bluuebunny/crossref_metadata_2025_split huggingface dataset:
Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage
Authors: Campbell Callum J. , Venkitaraman Ashok R. , Esposito Alessandro 
Published: October 2018

AbstractDNA damage in proliferating mammalian cells causes death1, senescence2 or continued survival, via checkpoints that monitor damage and regulate cell cycle progression, DNA repair and fate determination3. Cell cycle checkpoints facilitate tumour suppression by preventing the generation of proliferating mutated cells4, particularly by blocking passage of DNA lesions into replication and mitosis5. While checkpoint non-fidelity permits cells to carry genomic aberrations into subsequent cell cycle phases6, its long-term consequences on lineages descendant from damaged cells remains poorly characterised. Devising methods for microscopy-based lineage tracing, we unexpectedly demonstrate that transient DNA damage to single living cells bearing a negligent checkpoint induces heterogenous cell-fate outcomes in their descendant generations removed from the initial insult. After transiently damaged cells undergo an initial arrest, pairs of descendant cells without obvious cell-cycle abnormalities either divide or die in a seemingly stochastic way. Progeny of transiently damaged cells may die generations afterwards, creating considerable variability of lineage fitness that promotes overall persistence in a mutagenic environment. Descendants of damaged cells frequently form micronuclei, activating immunogenic signalling. Our findings reveal previously unrecognized, heterogenous effects of cellular DNA damage that manifest long afterwards in descendant cells. We suggest that these heterogenous descendant cell-fate responses may function physiologically to ensure the elimination and immune clearance of damaged cell lineages, but pathologically, may enable the prolonged survival of cells bearing mutagenic damage.
Scale-invariant geometric data analysis (SIGDA) provides robust, detailed visualizations of human ancestry specific to individuals and populations
Authors: Robinson Max , Zimmer Anat , Farrah Terry , Mauldin Denise E. , Price Nathan D. , Hood Leroy E. , Glusman Gustavo 
Published: October 2018

AbstractScale invariance is a common property of physical laws and a key concept in perspective drawing, which aims to provide a meaningful two-dimensional representation of a more complex, three-dimensional scene. Here we describe Scale Invariant Geometric Data Analysis (SIGDA), a new, general exploratory data analysis (EDA) method based on normalization of data to scale invariance. We discuss similarities and differences between SIGDA and two widely-used EDA methods, Correspondence Analysis (CA) and Principal Components Analysis (PCA). We then illustrate SIGDA’s ability to analyze and visualize population structure relationships within the data that inspired its development: genetic marker data, in which context PCA is considered a standard method. We show that SIGDA provides significant advantages over PCA of the same data, including: (a) robust detection and separation of a larger number of population axes, leading to (b) better separation of annotated populations; (c) separation of an independent allele frequency axis interpretable as a proxy for allele age, (d) visualization of marker flow between populations (populationhistory), and (d) robust detection and visualization of relationships between closely-related individuals and among family groups. Although this illustration focuses on a specific task, SIGDA is a general-purpose EDA method and derives its advantages from its novel approach to fundamental issues in data analysis, rather than clever sampling or other task-specific methodology.One Sentence SummaryWe illustrate the advantages of Scale Invariant Geometric Data Analysis (SIGDA), a new exploratory data analysis method similar to PCA, by applying SIGDA to derive detailed, robust visualizations of the complex history of human population structure from a large sample of single nucleotide variants.
GeneWeld: a method for efficient targeted integration directed by short homology
Authors: Wierson Wesley A. , Welker Jordan M. , Almeida Maira P. , Mann Carla M. , Webster Dennis A. , Torrie Melanie E. , Weiss Trevor J. , Vollbrecht Macy K. , Lan Merrina , McKeighan Kenna C. , Levey Jacklyn , Ming Zhitao , Wehmeier Alec , Mikelson Christopher S. , Haltom Jeffrey A. , Kwan Kristen M. , Chien Chi-Bin , Balciunas Darius , Ekker Stephen C. , Clark Karl J. , Webber Beau R. , Moriarity Branden , Solin Staci L. , Carlson Daniel F. , Dobbs Drena L. , McGrail Maura , Essner Jeffrey J. 
Published: October 2018

AbstractChoices for genome engineering and integration involve high efficiency with little or no target specificity or high specificity with low activity. Here, we describe a targeted integration strategy, called GeneWeld, and a vector series for gene tagging, pGTag (plasmids forGeneTagging), which promote highly efficient and precise targeted integration in zebrafish embryos, pig fibroblasts, and human cells utilizing the CRISPR/Cas9 system. Our work demonstrates thatin vivotargeting of a genomic locus of interest with CRISPR/Cas9 and a donor vector containing as little as 24 to 48 base pairs of homology directs precise and efficient knock-in when the homology arms are exposed with a double strand breakin vivo. Our results suggest that the length of homology is not important in the design of knock-in vectors but rather how the homology is presented to a double strand break in the genome. Given our results targeting multiple loci in different species, we expect the accompanying protocols, vectors, and web interface for homology arm design to help streamline gene targeting and applications in CRISPR and TALEN compatible systems.
Do Cells use Passwords in Cell-State Transitions? Is Cell Signaling sometimes Encrypted?
Authors: Root Alex 
Published: October 2018

