bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine learning of stem cell identities from single-cell expression data via regulatory network archetypes
Authors: Stumpf Patrick S , MacArthur Ben D 
Published: October 2017

AbstractThe molecular regulatory network underlying stem cell pluripotency has been intensively studied, and we now have a reliable ensemble model for the ‘average’ pluripotent cell. However, evidence of significant cell-to-cell variability suggests that the activity of this network varies within individual stem cells, leading to differential processing of environmental signals and variability in cell fates. Here, we adapt a method originally designed for face recognition to infer regulatory network patterns within individual cells from single-cell expression data. Using this method we identify three distinct network configurations in cultured mouse embryonic stem cells – corresponding to naïve and formative pluripotent states and an early primitive endoderm state – and associate these configurations with particular combinations of regulatory network activity archetypes that govern different aspects of the cell’s response to environmental stimuli, cell cycle status and core information processing circuitry. These results show how variability in cell identities arise naturally from alterations in underlying regulatory network dynamics and demonstrate how methods from machine learning may be used to better understand single cell biology, and the collective dynamics of cell communities.
Intrinsic specificity differences between transcription factor paralogs partly explain their differential in vivo binding
Authors: Shen Ning , Zhao Jingkang , Schipper Joshua , Zhang Yuning , Bepler Tristan , Leehr Dan , Bradley John , Horton John , Lapp Hilmar , Gordan Raluca 
Published: October 2017

ABSTRACTMembers of transcription factor (TF) families, i.e. paralogous TFs, are oftentimes reported to have identical DNA-binding motifs, despite the fact that they perform distinct regulatory functions in the cell. Differential genomic targeting by paralogous TFs is generally assumed to be due to interactions with protein cofactors or the chromatin environment. Contrary to previous assumptions, we find that paralogous TFs have different intrinsic preferences for DNA, not captured by current motif models, and these differences partly explain differential genomic binding and functional specificity. Our finding was possible due to a unique combination of carefully designed high-throughput assays and rigorous computation modeling, integrated into a unified framework called iMADS. We used iMADS to quantify, model, and analyze specificity differences between 11 paralogous TFs from 4 distinct human TF families. Our finding of differential specificity between closely related TFs has important implications for the interpretation of the regulatory effects of non-coding genetic variants.
A computational model of MGUS progression to Multiple Myeloma identifies optimum screening strategies and their effects on mortality
Authors: Altrock Philipp M. , Ferlic Jeremy , Galla Tobias , Tomasson Michael H. , Michor Franziska 
Published: October 2017

ABSTRACTRecent advances uncovered therapeutic interventions that might reduce the risk of progression of premalignant diagnoses, such as from Monoclonal Gammopathy of Undetermined Significance (MGUS) to multiple myeloma (MM). It remains unclear how to best screen populations at risk and how to evaluate the ability of these interventions to reduce disease prevalence and mortality at the population level. To address these questions, we developed a computational modeling framework. We used individual-based computational modeling of MGUS incidence and progression across a population of diverse individuals, to determine best screening strategies in terms of screening start, intervals, and risk-group specificity. Inputs were life tables, MGUS incidence and baseline MM survival. We measured MM-specific mortality and MM prevalence following MGUS detection from simulations and mathematical precition modeling. We showed that our framework is applicable to a wide spectrum of screening and intervention scenarios, including variation of the baseline MGUS to MM progression rate and evolving MGUS, in which progression increases over time. Given the currently available progression risk-point estimate of 61% risk, starting screening at age 55 and follow-up screening every 6yrs reduced total MM prevalence by 19%. The same reduction could be achieved with starting age 65 and follow-up every 2yrs. A 40% progression risk reduction per MGUS patient per year would reduce MM-specific mortality by 40%. Generally, age of screening onset and frequency impact disease prevalence, progression risk reduction impacts both prevalence and disease-specific mortality, and screeenign would generally be favorable in high-risk individuals. Screening efforts should focus on specifically identified groups of high lifetime risk of MGUS, for which screening benefits can be significant. Screening low-risk MGUS individuals would require improved preventions.
Continuous Biomarker Assessment by Exhaustive Survival Analysis
Authors: Pearce Dominic A. , Nirmal Ajit J. , Freeman Tom C. , Sims Andrew H. 
Published: October 2017

