bluuebunny/crossref_metadata_2025 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

Genomic 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

Targeted 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

Recombinant 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 Summary

A blood transcriptome signature predicts response to recombinant human growth hormone in both growth hormone deficient and Turner syndrome children

Trial 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

Objective

To determine the impact of a digital sepsis alert on patient outcomes in a UK multi-site hospital network.

Methods

A 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.

Results

The 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).

Discussion

Current 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.

Conclusions

These 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.

Funding

Imperial 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

Animal 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

Non-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

Tuberculosis (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

The 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

Camera 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

Purpose of review

We 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 findings

The 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.

Pregnancy 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

Social 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

The 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

Background

Retention 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.

Methods

We 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.

Results

Of 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).

Conclusion

Initiation 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.
An Empiricist’s Guide to Modern Coexistence Theory for Competitive Communities
Authors: Godwin Casey M. , Chang Feng-Hsun , Cardinale Bradley
Published: May 2019

While most ecological theories have historically invoked niche differences as the primary mechanism allowing species coexistence, we now know that species coexistence in competitive communities actually depends on the balance of two opposing forces: niche differences (ND) that determine how species limit their own growth rate versus that of their competitor, and relative fitness differences (RFD) that establish competitive hierarchies among species. Several different empirical methods have been proposed for measuring ND and RFD in order to make predictions about coexistence of species, yet it remains unclear which method(s) are appropriate for a given empirical study and whether or not those methods actually yield the same information. Here we summarize and compare five different empirical methods, with the aim of providing a practical guide for empiricists who want to predict coexistence among species. These include two phenomenological methods that estimate ND and RFD based on observing competitive interactions among species; two mechanistic methods that estimate ND and RFD based solely on information about species’ resource requirements; and a fifth method that does not yield ND and RFD but describes the impacts of those forces within communities. Based on the specific requirements, limitations, and assumptions of each approach, we offer a series of decision steps that can be used to determine which method(s) are best for a given study system. In particular, we show there are important tradeoffs between mechanistic methods, which require detailed understanding of species niches and physiology but are more tractable experimentally, and phenomenological methods which do not require this detailed information but can be impractical for some study designs. Importantly, we show that although each method can be used to estimate ND and RFD, the methods do not always yield the same values. Therefore we caution against future syntheses that compile these estimates from different empirical studies. Finally, we highlight several areas where modern coexistence theory could benefit from additional empirical work.
Single-Cell, Human Sperm Transcriptomes and Variants from Fathers of Autistic and Healthy Children
Authors: Tomoiaga Delia , Aguiar-Pulido Vanessa , Shrestha Shristi , Feinstein Paul , Levy Shawn E. , Rosenfeld Jeffrey A. , Mason Christopher E.
Published: May 2019

The human sperm is one of the smallest cells in the body, but also one of the most important, as it serves as the entire paternal genetic contribution to a child. This is especially relevant for diseases such as Autism Spectrum Disorders (ASD), which have been correlated with advance paternal age. Historically, most studies of sperm have focused on the assessment of a bulk sperm, wherein millions of individual sperm are present and only high-frequency variants can be detected. Using 10X Chromium single cell sequencing technology, we have assessed the RNA from >65,000 single sperm cells across 6 donors (scsperm-RNA-seq), including two of whom have autistic children and four that do not. Using multiple RNA-seq methods for differential expression and variant analysis, we found clusters of sperm mutations in each donor that are indicative of the sperm being produced by different stem cell pools. Moreover, by comparing the two groups, we have found expression changes that can separate out the two sets of donors. Finally, through our novel variant calling from single-cell RNA-seq methods, we have shown that we can detect mutation rates in sperm from ASD donors that is distinct from the controls, highlighting this method as a new means to characterize ASD risk.
Systematic interrogation of the distinct metabolic potential in gut microbiomes of inflammatory bowel disease patients with dysbiosis
Authors: Heinken Almut , Thiele Ines
Published: May 2019

