bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do available protein 3D structures reflect human genetic and functional diversity?
Authors: Sliwoski Gregory , Patel Neel , Sivley R. Michael , Sanders Charles R. , Meiler Jens , Bush William S. , Capra John A. 
Published: May 2019

ABSTRACTGenomic databases are substantially biased towards European ancestry populations, and this bias contributes to health disparities. Here, we quantify how well 66,971 experimentally characterized human protein 3D structures represent the diversity of protein sequences observed across the 1000 Genomes Project. More than 85% of available structures do not match a sequence observed in at least one individual, and on average structures match the sequence of 74% of individuals. Nearly 23% of human structures do not matchanyobserved sequences; however, after masking engineered/known mutations, this decreases to ~4%. African ancestry sequences are modestly, but significantly, less likely to be represented by structures (73.5% vs. 74.0%). These differences are mainly driven by the greater genetic diversity of African populations. We identify thousands of variants unrepresented in available structures that influence protein structure and function. Thus, the use of a single structure as representative of “the wild type” protein will often bias results against many individuals. The diversity of protein sequence and structure must be considered to enable accurate, reproducible, and generalizable conclusions from structural analyses.
Discovery of compounds inhibiting the ADP-ribosyltransferase activity of pertussis toxin
Authors: Ashok Yashwanth , Miettinen Moona , de Oliveira Danilo Kimio Hirabae , Tamirat Mahlet Z. , Näreoja Katja , Tiwari Avlokita , Hottiger Michael O. , Johnson Mark S. , Lehtiö Lari , Pulliainen Arto T. 
Published: May 2019

ABSTRACTTargeted pathogen-selective approach to antibiotic development holds promise to minimize collateral damage to the beneficial microbiome. The AB5-topology pertussis toxin (PtxS1-S5, 1:1:1:2:1) is a major virulence factor ofBordetella pertussis, the causative agent of the highly contagious respiratory disease whooping cough. Once internalized into the host cell, PtxS1 ADP-ribosylates α-subunits of the heterotrimeric Gαi-superfamily, thereby disrupting G-protein-coupled receptor signaling. Here, we report the discovery of the first small molecules inhibiting the ADP-ribosyltransferase activity of pertussis toxin. We developed protocols to purify mg-levels of truncated but highly active recombinantB. pertussisPtxS1 fromEscherichia coliand anin vitrohigh throughput-compatible assay to quantify NAD+consumption during PtxS1-catalyzed ADP-ribosylation of Gαi. Two inhibitory compounds (NSC228155 and NSC29193) with low micromolar IC50-values (3.0 µM and 6.8 µM) were identified in thein vitroNAD+consumption assay that also were potent in an independentin vitroassay monitoring conjugation of ADP-ribose to Gαi. Docking and molecular dynamics simulations identified plausible binding poses of NSC228155 and in particular of NSC29193, most likely owing to the rigidity of the latter ligand, at the NAD+-binding pocket of PtxS1. NSC228155 inhibited the pertussis AB5holotoxin-catalyzed ADP-ribosylation of Gαi in living human cells with a low micromolar IC50-value (2.4 µM). NSC228155 and NSC29193 might prove useful hit compounds in targetedB. pertussis-selective drug development.
Gene expression signatures predict response to therapy with growth hormone
Authors: Stevens Adam , Murray Philip , De Leonibus Chiara , Garner Terence , Koledova Ekaterina , Ambler Geoffrey , Hou Jia-Woei , Kapelari Klaus , Salles Jean Pierre , Binder Gerhard , Maghnie Mohamad , Zucchini Stefano , Bashnina Elena , Skorodok Julia , Yeste Diego , Belgorosky Alicia , Lopez Siguero Juan-Pedro , Coutant Regis , Vangsøy-Hansen Eirik , Hagenäs Lars , Dahlgren Jovanna , Deal Cheri , Chatelain Pierre , Clayton Peter 
Published: May 2019

AbstractRecombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response can only account for up to 60% of the variance. The aim of this work was to take a novel genomic approach to growth prediction. GHD (n=71) and TS patients (n=43) were recruited in a study on the long term response to r-hGH over five years of therapy. Pharmacogenomic analysis was performed using 1219 genetic markers and baseline blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria required for predictive value. However, we demonstrated that transcriptomic data can be used to predict growth with a high accuracy (AUC > 0.9) for short and long term therapeutic response in GHD and TS. Network models identified an identical core set of genes in both GHD and TS at each year of therapy whose expression can be used to classify therapeutic response to r-hGH. Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. We have characterised the utility of baseline transcriptome for the prediction of growth response including the identification of a set of common genes in GHD and TS. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management.One Sentence SummaryA blood transcriptome signature predicts response to recombinant human growth hormone in both growth hormone deficient and Turner syndrome childrenTrial registration numbers:NCT00256126&NCT00699855
Evaluating a digital sepsis alert in a London multi-site hospital network: a natural experiment using electronic health record data
Authors: Honeyford Kate , Cooke Graham S , Kinderlerer Anne , Williamson Elizabeth , Gilchrist Mark , Holmes Alison ,   The Sepsis Big Room, Glampson Ben , Mulla Abdulbrahim , Costelloe Ceire 
Published: May 2019

ABSTRACTObjectiveTo determine the impact of a digital sepsis alert on patient outcomes in a UK multi-site hospital network.MethodsA natural experiment utlising the phased introduction of a digital sepsis alert into a multi-site hospital network. Sepsis alerts were either visible to clinicans (the ‘intervention’ group) or running silently and not visible (the control group). Inverse probability of treatment weighted multivariable logistic regression was used to estimate the effect of the intervention on patient outcomes.Outcomes: In-hospital 30-day mortality (all inpatients), prolonged hospital stay (≥7 days) and timely antibiotics (≤60 minutes of the alert) for patients who alerted in the Emergency Department.ResultsThe introduction of the alert was associated with lower odds of death (OR:0.76; 95%CI:(0.70, 0.84) n=21,183); lower odds of prolonged hospital stay ≥7 days (OR:0.93; 95%CI:(0.88, 0.99) n=9988); and in patients who required antibiotics, an increased odds of receiving timely antibiotics (OR:1.71; 95%CI:(1.57,1.87) n=4622).DiscussionCurrent evidence that digital sepsis alerts are effective is mixed. In this large UK study a digital sepsis alert has been shown to be associated with improved outcomes, including timely antibiotics, which may suggest a causal pathway. It is not known whether the presence of alerting is responsible for improved outcomes, or whether the alert acted as a useful driver for quality improvement initiatives.ConclusionsThese findings strongly suggest that the the introduction of a network-wide digital sepsis alert is associated with improvements in patient outcomes, demonstrating that digital based interventions can be successfully introduced and readily evaluated.FundingImperial NIHR Biomedical Research Centre: NIHR-BRC-P68711.
Neuron-specific knockouts indicate the importance of network communication to Drosophila rhythmicity
Authors: Schlichting M , Diaz MM , Xin J , Rosbash M 
Published: May 2019

AbstractAnimal circadian rhythms persist in constant darkness and are driven by intracellular transcription-translation feedback loops. Although these cellular oscillators communicate, isolated mammalian cellular clocks continue to tick away in darkness without intercellular communication. To investigate these issues in Drosophila, we assayed behavior as well as molecular rhythms within individual brain clock neurons while blocking communication within the ca. 150 neuron clock network. We also generated CRISPR-mediated neuron-specific circadian clock knockouts. The results point to two key clock neuron groups: loss of the clock within both regions but neither one alone has a strong behavioral phenotype in darkness; communication between these regions also contributes to circadian period determination. Under these dark conditions, the clock within one region persists without network communication. The clock within the famous PDF-expressing s-LNv neurons however was strongly dependent on network communication, likely because clock gene expression within these vulnerable sLNvs depends on neuronal firing or light.
The physiological effects of non-invasive brain stimulation fundamentally differ across the human cortex
Authors: Castrillon Gabriel , Sollmann Nico , Kurcyus Katarzyna , Razi Adeel , Krieg Sandro M. , Riedl Valentin 
Published: May 2019