AbstractPublicly available high-throughput molecular data can enable biomarker identification and evaluation in a meta-analysis. However, a continuous biomarker’s underlying distribution and/or potential confounding factors associated with outcome will inevitably vary between cohorts and is often ignored. ThesurvivALLR package (https://CRAN.R-project.org/package=survivALL) allows researchers to generate visual and numerical comparisons of all possible points-of-separation, enabling quantitative biomarkers to be reliably evaluated within and across datasets, independent of compositional variation. Here, we demonstratesurvivALL’sability to robustly and reproducibly determine an applicable level of gene expression for patient prognostic classification, in datasets of similar and dissimilar compositions. We believesurvivALLrepresents a significant improvement over existing methodologies in stratifying patients and determining quantitative biomarker(s) cut-points for public and novel datasets.
Metabolic Interactions Between Dynamic Bacterial Subpopulations
Authors: Rosenthal Adam Z. , Qi Yutao , Hormoz Sahand , Park Jin , Hsin-Jung Li Sophia , Elowitz Michael 
Published: October 2017

AbstractWithin multi-species microbial communities, individual species are known to occupy distinct metabolic niches. By contrast, it has remained largely unclear whether and how metabolic specialization occurs within clonal bacterial populations. The possibility of such metabolic specialization in clonal populations raises several questions: Does specialization occur, and if it does, which metabolic processes are involved? How is specialization coordinated? How rapidly do cells switch between states? And finally, what functions might metabolic specialization provide? One potential function of metabolic specialization could be to manage overflow metabolites such as acetate, which presents a toxic challenge due to low pH, and protective pH-neutral overflow metabolites. Here we show that exponentially dividing Bacillus subtilis cultures divide into distinct interacting metabolic subpopulations including one population that produces acetate, and another population that differentially expresses metabolic genes for the production of acetoin, a pH-neutral storage molecule. These subpopulations grew at distinct rates, and cells switched dynamically between states, with acetate influencing the relative sizes of the different subpopulations. These results show that clonal populations can use metabolic specialization to control the environment through a process of dynamic, environmentally-sensitive state-switching.
Id proteins suppress E2A-driven innate-like T cell development prior to TCR selection
Authors: Roy Sumedha , Moore Amanda J. , Love Cassandra , Reddy Anupama , Rajagopalan Deepthi , Dave Sandeep S. , Li Leping , Murre Cornelis , Zhuang Yuan 
Published: October 2017

AbstractId proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give rise to these distinct cell fates. Here we report that in the absence of Id2 and Id3 proteins, E2A prematurely activates genes critical for the iNKT cell lineage prior to TCR expression. Enhanced iNKT development in Id3-deficient mice lacking γδ NKT cells suggests that Id3 regulates the lineage competition between these populations. RNA-Seq analysis establishes E2A as the transcriptional regulator of both iNKT and γδNKT development. In the absence of pre-TCR signaling, Id2/Id3 deletion gives rise to a large population of iNKT cells and a unique innate-like DP population, despite the block in conventional αβ T cell development. The transcriptional profile of these unique DP cells reflects enrichment of innate-like signature genes, including PLZF (Zbtb16) and Granzyme A (Gzma). Results from these genetic models and genome-wide analyses suggest that Id proteins suppress E2A-driven innate-like T cell programs prior to TCR selection to enforce predominance of conventional T cells.
Imitation Predicts Social Favor in Adolescent Rhesus Macaques (Macaca mulatta)
Authors: Anderson Jordan , Kinnally Erin L 
Published: October 2017