AbstractOrganisms must maintain proper regulation including defense and healing. Life-threatening problems may be caused by pathogens or by a multicellular organism’s own cells through cancer or auto-immune disorders. Life evolved solutions to these problems that can be conceptualized through the lens of information security, which is a well-developed field in computer science. Here I argue that taking an information security view of cells is not merely semantics, but useful to explain features of signaling, regulation, and defense. An information security perspective also offers a conduit for cross-fertilization of advanced ideas from computer science, and the potential for biology to inform computer science. First, I consider whether cells use passwords, i.e., initiation sequences that are required for subsequent signals to have effects, by analyzing the concept of pioneer transcription factors in chromatin regulation and cellular reprogramming. Second, I consider whether cells may encrypt signal transduction cascades. Encryption could benefit cells by making it more difficult for pathogens or oncogenes to hijack cell networks. By using numerous molecules cells may gain a security advantage in particular against viruses, whose genome sizes are typically under selection pressure. I provide a simple conceptual argument for how cells may peform encryption through post-translational modifications, complex formation, and chromatin accessibility. I invoke information theory to provide a criterion of an entropy spike to assess whether a signaling cascade has encryption-like features. I discuss how the frequently invoked concept of context-dependency may over-simplify more advanced features of cell signaling networks, such as encryption. Therefore, by considering that biochemical networks may be even more complex than commonly realized we may be better able to understand defenses against pathogens and pathologies.
Application of Long Read Sequencing to Determine Expressed Antigen Diversity inTrypanosoma BruceiInfections
Authors: Jayaraman Siddharth , Harris Claire , Paxton Edith , Donachie Anne-Marie , Vaikkinen Heli , McCulloch Richard , Hall James P. J. , Kenny John , Lenzi Luca , Hertz-Fowler Christiane , Cobbold Christina , Reeve Richard , Michoel Tom , Morrison Liam J. 
Published: October 2018

AbstractAntigenic variation is employed by many pathogens to evade the host immune response, andTrypanosoma bruceihas evolved a complex system to achieve this phenotype, involving sequential use of variant surface glycoprotein (VSG) genes encoded from a large repertoire of ∼2,000 alleles.T. bruceiexpress multiple, sometimes closely related, VSGs in a population at any one time, and the ability to resolve and analyse this diversity has been limited. We applied long read sequencing (PacBio) to VSG amplicons generated from blood extracted from batches of mice sacrificed at time points (days 3, 6, 10 and 12) post-infection with T. brucei TREU927. The data showed that long read sequencing is reliable for resolving allelic differences between VSGs, and demonstrated that there is significant expressed diversity (449 VSGs detected across 20 mice) and across the timeframe of study there was a clear semi-reproducible pattern of expressed diversity (median of 27 VSGs per sample at day 3 post infection (p.i.), 82 VSGs at day 6 p.i., 187 VSGs at day 10 p.i. and 132 VSGs by day 12 p.i.). There was also consistent detection of one VSG dominating expression across replicates at days 3 and 6, and emergence of a second dominant VSG across replicates by day 12. The innovative application of ecological diversity analysis to VSG reads enabled characterisation of hierarchical VSG expression in the dataset, and resulted in a novel method for analysing such patterns of variation. Additionally, the long read approach allowed detection of mosaic VSG expression from very few reads – this was observed as early as day 3, the earliest that such events have been detected. Therefore, our results indicate that long read analysis is a reliable tool for resolving diverse allele expression profiles, and provides novel insights into the complexity and nature of VSG expression in trypanosomes, revealing significantly higher diversity than previously shown and identifying mosaic gene formation unprecedentedly early during the infection process.
Genetic risk for coronary heart disease alters the influence of Alzheimer’s genetic risk on mild cognitive impairment
Authors: Elman Jeremy A. , Panizzon Matthew S. , Logue Mark W. , Gillespie Nathan A. , Neale Michael C. , Reynolds Chandra A. , Gustavson Daniel E. , Andreassen Ole A. , Dale Anders M. , Franz Carol E. , Lyons Michael J. , Kremen William S. 
Published: October 2018