The human gut microbiome plays an important role in human health. In order to investigate changes in metabolic activity associated with dysbiotic microbiomes, we retrieved strain-level relative abundances from metagenomics data from a cohort of pediatric Crohn’s Disease patients with and without dysbiosis, and healthy control children to construct a personalized microbiome model for each sample using the AGORA resource of genome-scale gut microbial reconstructions. Subsequently, we systematically profiled each individual microbiome by predicting the quantitative biosynthesis potential for all secreted metabolites as well as the strain-level contributions to each metabolite in each individual microbiome. The predicted fecal metabolomes and strain-metabolite contributions of microbiomes from patients with dysbiosis were distinct from healthy controls and patients without dysbiosis. Finally, we validated the predicted amino acid production profiles against fecal metabolomic measurements. Taken together, we presented an efficient, scalable, tractable computational approach to systematically interrogate the metabolic potential of individual microbiomes.
Hermes: an ensemble machine learning architecture for protein secondary structure prediction
Authors: Bliss Larry , Pascoe Ben , Sheppard Samuel K
Published: May 2019

Motivation

Protein structure predictions, that combine theoretical chemistry and bioinformatics, are an increasingly important technique in biotechnology and biomedical research, for example in the design of novel enzymes and drugs. Here, we present a new ensemble bi-layered machine learning architecture, that directly builds on ten existing pipelines providing rapid, high accuracy, 3-State secondary structure prediction of proteins.

Results

After training on 1348 solved protein structures, we evaluated the model with four independent datasets: JPRED4 - compiled by the authors of the successful predictor with the same name, and CASP11, CASP12 & CASP13 - assembled by the Critical Assessment of protein Structure Prediction consortium who run biannual experiments focused on objective testing of predictors. These rigorous, pre-established protocols included 7-fold cross-validation and blind testing. This led to a mean Hermes accuracy of 95.5%, significantly (p<0.05) better than the ten previously published models analysed in this paper. Furthermore, Hermes yielded a reduction in standard deviation, lower boundary outliers, and reduced dependency on solved structures of homologous proteins, as measured by NEFF score. This architecture provides advantages over other pipelines, while remaining accessible to users at any level of bioinformatics experience.

Availability and Implementation

The source code for Hermes is freely available at:https://github.com/HermesPrediction/Hermes. This page also includes the cross-validation with corresponding models, and all training/testing data presented in this study with predictions and accuracy.
Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light
Authors: Lindberg Markus , Boström Martin , Elliott Kerryn , Larsson Erik
Published: May 2019

Mutational signatures can reveal properties of underlying mutational processes and are important when assessing signals of selection in cancer. Here we describe the sequence characteristics of mutations induced by ultraviolet (UV) light, a major mutagen in several human cancers, in terms of extended (longer than trinucleotide) patterns as well as variability of the signature across chromatin states. Promoter regions display a distinct UV signature with reduced TCG>TTG transitions, and genome-wide mapping of UVB-induced DNA photoproducts (pyrimidine dimers) showed that this may be explained by decreased damage formation at hypomethylated promoter CpG sites. Further, an extended signature model encompassing additional information from longer patterns improves modeling of UV mutation rate, which may enhance discrimination between drivers and passenger events. Our study presents a refined picture of the UV signature and underscores that the characteristics of a single mutational process may vary across the genome.
A Hotspot Atop: Rivers of the Guyana Highlands Hold High Diversity of Endemic Pencil Catfish
Authors: Paz Holden J. , Hayes Malorie M. , Stout Carla C. , Werneke David C. , Armbruster Jonathan W.
Published: May 2019

Aim

The Pakaraima Mountains are an ancient mountain range along the borders of Guyana, Brazil, and Venezuela. The high plateau is drained by multiple river systems in all directions. Although hypotheses have been presented for the biogeographic relationships of lowland rivers, the interconnectivity of rivers on the top of the plateau is unknown. With multiple complex rivers in a small, upland area we predicted a high level of endemism for stream fishes and complex biogeographic relationships. We explore this with the incredibly diverse pencil catfish genusTrichomycterus. Only two species are known from the region. In this study, we 1) confirm the discovery of multiple endemicTrichomycterusspecies in the region, 2) determine the phylogenetic placement of our samples to posit biogeographical scenarios, and 3) provide clarification for the identification ofT. guianensisbased on morphology.

Location

Pakaraima Mountains, a part of the Guiana Shield in Guyana, South America

Taxon

Pencil catfish genusTrichomycterus

Methods

Using collections from recent expeditions to the Pakaraima Mountains of Guyana, we amplified three mitochondrial (16S, COI, and cytb) and two nuclear markers (myh6 and RAG2). We constructed individual gene trees as well as a concatenated tree to determine the placement of these taxa within theTrichomycterusof the Trans-andean/Amazonian clade.

Results

Our results identify six unique lineages in the highlands of Guyana. Only two species,Trichomycterus guianensisandT. conradi, were previously known to science.

