bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ancestral Roles of the Fam20C Family of Secreted Protein Kinases Revealed by Functional Analysis inC. elegans
Authors: Gerson-Gurwitz Adina , Worby Carolyn A. , Lee Kian-Yong , Khaliullin Renat , Bouffard Jeff , Cheerambathur Dhanya , Cram Erin J. , Oegema Karen , Dixon Jack E. , Desai Arshad 
Published: July 2018

ABSTRACTFam20C is a secreted protein kinase mutated in Raine syndrome, a human skeletal disorder. In vertebrates, bone and enamel proteins are major Fam20C substrates. However, Fam20 kinases are conserved in invertebrates lacking bone and enamel, suggesting other ancestral functions. We show that FAMK-1, theC. elegansFam20C ortholog, contributes to fertility, embryogenesis, and development. These functions are not fulfilled when FAMK-1 is retained in the early secretory pathway. During embryogenesis, FAMK-1 maintains inter-cellular partitions and prevents multinucleation; notably, temperature elevation or lowering cortical stiffness reduces requirement for FAMK-1 in this context. FAMK-1 is expressed in multiple adult tissues that undergo repeated mechanical strain, and selective expression in the spermatheca restores fertility. Informatic, biochemical and functional analysis implicate lectins as FAMK-1 substrates. These findings suggest that FAMK-1 phosphorylation of substrates, including lectins, in the late secretory pathway is important in embryonic and tissue contexts where cells are subjected to mechanical strain.
Integrated Disease Surveillance and Response (IDSR) in Malawi: Implementation Gaps and Challenges for Timely Alert
Authors: Wu Tsung-Shu Joseph , Kagoli Matthew , Kaasbøll Jens Johan , Bjune Gunnar Aksel 
Published: July 2018

AbstractObjectiveThe emerging and recent 2014 Ebola Virus Disease (EVD) outbreaks rang the bell to call upon efforts from globe to assist resource-constrained countries to strengthen public health surveillance system for early response. Malawi adopted the Integrated Disease Surveillance and Response (IDSR) strategy to develop its national surveillance system since 2002 and revised its guideline to fulfill the International Health Regulation (IHR) requirements in 2014. This study aimed to understand the state of IDSR implementation and differences between guideline and practice for future disease surveillance system strengthening.MethodsThis was a mixed-method observational study. Quantitative data were to analyze completeness and timeliness of surveillance system performance from national District Health Information System 2 (DHIS2). Qualitative data were collected through interviews with 29 frontline health service providers from the selected district and key informants of the IDSR system implementation and administration at district and national levels.FindingsThe current IDSR system showed relatively good completeness (76.4%) but poor timeliness (41.5%) of total expected monthly reports nationwide and zero weekly reports. The challenges of IDSR implementation revealed through qualitative data included lack of supervision, inadequate resources for training and difficulty to implement weekly report due to overwhelming paperwork at frontline health services.ConclusionsThe differences between IDSR technical guideline and actual practice were huge. The developing information technology infrastructure in Malawi and emerging mobile health (mHealth) technology can be opportunities for the country to overcome these challenges and improve surveillance system to have better timeliness for the outbreaks and unusual events detection.
Self-assembling Manifolds in Single-cell RNA Sequencing Data
Authors: Tarashansky Alexander J. , Xue Yuan , Li Pengyang , Quake Stephen R. , Wang Bo 
Published: July 2018

AbstractSingle-cell RNA sequencing has spurred the development of computational methods that enable researchers to classify cell types, delineate developmental trajectories, and measure molecular responses to external perturbations. Many of these technologies rely on their ability to detect genes whose cell-to-cell variations arise from the biological processes of interest rather than transcriptional or technical noise. However, for datasets in which the biologically relevant differences between cells are subtle, identifying these genes is a challenging task. We present the self-assembling manifold (SAM) algorithm, an iterative soft feature selection strategy to quantify gene relevance and improve dimensionality reduction. We demonstrate its advantages over other state-of-the-art methods with experimental validation in identifying novel stem cell populations of Schistosoma, a prevalent parasite that infects hundreds of millions of people. Extending our analysis to a total of 56 datasets, we show that SAM is generalizable and consistently outperforms other methods in a variety of biological and quantitative benchmarks.
Algorithm for Reliable Detection of Beat Onsets in Cerebral Blood Flow Velocity Signals
Authors: Canac Nicolas , Ranjbaran Mina , O’Brien Michael J. , Asgari Shadnaz , Scalzo Fabien , Thorpe Samuel G. , Jalaleddini Kian , Thibeault Corey M. , Wilk Seth J. , Hamilton Robert B. 
Published: July 2018