AbstractNon-invasive brain stimulation reliably modulates brain activity and symptoms of neuropsychiatric disorders. However, stimulation effects substantially vary across individuals and brain regions. We combined transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) to investigate the neuronal basis of inter-individual and inter-areal differences after TMS. We found that stimulating sensory and cognitive areas yielded fundamentally heterogeneous effects. Stimulation of occipital cortex enhanced brain-wide functional connectivity and biophysical modeling identified increased local inhibition and enhanced forward-signaling after TMS. Conversely, frontal stimulation decreased functional connectivity, associated with local disinhibition and disruptions of both feedforward and feedback connections. Finally, we identified brain-wide functional integration as a predictive marker for these heterogeneous stimulation effects in individual subjects. Together, our study suggests that modeling of local and global signaling parameters of a target area will improve the specificity of non-invasive brain stimulation for research and clinical applications.
A model of tuberculosis clustering in low incidence countries reveals more on-going transmission in the United Kingdom than the Netherlands between 2010 and 2015
Authors: Brooks-Pollock Ellen , Danon Leon , Altes Hester Korthals , Davidson Jennifer A. , Pollock Andrew M. T. , van Soolingen Dick , Campbell Colin , Lalor Maeve K. 
Published: May 2019

AbstractTuberculosis (TB) is a major public health threat, including in low TB incidence countries, through a combination of imported infection and onward transmission. Using data from the Enhanced Tuberculosis Surveillance system in the United Kingdom (UK) and the Netherlands (NL) Tuberculosis Register, we developed a mathematical model of TB importation and transmission in low-incidence settings. We apply this method to compare the effective reproduction number for TB, the contribution of importation and the role of superspreaders in the UK and the NL. We estimate that on average, between 2010 and 2015, a TB case generated 0·41(0·30,0·60) secondary cases in the UK, and 0·24(0·14,0·48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 26% (21%,36%) of UK cases and 19%(11%,31%) of NL cases. We predict that reducing UK transmission rates to those observed in NL would result in 538(266,818) fewer cases annually in the UK. This methodology reveals common transmission mechanisms across two low-incidence countries and can be applied to other settings. Control policies aimed at limiting spread have a role to play in eliminating TB in low incidence countries.
An optimized tissue clearing protocol for rat brain labeling, imaging, and high throughput analysis
Authors: Branch Audrey , Tward Daniel , Kolstad Anna C , Pulyadi Vyash , Vogelstein Joshua T , Wu Zhuhao , Gallagher Michela 
Published: May 2019

AbstractThe advent of whole brain clearing and imaging methods extends the breadth and depth at which brain-wide neural populations and structures can be studied. However, these methods have yet to be applied to larger brains, such as the brains of the common laboratory rat, despite the importance of these models in behavioral neuroscience research. Here we introduce AdipoClear+, an optimized immunolabeling and clearing methodology for application to adult rat brain hemispheres, and validate its application through the testing of common antibodies and electrode tract visualization. In order to extend the accessibility of this methodology for general use, we have developed an open source platform for the registration of rat brain volumes to standard brain atlases for high throughput analysis.
FoxMask: a new automated tool for animal detection in camera trap images
Authors: Devost Eric , Lai Sandra , Casajus Nicolas , Berteaux Dominique 
Published: May 2019

SUMMARYCamera traps now represent a reliable, efficient and cost-effective technique to monitor wildlife and collect biological data in the field. However, efficiently extracting information from the massive amount of images generated is often extremely time-consuming and may now represent the most rate-limiting step in camera trap studies.To help overcome this challenge, we developed FoxMask, a new tool performing the automatic detection of animal presence in short sequences of camera trap images. FoxMask uses background estimation and foreground segmentation algorithms to detect the presence of moving objects (most likely, animals) on images.We analyzed a sample dataset from camera traps used to monitor activity on arctic fox Vulpes lagopus dens to test the parameter settings and the performance of the algorithm. The shape and color of arctic foxes, their background at snowmelt and during the summer growing season were highly variable, thus offering challenging testing conditions. We compared the automated animal detection performed by FoxMask to a manual review of the image series.The performance analysis indicated that the proportion of images correctly classified by FoxMask as containing an animal or not was very high (> 90%). FoxMask is thus highly efficient at reducing the workload by eliminating most false triggers (images without an animal). We provide parameter recommendations to facilitate usage and we present the cases where the algorithm performs less efficiently to stimulate further development.FoxMask is an easy-to-use tool freely available to ecologists performing camera trap data extraction. By minimizing analytical time, computer-assisted image analysis will allow collection of increased sample sizes and testing of new biological questions.
Drug safety in pregnancy: review of study approaches required by regulatory agencies
Authors: Margulis Andrea V , Anthony Mary , Rivero-Ferrer Elena 
Published: May 2019