Main Conclusions

The Pakaraima Mountains of South America are a region of high endemism, as demonstrated here inTrichomycteruscatfishes. We find two species occupying multiple basins, suggesting that Pakaraima streams either maintain or had some degree of recent connectivity. We identify six endemic lineages ofTrichomycterusfrom the highlands of the Pakaraima Mountains. The upper portions of the study rivers have been connected either through surface flow or by stream capture. Both processes have occurred on multiple time scales and are independent of the patterns seen in the lowlands.
Small molecule inhibitors of G9a reactivate the maternal PWS genes in Prader-Willi-Syndrome patient derived neural stem cells and differentiated neurons
Authors: Wu Hao , Ng Carrie , Villegas Vivian , Chamberlain Stormy , Cacace Angela , Wallace Owen
Published: May 2019

Abstract/Summary

Patients with Prader-Willi-Syndrome (PWS) display intellectual impairment, hyperphagia, and various behavioral problems during childhood that converge on a neurologic deficit. The majority of PWS patients have genetic deletions of the paternal 15q11–q13 chromosomal region, with their maternal PWS locus intact but epigenetically silenced by hypermethylation and repressive histone modulation of the PWS imprinting center (PWS-IC). Inhibition of the euchromatin histone methyltransferase G9a by small molecules has been recently reported to reactivate PWS genes in patient fibroblasts and a mouse model. However, it is unknown if inhibition of G9a could have similar effect in human PWS neural cells, the cell types that have direct pathophysiological relevance to PWS. Here, we use neural progenitor cells (NPCs) and cortical excitatory neurons derived from a patient iPSC to model PWS, and quantitatively profile the expression of PWS genes using a NanoString panel. We demonstrated that the methylation of the PWS-IC is stable during neuronal lineage conversion, and that the maternal PWS genes remain silenced in PWS NPCs and neurons. Multiple small molecule inhibitors of G9a activate maternal PWS genes in a dose dependent manner in both NPCs and neurons. In addition, G9a inhibitors induceGNRH1andHTR2C, two neuronal specific genes that contribute to PWS pathology in neurons. Interestingly, distinct from 5-Azacytidine, G9a inhibition does not induce methylation changes of the maternal PWS-IC, indicating that disruption of the histone repressive complex alone is sufficient to drive an open chromatin state at the PWS-IC that leads to partial reactivation of PWS genes.

Highlights

Modeling PWS disease in a dish using patient derived NPCs and neurons

G9a inhibition activates maternal PWS genes in patient-derived neural cells

G9a inhibition activates maternalSNORD116and other PWS genes in patient-derived neurons

Inhibition of G9a induces PWS downstream genesGNRH1andHTR2Cin PWS neurons
Three points of consideration before testing the effect of patch connectivity on local species richness: patch delineation, scaling and variability of metrics
Authors: Laroche Fabien , Balbi Manon , Grébert Théophile , Jabot Franck , Archaux Frédéric
Published: May 2019

Abstract

The Theory of Island Biogeography (TIB) promoted the idea that species richness within sites depends on site connectivity, i.e. its connection with surrounding potential sources of immigrants. TIB has been extended to a wide array of fragmented ecosystems, beyond archipelagoes, surfing on the analogy between habitat patches and islands and on the patch-matrix framework. However, patch connectivity often little contributes to explaining species richness in empirical studies. Before interpreting this trend as questioning the broad applicability of TIB principles, one first needs a clear identification of methods and contexts where strong effects of patch structural connectivity are likely to occur. Here, we use spatially explicit simulations of neutral metacommunities to show that patch connectivity effect on local species richness is maximized under a set of specific conditions: (i) patch delineation should be fine enough to ensure that no dispersal limitation occurs within patches, (ii) patch connectivity indices should be scaled according to target organisms’ dispersal distance and (iii) the habitat amount around sampled sites (within a distance adapted to organisms’ dispersal) should be highly variable. When those three criteria are met, the absence of an effect of connectivity on species richness should be interpreted as contradicting TIB hypotheses
Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability
Authors: Klorig D.C. , Alberto G.E. , Smith T. , Godwin D.W.
Published: May 2019

Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function, and at the extreme, their susceptibility to seizure. We have developed a novel optogenetic intensity response procedure that provides a sensitive, quantitative estimate of network excitability. By combining optogenetic stimulation of the hippocampus with chronic multi-site recordings in peri-hippocampal structures of awake behaving mice, we induced abnormal network-wide epileptiform population discharges (PD) that were nearly indistinguishable from spontaneously occurring interictal spikes. By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. This probability curve was well fit by a Boltzmann function, from which we calculated the intensity that produces a half-maximal probability of discharge (I50). This novel metric, the I50, is correlated with the optogenetic after-discharge threshold (oADT) in the same mice. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced population discharge threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations. The oPDT is a sensitive measure of subconvulsive network excitability, with broad applicability to a number of areas of investigation.

