveness of CPMs are used for performance values of CPMs.
A relational perspective on pure project performance
Authors: Chan Jimmy H.T. , Ko Anthony C.K. , Au Alan K.M. , Yeung Matthew C.H. 
Published: May 2018

PurposeThe understanding of leaders’ network centrality in social networks has been acknowledged as a major topic that can advance the social network field; most studies in this area have either taken firms as the subject by which the network centrality of firms was measured or/and have been conducted for the functional project context. Very little research has been done in the pure project context. This paper aims to revisit the centrality–performance link in the singular specialized project context.Design/methodology/approachThe proposed relationships using panel data on 48 movie directors who lead pure projects has been studied. Freeman’s (1979) and Wasserman and Faust’s (1994) procedures have been adopted to compute our three centrality measures and their effects have been examined on box-office and artistic performance. A random effect and a mixed-effects Poisson model have been fit to examine the significance of the centrality–performance relationship.FindingsThe findings provide empirical evidence to support three out of the six hypotheses. The findings suggested that degree and closeness centrality are positively related to commercial performance and betweenness centrality is negatively related to commercial performance. However, it was found that only the degree centrality is related to artistic performance.Originality/valueThis study has two features that distinguish it from prior studies that link centrality to performance. First, the focus is on centrality attached to the leaders instead of the centrality attached to functional project teams or firms, as previously investigated. Second, this study is the first attempt of its kind to analyse the proposed relationship for an Asian market.