ABSTRACTBACKGROUNDAlzheimer’s disease (AD) is under considerable genetic influence. However, known susceptibility loci only explain a modest proportion of variance in disease outcomes. This small proportion could occur if the etiology of AD is heterogeneous. We previously found that an AD polygenic risk score (PRS) was significantly associated with mild cognitive impairment (MCI), an early stage of AD. Poor cardiovascular health is also associated with increased risk for AD and has been found to interact with AD pathology. Conditions such as coronary artery disease (CAD) are also heritable, and may contribute to heterogeneity if there are interactions of genetic risk for these conditions as there is phenotypically. However, case-control designs based on prevalent cases of a disease with relatively high case-fatality rate such as CAD may be biased toward individuals who have long post-event survival times and may therefore also identify loci with protective effects.METHODSWe compared interactions between an AD-PRS and two CAD-PRSs, one based on a GWAS of incident cases and one on prevalent cases, on MCI status in 1,209 individuals.RESULTSAs expected, the incidence-based CAD-PRS interacts with the AD-PRS to further increase MCI risk. Conversely, higher prevalence-based CAD-PRSs reduced the effect of AD genetic risk on MCI status.CONCLUSIONSThese results demonstrate: i) the utility of including multiple PRSs and their interaction effects; ii) how genetic risk for one disease may modify the impact of genetic risk for another; and iii) the importance of considering ascertainment procedures of GWAS being used for genetic risk prediction.
In silico results of ϰ-Opioid receptor antagonists as ligands for the second bromodomain of the Pleckstrin Homology Domain Interacting Protein
Authors: El Assal Lemmer R. P. 
Published: October 2018

AbstractPleckstrin Homology Domain Interacting Protein (PHIP) is a member of the BRWD1-3 Family (Bromodomain and WD repeat-containing proteins). PHIP (BRWD2, WDR11) contains a WD40 repeat (methyl-lysine binder) and 2 bromodomains (acetyl-lysine binder). It was discovered through interactions with the pleckstrin homology domain of Insulin Receptor Signalling (IRS) proteins and has been shown to mediate transcriptional responses in pancreatic islet cells and postnatal growth. An initial hit for the second bromodomain of PHIP (PHIP(2)) was discovered in 2012, with consecutive research yielding a candidate with a binding affinity of 68μM. PHIP(2) is an atypical category III bromodomain with a threonine (THR1396) where an asparagine residue would usually be. In the standard case, this pocket holds four water molecules, but in the case of PHIP(2), there is room for one extra water molecule - also known as “PHIP water”, able to mediate interaction between THR1396 and the typical water network at the back of the binding pocket. We present first ever results of two ϰ-Opioid receptor (KOR) antagonists with distinct pharmacophores having an estimated binding affinity in the nM to μM range, as well as higher binding affinities for every currently discovered PHIP(2) ligand towards KOR. Finally, we also demonstrate selectivity of LY-255582 and LY-2459989 towards PHIP(2) over other bromodomains.
Gene fitness landscape of group A streptococcus during necrotizing myositis
Authors: Zhu Luchang , Olsen Randall J. , Beres Stephen B. , Eraso Jesus M. , Saavedra Matthew Ojeda , Kubiak Samantha L. , Cantu Concepcion C. , Jenkins Leslie , Charbonneau Amelia R. L. , Waller Andrew S. , Musser James M. 
Published: October 2018

ABSTRACTNecrotizing fasciitis and myositis are devastating infections characterized by high mortality. Group A streptococcus (GAS) is a common cause of these infections, but the molecular pathogenesis is poorly understood. We report a genome-wide analysis using serotype M1 and M28 strains that identified novel GAS genes contributing to necrotizing myositis in nonhuman primates (NHP), a clinically relevant model. Using transposon directed insertion-site sequencing (TraDIS) we identified 126 and 116 GAS genes required for infection by serotype M1 and M28 organisms, respectively. For both M1 and M28 strains, more than 25% of the GAS genes required for necrotizing myositis encode known or putative transporters. Thirteen GAS transporters contributed to both M1 and M28 strain fitness in NHP myositis, including putative importers for amino acids, carbohydrates, and vitamins, and exporters for toxins, quorum sensing peptides, and uncharacterized molecules. Targeted deletion of genes encoding five transporters confirmed that each isogenic mutant strain was significantly impaired in causing necrotizing myositis in NHPs. qRT-PCR analysis showed that these five genes are expressed in infected NHP and human skeletal muscle. Certain substrate-binding lipoproteins of these transporters, such as Spy0271 and Spy1728, were previously documented to be surface-exposed, suggesting that our findings have translational research implications.
A target enrichment bait set for studying relationships among ostariophysan fishes
Authors: Faircloth Brant C. , Alda Fernando , Hoekzema Kendra , Burns Michael D. , Oliveira Claudio , Albert James S. , Melo Bruno F. , Ochoa Luz E. , Roxo Fábio F. , Chakrabarty Prosanta , Sidlauskas Brian L. , Alfaro Michael E. 
Published: October 2018