AbstractObjectivesImitation is a highly conserved component of animal behavior with multifaceted connections to sociality across taxa. One intriguing consequence of imitation in primates is that it promotes positive social feedback from the imitated toward the imitator. This suggests that imitation in primates may facilitate positive social interactions, but few studies have tracked imitation in socially housed primates. Here, we designed a novel ethogram to characterize imitation between conspecifics, to better understand whether imitation is associated with affiliation between primates in a semi-natural setting.Materials and MethodsIn this study, 15 juvenile rhesus macaques (Macaca mulatta) were observed at the California National Primate Research Center. Using focal sampling, frequencies of imitative events (e.g. following, postural mimicry, etc.) by the focal were observed over a course of 12 weeks. In separate observations, focal social behavior (e.g. aggression, play, etc.) was also observed.ResultsSubjects that exhibited higher degrees of imitation were not necessarily more prosocial, but, consistent with our hypothesis, they received significantly more play overtures from social partners (p<.01). In addition, imitation rates generally decrease with age.ConclusionsTogether, these results suggest that imitation is associated with receiving positive social behavior in a complex, semi-natural setting in primates, and that imitation may be more common in adolescence as opposed to adulthood. These preliminary results in a small sample set represent an important step in characterizing imitation in context of social interactions during development. Tracking these behaviors over time will elucidate whether imitation is directly recruiting these positive social interactions, as has been demonstrated in captivity.
HPViewer: Sensitive and specific genotyping of human papillomavirus in metagenomic DNA
Authors: Hao Yuhan , Yang Liying , Neto Antonio Galvao , Amin Milan R. , Kelly Dervla , Brown Stuart M. , Branski Ryan C. , Pei Zhiheng 
Published: October 2017

AbstractBackgroundShotgun DNA sequencing provides sensitive detection of all 182 HPV types in tissue and body fluid. However, existing computational methods either produce false positives misidentifying HPV types due to shared sequences among HPV, human, and prokaryotes, or produce false negative since they identify HPV by assembled contigs requiring large abundant of HPV reads.ResultsWe show that HPV shares extensive simple repeats with human and prokaryotes and homologous sequences among different HPV types. The shared sequences caused errors in HPV genotyping and the repeats of human origin caused false positives in HPVDetector. Programs, such as VirusTAP and Vipie, which require de novo assembly of shotgun reads into contigs, eliminated false positives at a cost of substantial reduction in sensitivity. Here, we designed HPViewer with two custom HPV reference databases masking simple repeats and homology sequences respectively and one homology distance matrix to hybridize these two databases. It directly identified HPV from short DNA reads rather than assembled contigs. Using 100,100 simulated samples, we revealed that HPViewer was robust for samples containing either high or low number of HPV reads. Using 12 shotgun sequencing samples from respiratory papillomatosis, HPViewer was equal to VirusTAP, and Vipie and better than HPVDetector with the respect to specificity and was the most sensitive method in the detection of HPV types 6 and 11. We demonstrated that contigs-based approaches had disadvantages of detection of HPV. In 1,573 sets of metagenomic data from 18 human body sites, HPViewer identified 104 types of HPV in a body-site associated pattern and 89 types of HPV co-occurring in one sample with other types of HPV at least once.ConclusionsWe demonstrated HPViewer was sensitive and specific for HPV detection in metagenomic data. It was also suggested that masking shared sequences is an effective approach to avoid false positive detection and identifying HPV from short metagenomic reads is more sensitive than assembled contigs. The innovative homology distance matrix connecting two HPV databases, repeat-mask and homology-mask, optimized the balance of sensitivity and specificity. HPViewer can be accessed at https://github.com/yuhanH/HPViewer/.
Division-independent differentiation mandates proliferative competition among stem cells
Authors: Reilein Amy , Melamed David , Tavaré Simon , Kalderon Daniel 
Published: October 2017