ABSTRACTPurpose of reviewWe reviewed postauthorization pregnancy safety studies requested by regulatory agencies to explore which study approaches have been typically requested and to what extent these have changed over time.Recent findingsThe most common study approach requested by the US Food and Drug Administration (FDA) is pregnancy exposure registries (observational cohorts with prospective data collection), per the FDA’s Postmarketing Requirements and Commitments (PMR/PMC) database. Since 2017, this requirement has often been paired with a request for a database study (observational study using preexisting electronic health care data), both approaches assessing pregnancy and fetal outcomes. From studies registered in the European Union electronic Register of Post-Authorisation Studies, we observed a similar number of pregnancy exposure registries and database studies, both approaches also assessing pregnancy and fetal outcomes. In requests for drugs approved since 2014, preference appears to have shifted toward studies using preexisting electronic health care databases from multiple countries.SummaryPregnancy exposure registries have been the most commonly required study approach on drug safety in pregnancy. Recent regulatory requests and activities denote an increasing interest in other approaches.
Specialized medial prefrontal-amygdala coordination in other-regarding decision preference
Authors: Monte Olga Dal , Chu Cheng-Chi J. , Fagan Nicholas A. , Chang Steve W. C. 
Published: May 2019

AbstractSocial behaviors recruit multiple cognitive processes requiring coordinated interactions among brain regions. Oscillatory coupling provides one mechanism for cortical and subcortical neurons to synchronize their activity. However, it remains unknown how neurons from different nodes in the social brain network interact when making social decisions. We investigated neuronal coupling between the rostral anterior cingulate gyrus of the medial prefrontal cortex and the basolateral amygdala while monkeys expressed context-dependent positive other-regarding preference (ORP) or negative ORP impacting the reward of another monkey. We found an enhanced synchronization between the two nodes for positive ORP, but a suppressed synchronization for negative ORP. These interactions occurred in dedicated frequency channels depending on the area contributing spikes, exhibited a specific directionality of information flow associated with expressing positive ORP, and could be used to decode social decisions. These findings support that specialized coordination in the medial prefrontal-amygdala network underlies social decision preference.
National Wetland Map 5 – An improved spatial extent and representation of inland aquatic and estuarine ecosystems in South Africa
Authors: van Deventer Heidi , van Niekerk Lara , Adams Janine , Dinala Millicent Ketelo , Gangat Ridhwannah , Lamberth Stephen J , Lötter Mervyn , Mbona Namhla , MacKay Fiona , Nel Jeanne L , Ramjukadh Carla-Louise , Skowno Andrew , Weerts Steven P 
Published: May 2019