AbstractTranscranial Doppler (TCD) ultrasound has been demonstrated to be a valuable tool for assessing cerebral hemodynamics via measurement of cerebral blood flow velocity (CBFV), with a number of established clinical indications. However, CBFV waveform analysis depends on reliable pulse onset detection, an inherently difficult task for CBFV signals acquired via TCD. We study the application of a new algorithm for CBFV pulse segmentation, which locates pulse onsets in a sequential manner using a moving difference filter and adaptive thresholding. The test data set used in this study consists of 92,012 annotated CBFV pulses, whose quality is representative of real world data. On this test set, the algorithm achieves a true positive rate of 99.998% (2 false negatives), positive predictive value of 99.998% (2 false positives), and mean temporal offset error of 6.10 ± 4.75 ms. We do note that in this context, the way in which true positives, false positives, and false negatives are defined caries some nuance, so care should be taken when drawing comparisons to other algorithms. Additionally, we find that 97.8% and 99.5% of onsets are detected within 10 ms and 30 ms, respectively, of the true onsets. The algorithm’s performance in spite of the large degree of variation in signal quality and waveform morphology present in the test data suggests that it may serve as a valuable tool for the accurate and reliable identification of CBFV pulse onsets in neurocritical care settings.
Expression reflects population structure
Authors: Brown Brielin C , Bray Nicolas L. , Pachter Lior 
Published: July 2018

AbstractPopulation structure in genotype data has been extensively studied, and is revealed by looking at the principal components of the genotype matrix. However, no similar analysis of population structure in gene expression data has been conducted, in part because a naïve principal components analysis of the gene expression matrix does not cluster by population. We identify a linear projection that reveals population structure in gene expression data. Our approach relies on the coupling of the principal components of genotype to the principal components of gene expression via canonical correlation analysis. Futhermore, we analyze the variance of each gene within the projection matrix to determine which genes significantly influence the projection. We identify thousands of significant genes, and show that a number of the top genes have been implicated in diseases that disproportionately impact African Americans.Author SummaryHigh dimensional, multi-modal genomics datasets are becoming increasingly common, which warrants investigation into analysis techniques that can reveal structure in the data without over-fitting. Here, we show that the coupling of principal component analysis to canonical correlation analysis offers an efficient approach to exploratory analysis of this kind of data. We apply this method to the GEUVADIS dataset of genotype and gene expression values of European and Yoruban individuals, finding as-of-yet unstudied population structure in the gene expression values. Moreover, many of the top genes identified by our method have been previously implicated in diseases that disproportionately impact African Americans.
A common neural substrate for elevated PTSD symptoms and reduced pulse rate variability in combat-exposed veterans
Authors: Grupe Daniel W. , Imhoff-Smith Ted , Wielgosz Joseph , Nitschke Jack B. , Davidson Richard J. 
Published: July 2018

AbstractBackgroundPrevious studies have identified reduced heart rate variability (HRV) in posttraumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research suggests that the ventromedial prefrontal cortex (vmPFC) — a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate — shows functional and structural abnormalities in PTSD. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals.MethodsWe collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male, combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV) – an HRV surrogate calculated from pulse oximetry – was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between vmPFC activation, PRV, and distinct dimensions of PTSD symptomatology.ResultsRe-experiencing PTSD symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Lower HF-PRV was associated with reduced vmPFC activation for the contrast of safety-threat in a region that also showed an inverse relationship with re-experiencing symptoms.ConclusionsReduced vmPFC responses to safety vs. threat were associated with both reduced HF-PRV and increased re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.
Extreme nuclear branching in healthy epidermal cells of theXenopustail fin
Authors: Arbach Hannah E. , Harland-Dunaway Marcus , Chang Jessica K. , Wills Andrea E. 
Published: July 2018