SUMMARYCancer-initiating gatekeeper mutations that arise in stem cells would be especially potent if they stabilize and expand an affected stem lineage (1, 2). It is therefore important to understand how different stem cell organization strategies promote or prevent variant stem cell amplification in response to different types of mutation, including those that activate stem cell proliferation. Stem cell numbers can be maintained constant while producing differentiated products through individually asymmetric division outcomes or by population asymmetry strategies, in which individual stem cell lineages necessarily compete for niche space. We considered alternative mechanisms underlying population asymmetry and used quantitative modeling to predict starkly different consequences of altering proliferation rate: a variant, faster-proliferating mutant stem cell should compete better only when stem cell division and differentiation are independent processes. For most types of stem cell it has not been possible to ascertain experimentally whether division and differentiation are coupled. However, Drosophila Follicle Stem Cells (FSCs) provided a favorable model system to investigate population asymmetry mechanisms and also for measuring the impact of altered proliferation on competition. We found from detailed cell lineage studies that FSC division and FSC differentiation are not coupled. We also found that FSC representation, reflecting maintenance and amplification, was highly responsive to genetic changes that altered only the rate of FSC proliferation. The FSC paradigm therefore provides definitive experimental evidence for the general principle that relative proliferation rate will always be a major determinant of competition among stem cells specifically when stem cell division and differentiation are independent.SIGNIFICANCEAdult stem cells support tissue maintenance throughout life but they also can be cells of origin for cancer, allowing clonal expansion and long-term maintenance of the first oncogenic mutations. We considered how a mutation that increases the proliferation rate of a stem cell would affect the probability of its competitive survival and amplification for different potential organizations of stem cells. Quantitative modeling showed that the key characteristic predicting the impact of relative proliferation rate on competition is whether differentiation of a stem cell is coupled to its division. We then used Drosophila Follicle Stem Cells to provide definitive experimental evidence for the general prediction that relative proliferation rates dictate stem cell competition specifically for stem cells that exhibit division-independent differentiation.
Synergism between a simple sugar and a small intrinsically disordered protein mitigate the lethal stresses of severe water loss
Authors: Kim Skylar X. , Çamdere Gamze , Hu Xuchen , Koshland Douglas , Tapia Hugo 
Published: October 2017

ABSTRACTAnhydrobiotes are rare microbes, plants and animals that tolerate severe water loss. Understanding the molecular basis for their desiccation tolerance may provide novel insights into stress biology and critical tools for engineering drought-tolerant crops. Using the anhydrobiote, budding yeast, we show that trehalose and Hsp12, a small intrinsically disordered protein (sIDP) of the hydrophilin family, synergize to mitigate completely the inviability caused by the lethal stresses of desiccation. We show that these two molecules help to stabilize the activity and prevent aggregation of model proteins both in vivo and in vitro. We also identify a novel role for Hsp12 as a membrane remodeler, a protective feature not shared by another yeast hydrophilin, suggesting that sIDPs have distinct biological functions.
Improving Access to Psychological Therapies for people with intellectual disabilities – role of a reference group in achieving change
Authors: Dodd Karen , Burke Christine , Gibson Alex , Hines Emma , Howarth Patrick , Jennison Jo , Mackintosh Reiko , Radcliffe Alisdair , Vieira Filipe , Unsworth Gisela 
Published: October 2017

Purpose
The purpose of this paper is to explore the importance of equal access to Improving Access to Psychological Therapies (IAPT) for people with intellectual disabilities.

Design/methodology/approach
The paper identifies barriers to access and shows how a reference group can work to solve the barriers and increase access.

Findings
The paper evaluates the authors’ progress to date and how the authors plan to continue to take the work forward.

Practical implications
The paper highlights some of the factors responsible for the authors’ success and gives information that will be helpful to other areas who are interested in facilitating equal access.