AbstractThe improved representation of inland aquatic (freshwater) and estuarine ecosystems and associated data was a key component of the 2018 National Biodiversity Assessment, and is an essential step in enhancing defensible land use planning and decision making. This paper reports on this enhancement of the National Wetland Map version 5 (NWM5) for South Africa and other data layers associated with the South African Inventory of Inland Aquatic Ecosystems. Detail is provided on (i) the extent of wetlands mapped in NWM5, compared to previous versions of the NWMs; (ii) the improved extent of inland wetlands mapped in focus areas in NWM5 relative to NWM4; (iii) the type of cover associated with the wetlands (inundated, vegetated or arid); (iv) the ecotone between rivers or inland wetlands and estuaries mapped as freshwater—estuarine transition zones; and (v) level of confidence for the inland wetlands in terms of how well the extent and hydrogeomorphic units were captured for each sub-quaternary catchment of South Africa. A total of 4 698 824 ha (3.9% of South Africa) of inland aquatic ecosystems and artificial wetlands have now been mapped, with NWM5 delineating 123% more inland wetlands (2 635 809 ha or 2.2% of SA) compared with NWM4. The estuarine functional zone, which encapsulates all estuarine processes, associated habitats and biota, was refined for 292 systems totalling 188 944 ha, with the addition of 42 micro-estuaries totalling 246 ha. Nearly 600 000 ha (0.5% of SA) of artificial wetlands were mapped in SA. Inland wetlands are predominantly palustrine (55%), some arid (34%) and few inundated systems (11%). Transition zones between freshwater ecosystems and estuaries formed a small fraction (<1.5%) of river total extent (164 018 km), indicating an ecotone where biota and processes continuously vary from freshwater to estuarine. The majority of inland wetlands (~70%) had a low confidence ranking for designation of extent and typing. Future improvements of the map should be focussed on catchment-based improvements particularly in strategic water-source areas, areas of high development pressure and those with low confidence designation of wetland type.
Starting antiretroviral therapy within seven days of a positive HIV test increased the risk of loss to follow up in a primary healthcare clinic: a retrospective cohort study in Masaka, Uganda
Authors: Kiwanuka Julius , Waila Jacinta Mukulu , Muhindo Kahungu Methuselah , Kitonsa Jonathan , Kiwanuka Noah 
Published: May 2019

AbstractBackgroundRetention of patients initiated on antiretroviral therapy (ART) and good adherence remain cornerstones to long-term viral suppression. In this era of test and treat (T&T), ensuring that patients initiated on ART remain connected to HIV clinics will be key to the achievement of the UNAIDS 90-90-90 targets. Currently, limited studies have evaluated the effect instant ART initiation has on loss to follow up in a typical service healthcare setting. We studied the cumulative incidence, incidence rate of loss to follow up (LTFU), and factors associated with loss to follow up (LTFU) in a primary healthcare clinic that has practiced test and treat since 2012.MethodsWe retrospectively drew routine program data of patients initiated on ART from January 2012 to December 2016. We defined LTFU as failure of a patient to return to the HIV clinic for at least 90 days from the date of their last appointment. We calculated cumulative incidence, incidence rate and fitted a multivariable Cox proportion hazards regression model to determine factors associated with LTFU.ResultsOf the 8,136 patients included in our sample, 3,606 (44.3%) started ART within seven days of HIV diagnosis. Females were 62.3%, median (interquartile range) age at start of ART was 30 (25, 37) years, 50.1% had access to a mobile phone, 54.0% had a baseline CD4 cell count of <350 cells/ml, 14.8% were in either WHO stage 3 or 4 at baseline and 75.9% had a normal body mass index (BMI). There were 1,207 cases of LTFU observed over 15953.0 person years at risk. The overall incidence rate (IR) of LTFU was 7.6 (95% CI=7.2-8.0) per 100 person years of observation (pyo). Cumulative incidence of LTFU increased with duration of follow up from 8.8% (95% CI=8.2-9.4%) and 12.0% (95% CI=11.2-12.7%) at 6 and 12 months, to 17.9% (95% CI=16.9-18.9%) and 20.1% (95% CI=18.9-21.3%) at 36, and 48 months respectively. Predictors of elevated risk of LTFU were; starting ART within 7 days of a positive diagnosis ((aHR) =1.39, 95% CI, 1.13-1.71), lack of access to a telephone set (aHR=1.60, 95% CI, 1.29-1.99) and baseline WHO clinical stage 3 or 4 (aHR =1.53, 95% CI, 1.11-2.11). Factors associated with a reduced risk of LTFU were; baseline age ≥25years, and having a BMI ≥ 30 (aHR =0.28, 95% CI, 0.15-0.51).ConclusionInitiation of ART within 7 days of an HIV diagnosis was associated with an elevated risk of loss to follow up. Steep ART initiation needs to be backed by enhanced adherence and retention counseling to reach the 2020 UNAIDS goals and beyond.