AbstractChanges in nuclear morphology contribute to regulation of complex cell properties, including differentiation and tissue elasticity. Perturbations of nuclear morphology are associated with pathologies that include, progeria, cancer, and muscular dystrophy. The mechanisms governing nuclear shape changes in healthy cells remain poorly understood, partially because there are few healthy models of nuclear shape variation. Here, we introduce nuclear branching in epidermal fin cells ofXenopus tropicalisas a model for extreme variation of nuclear morphology in a diverse population of healthy cells. We find that nuclear branching arises and elaborates during embryonic development. They contain broadly distributed marks of transcriptionally active chromatin and heterochromatin and have active cell cycles. We find that nuclear branches are disrupted by loss of filamentous actin and depend on epidermal expression of the nuclear lamina protein Lamin B1. Inhibition of nuclear branching disrupts fin morphology, suggesting that nuclear branching may be involved in fin development. This study introduces the nuclei of the fin as a powerful new model for extreme nuclear morphology in healthy cells to complement studies of nuclear shape variation in pathological contexts.List of abbreviations and symbolsLINC-Linker of Nucleoskeleton and Cytoskeleton, HGPS – Hutchinson-Gilford Progeria Syndrome, TEM – Transmission electron microscopy, PH3 – Phosphorylated Histone 3, Lat B – Latrunculin B, WT-Wild type, Cyto D-Cytochalasin D,Lmnb1CRISPR –lmnb1mutants generated by CRISPR/Cas9, E-Lmnb1 CRISPR – epidermal specificlmnb1mutants generated by CRISPR/Cas9, Scrmbl-tadpoles injected with a scrambled version of thelmnb1targeted sgRNA, Lmnb1-rod – dominant-negative Lamin B1 containing only the rod domainSummary StatementNuclei are highly branched throughout the heterogeneous population of healthy epidermal cells that comprise theXenopustail fin periphery, and disruption of nuclear branching mechanisms results in improper fin morphology.
Dissociable forms of uncertainty-driven representational change across the human brain
Authors: Nassar Matthew R. , McGuire Joseph T. , Ritz Harrison , Kable Joseph 
Published: July 2018

AbstractEnvironmental change can lead decision makers to shift rapidly among different behavioral regimes. These behavioral shifts can be accompanied by rapid changes in the firing pattern of neural networks. However, it is unknown what the populations of neurons that participate in such “network reset” phenomena are representing. Here we examined 1) whether and where rapid changes in multivariate activity patterns are observable with fMRI during periods of rapid behavioral change, and 2) what types of representations give rise to these phenomena. We did so by examining fluctuations in multi-voxel patterns of BOLD activity from human subjects making sequential inferences about the state of a partially observable and discontinuously changing variable. We found that, within the context of this sequential inference task, the multivariate patterns of activity in a number of cortical regions contain representations that change more rapidly during periods of uncertainty following a change in behavioral context. In motor cortex, this phenomenon was indicative of discontinuous change in behavioral outputs, whereas in visual regions the same basic phenomenon was evoked by tracking of salient environmental changes. In most other cortical regions, including dorsolateral prefrontal and anterior cingulate cortex, the phenomenon was most consistent with directly encoding the degree of uncertainty. However, in a few other regions, including orbitofrontal cortex, the phenomenon was best explained by representations of a shifting context that evolve more rapidly during periods of rapid learning. These representations may provide a dynamic substrate for learning that facilitates rapid disengagement from learned responses during periods of change.
Non-random associations of maternally transmitted symbionts in insects: The roles of drift versus co-transmission and selection
Authors: Hugo Mathé-Hubert , Kaech Heidi , Hertaeg Corinne , Vorburger Christoph 
Published: July 2018

AbstractVirtually all higher organisms form holobionts with associated microbiota. To understand the biology of holobionts we need to know how species assemble and interact. Controlled experiments are suited to study interactions between particular symbionts, but they can only inform about a tiny portion of the diversity within each species. Alternatively, interactions can be inferred from associations among symbionts in the field that are more or less frequent than expected under random assortment. However, random assortment may not be a valid null hypothesis for maternally transmitted symbionts in finite populations, where drift alone can result in associations. Here we report results from a European field survey of endosymbionts in the pea aphid (Acyrthosiphon pisum), and we develop a model to study the effect of drift on symbiont associations under different population sizes, considering varying rates of horizontal and maternal transmission. The model showed that even though horizontal transmissions and maternal transmission failures tend to randomise symbiont associations, drift can induce significant departures from random assortment, at least in moderate-sized populations. Based on these results, we carefully interpret our field survey and we re-visit the association betweenSpiroplasmaandWolbachiainDrosophila neotestaceareported by Jaenikeet al. (2010). For this and for several significant associations between symbionts in European pea aphids we conclude that under reasonable assumptions of effective population size, they are indeed likely to be maintained by biased co-transmission or selection. Our study shows that formulating appropriate null expectations can strengthen the biological inference from co-occurrence patterns in the field.
The PedS2/PedR2 two-component system is crucial for the rare earth element switch in Pseudomonas putida KT2440
Authors: Wehrmann Matthias , Berthelot Charlotte , Billard Patrick , Klebensberger Janosch 
Published: July 2018