Originality/value
The paper demonstrates how the focus of a reference group can drive improvements across services to improve access for people with intellectual disabilities to IAPT services.
Mixed practices including use of ideas from narrative therapy with a woman with diagnosis of an intellectual disability and personality disorder
Authors: El-Tahir Mohamed Omer , Bayley Amanda 
Published: October 2017

Purpose
The purpose of this paper is to present outcomes of mixed practices including use of ideas from narrative therapy (NT) in a case of mild intellectual disability (ID) and personality disorder. The formulation, therapy adaptation and outcomes are presented.

Design/methodology/approach
The study is a single case report describing patient presentation, assessments, psychological formulation and the mixed interventions approaches used, including ideas from NT. Adaptations to meet the needs of patients with ID were described, and therapy outcome measured using Health of the Nation Outcome scale and Psychiatric Assessment Schedule for Adults with Developmental Disorders was presented.

Findings
The ideas used from NT suggest this is potentially a useful approach in practice for people with intellectual disabilities and personality disorder. However, adaptation is needed for it to be used successfully in practice as a therapeutic intervention.

Research limitations/implications
A single case study has its limitations, and further work on using ideas from NT, its adaptation and use in this population will be needed.

Originality/value
There is no previous case of use of NT among patients with ID and personality disorder.
Management innovation and social innovation: convergences and divergences
Authors: Lopes Daniel Paulino Teixeira , Vieira Naldeir dos Santos , Barbosa Allan Claudius Queiroz , Parente Cristina 
Published: October 2017

PurposeThe purpose of this paper is to discuss recent developments in the fields of management innovation and social innovation, in order to discover any possible convergences and divergences between them.Design/methodology/approachBy examining the state of the art of the literature in both fields of study, this paper proposes a framework of theoretical approaches, conceptual dimensions, goals and objectives, processes, agents, outcomes, methods, and literature gaps.FindingsThere are substantial differences between management and social innovation in terms of theoretical and conceptual foundations. Although both share similarities given the relevance of technology and their focus on social relations, their generation and diffusion processes, among their other characteristics, are distinct.Research limitations/implicationsAs this is a theoretical paper concerning innovations that involve social elements at their core, the challenge is to incorporate technological innovation into the theoretical framework. This would help empirically oriented research on more types of innovation.Practical implicationsThe agenda of practitioners, scholars, government, and civil society should take different types of innovation into account, particularly those that go beyond technology.Originality/valueThis paper contributes to a better understanding of innovations that go beyond technology, by analysing innovations (i.e. management and social innovation) that involve social aspects at their core. Few researchers have analysed these types of innovations jointly.
Geo-fencing to secure airport perimeter against sUAS
Authors: Boselli Chris , Danis Jason , McQueen Sandra , Breger Alex , Jiang Tao , Looze Douglas , Ni Daiheng 
Published: October 2017

Purpose
Small unmanned aircraft systems (sUAS) are becoming increasingly popular among hobbyists, and with this popularity there comes the risk of runway incursion between a commercial aircraft and sUAS around airports. To keep airports safe and secure, the purpose of this paper is to propose a module, called the Airport Secure Perimeter Control System, that can be attached to every hobbyist’s sUAS for the purpose of notification and prevention.

Design/methodology/approach
Upon startup, the module connects to a database containing the central coordinates of every airport in the USA. A five-mile critical radius plus an additional one-mile buffer region is established around each point. The buffer region is created in order to inform the user that he/she is approaching a safe airspace and needs to take corrective action. Once the five-mile zone has been breached, autopilot software takes over the manual controls, and the sUAS is landed in a controlled manner, while the user still has lateral control of the vehicle in order to avoid any potential hazards below it. Then, both operator and airport receive messages about the event.

Findings
To demonstrate the proposed design, a prototype was developed that successfully implemented this system, and was formally tested within a controlled environment.

Originality/value
This solution would drastically reduce the security threat of sUAS breaching the critical regions surrounding airports, and its implementation is relatively simple.