SummaryTarget enrichment of conserved nuclear loci has helped reconstruct evolutionary relationships among a wide variety of species. While there are preexisting bait sets to enrich a few hundred loci across all fishes or a thousand loci from acanthomorph fishes, no bait set exists to enrich large numbers (>1000 loci) of ultraconserved nuclear loci from ostariophysans, the second largest actinopterygian superorder.In this manuscript, we describe how we designed a bait set to enrich 2,708 ultraconserved nuclear loci from ostariophysan fishes by combining an existing genome assembly with low coverage sequence data collected from two ostariophysan lineages.We perform a series of enrichment experiments using this bait set across the ostariophysan Tree of Life, from the deepest splits among the major groups (>150 MYA) to more recent divergence events that have occured during the last 50 million years.Our results demonstrate that the bait set we designed is useful for addressing phylogenetic questions from the origin of crown ostariophysans to more recent divergence events, and our in silico results suggest that this bait set may be useful for addressing evolutionary questions in closely related groups of fishes, like Clupeiformes.
Reductions in prefrontal activation predict off-topic utterances during speech production
Authors: Hoffman Paul 
Published: October 2018

AbstractThe ability to speak coherently is essential for effective communication but declines with age: older people more frequently produce tangential, off-topic speech. Little is known, however, about the neural systems that support coherence in speech production. Here, fMRI was used to investigate extended speech production in healthy older adults. Computational linguistic analyses were used to quantify the coherence of utterances produced in the scanner, allowing identification of the neural correlates of coherence for the first time. Highly coherent speech production was associated with increased activity in bilateral inferior prefrontal cortex (BA45), an area implicated in selection of task-relevant knowledge from semantic memory, and in bilateral rostrolateral prefrontal cortex (BA10), implicated more generally in planning of complex goal-directed behaviours. These findings demonstrate that neural activity during spontaneous speech production can be predicted from formal analysis of speech content, and that multiple prefrontal systems contribute to coherence in speech.
An anti-Gn glycoprotein antibody from a convalescent patient potently inhibits the infection of severe fever with thrombocytopenia syndrome virus
Authors: Kim Ki Hyun , Kim Jinhee , Ko Meehyun , Chun June Young , Kim Hyori , Kim Seungtaek , Min Ji-Young , Park Wan Beom , Oh Myoung-don , Chung Junho 
Published: October 2018

AbstractSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 reported SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates.Author summarySevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea. This tick-borne virus has infected more than 5,000 humans with a 6.4% to 20.9% fatality rate. Currently, there are no prophylactic or therapeutic measures against this virus. Historically, antibodies from patients who recovered from viral infection have been used to treat new patients. Until now, one recombinant monoclonal antibody was approved for the prophylaxis of respiratory syntial virus infection. We selected 10 antibodies from a patient who recovered from SFTS and found that one antibody potently inhibited SFTS viral infection in both test tube and animal studies. We determined the binding site of this antibody to SFTS virus, which allowed us to predict that this antibody could bind 247 out of 272 SFTS virus isolates reported up to now. We anticipate that this antibody could be developed into a therapeutic measure against SFTS.
Productivity benefits of employer-sponsored training
Authors: Chhetri Prem , Gekara Victor , Manzoni Alex , Montague Alan 
Published: October 2018

Purpose
The purpose of this paper is to examine the impact of employer-sponsored workforce training on employee productivity in the Australian transport and logistics industry. It challenges the quantitative notion of the ratio of input–output per labour hour as the single most important measure of productivity.

Design/methodology/approach
The study utilised a mixed-method approach, involving online and on-site survey questionnaires and on-site semi-structured interviews of employers, employees and students within the industry. Survey questionnaires were administered to Vocational Education and Training (VET) learners to determine the dimensions of productivity gains, while qualitative interviews were conducted specifically to capture employers’ perceptions and expectations of the benefits of training.

Findings
Results show that the relationship between employer-sponsored training and workforce productivity is multi-dimensional where, ideally, all essential dimensions must be fulfilled to effectively achieve sustainable productivity level. One dimension is the quantitative measure of increased performance as an outcome of enhanced knowledge, skills and competencies. Another relates to the increased self-confidence, job satisfaction and pride. The third dimension is the cost savings that come with increasing employees’ overall awareness and appreciation of occupational health and safety. The results show that, aside from the dominant theories on training and labour productivity, the perception of the benefits of training on workplace productivity is not merely limited to the conventional understanding of productivity as a simplistic relationship between resource inputs and tangible outputs.

Practical implications
Firms should consider redefining the benefits of training to include employee well-being and individual contribution to common team and organisational goals. Organisations therefore should broaden the notion of productivity to incorporate intangible benefits.

Originality/value
The use of multi-method approach to investigate the views and perceptions of employees, employers and trainers about the productivity benefits of training and key concerns and challenges for the industry.