ABSTRACTIn Pseudomonas putida KT2440, two pyrroloquinoline quinone-dependent ethanol dehydrogenases (PQQ-EDHs) are responsible for the periplasmic oxidation of a broad variety of volatile organic compounds (VOCs). Depending on the availability of rare earth elements (REEs) of the lanthanide series (Ln3+), we have recently described that the transcription of the genes encoding the Ca2+-utilizing enzyme PedE and the Ln3+-utilizing enzyme PedH are inversely regulated. With adaptive evolution experiments, site-specific mutations, transcriptional reporter fusions, and complementation approaches, we herein demonstrate that the PedS2/PedR2 (PP_2671/PP_2672) two-component system (TCS) plays a central role in the observed REE-mediated switch of PQQ-EDHs in P. putida. We provide evidence that in the absence of lanthanum (La3+), the sensor histidine kinase PedS2 phosphorylates its cognate LuxR-type response regulator PedR2, which in turn not only activates pedE gene transcription but is also involved in repression of pedH. Our data further suggests that the presence of La3+ lowers kinase activity of PedS2, either by the direct binding of the metal ions to the periplasmic region of PedS2 or by an uncharacterized indirect interaction, leading to reduced levels of phosphorylated PedR2. Consequently, the fading pedE expression and concomitant alleviation of pedH repression causes – in conjunction with the transcriptional activation of the pedH gene by a yet unknown regulatory module – the Ln3+-dependent transition from PedE to PedH catalysed oxidation of alcoholic VOCs.IMPORTANCEThe function of lanthanides for methano- and methylotrophic bacteria is gaining increasing attention, while knowledge about the role of rare earth elements (REEs) in non-methylotrophic bacteria is still limited. The present study investigates the recently described differential expression of the two PQQ-EDHs of P. putida in response to lanthanides. We demonstrate that a specific TCS is crucial for their inverse regulation and provide evidence for a dual regulatory function of the LuxR-type response regulator involved. Thus, our study represents the first detailed characterization of the molecular mechanism underlying the REE switch of PQQ-EDHs in a non-methylotrophic bacterium and stimulates subsequent investigations for the identification of additional genes or phenotypic traits that might be co-regulated during REE-dependent niche adaptation.
NHA2 promotes cyst development in an in vitro model of polycystic kidney disease
Authors: Prasad Hari , Dang Donna K. , Kondapalli Kalyan C. , Natarajan Niranjana , Cebotaru Valeriu , Rao Rajini 
Published: July 2018

SummaryAutosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up-regulation of NHA2, a member of the SLC9B family of Na+/H+ exchangers that correlated with cyst size and disease severity in ADPKD patients. Using three-dimensional cultures of MDCK cells to model cystogenesis in vitro, we show that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store-dependent and independent pathways, whereas reciprocal activation of Ca2+ influx by a dominant negative, membrane-anchored C-terminal tail fragment of PC1 elevated NHA2. We show that NHA2 is a target of Ca2+/NFAT signaling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observe robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up-regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for PKD and reveal a potential new regulator of transepithelial salt and water transport in the kidney.
Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
Authors: Earle Ashley J. , Kirby Tyler J. , Fedorchak Gregory R. , Isermann Philipp , Patel Jineet , Iruvanti Sushruta , Moore Steven A. , Bonne Gisèle , Wallrath Lori L. , Lammerding Jan 
Published: July 2018

ABSTRACTMutations in the humanLMNAgene, which encodes the nuclear envelope (NE) proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found thatLmnamutations caused extensive NE abnormalities, consisting of chromatin protrusions into the cytoplasm and transient rupture of the NE in skeletal muscle cells. NE damage was associated with DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, NE damage resulted from nuclear migration in maturing skeletal muscle cells, rather than actomyosin contractility. NE damage and DNA damage was reduced by either depletion of kinesin-1 or disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. LINC complex disruption rescued myofiber function and viability inLmnamutant myofibers, indicating that the myofiber dysfunction is the result of mechanically induced NE damage. The extent of NE damage and DNA damage inLmnamouse models correlated with the disease onset and severityin vivo. Moreover, inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients withLMNAmuscular dystrophy revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor forLMNAskeletal muscle diseases.