Significance Statement

Network excitability is carefully regulated by homeostatic mechanisms in the brain in order to maintain optimal functional conditions. Abnormal excitability is associated with a number of neurological disorders including epilepsy. Excitability can be measured in single cellsin vitro, but it is difficult to extrapolate from these values to the functional impact on the network as a whole. Epileptiform discharges are network wide events that represent a distinct transition from normal to abnormal functional modes. We developed a new technique that uses light intensity-response curves to precisely determine the threshold for this transition as a surrogate measure of network excitability and seizure susceptibility.
cRacle: R Tools for Estimating Climate from Vegetation
Authors: Harbert Robert S. , Baryiames Alex A.
Published: May 2019

Premise of the study

The Climate Reconstruction Analysis using Coexistence Likelihood Estimation (CRACLE) method for the estimation of climate from vegetation is a robust set of modeling tools for estimating climate and paleoclimate that makes use of large repositories of biodiversity data and open-access R software.

Methods

Here we implement a new R library for the estimation of climate from vegetation. The ‘cRacle’ library implements functions for data access, aggregation, and models to estimate climate from plant community composition. ‘cRacle’ is modular and features many best-practice features.

Results

Performance tests using modern vegetation survey data from North and South America shows that CRACLE outperforms alternative methods. CRACLE estimates of mean annual temperature (MAT) are usually within 1°C of the actual when optimal model parameters are used. Generalized Boosted Regression (GBR) model correction is also shown here to improve on CRACLE models by reducing bias.

Discussion

CRACLE provides accurate estimates of climate from modern plant communities. Non-parametric CRACLE modeling coupled to GBR model correction produces the most accurate results to date. The ‘cRacle’ R library streamlines the estimation of climate from plant community data, and will make this modeling more accessible to a wider range of users.
BERMUDA: A novel deep transfer learning method for single-cell RNA sequencing batch correction reveals hidden high-resolution cellular subtypes
Authors: Wang Tongxin , Johnson Travis S , Shao Wei , Lu Zixiao , Helm Bryan R , Zhang Jie , Huang Kun
Published: May 2019

To fully utilize the power of single-cell RNA sequencing (scRNA-seq) technologies for cell lineation and identifyingbona fidetranscriptional signals, it is necessary to combine data from multiple experiments. We presentBERMUDA(Batch-Effect ReMoval Using Deep Autoencoders) — a novel transfer-learning-based method for batch-effect correction in scRNA-seq data.BERMUDAeffectively combines different batches of scRNA-seq data with vastly different cell population compositions and amplifies biological signals by transferring information among batches. We demonstrate thatBERMUDAoutperforms existing methods for removing batch effects and distinguishing cell types in multiple simulated and real scRNA-seq datasets.
Neuron subtype-specific effector gene expression in the Motor Ganglion of Ciona
Authors: Gibboney Susanne , Kim Kwantae , Johnson Christopher J. , Orvis Jameson , Martínez-Feduchi Paula , Lowe Elijah K. , Sharma Sarthak , Stolfi Alberto
Published: May 2019

The central nervous system of theCionalarva contains only 177 neurons. The precise regulation of neuron subtype-specific morphogenesis and differentiation observed in during the formation of this minimal connectome offers a unique opportunity to dissect gene regulatory networks underlying chordate neurodevelopment. Here we compare the transcriptomes of two very distinct neuron types in the hindbrain/spinal cord homolog ofCiona, the Motor Ganglion (MG): the Descending decussating neuron (ddN, proposed homolog of Mauthner Cells in vertebrates) and the MG Interneuron 2 (MGIN2). Both types are invariantly represented by a single bilaterally symmetric left/right pair of cells in every larva. Supernumerary ddNs and MGIN2s were generated in synchronized embryos and isolated by fluorescence-activated cell sorting for transcriptome profiling. Differential gene expression analysis revealed ddN- and MGIN2-specific enrichment of a wide range of genes, including many encoding potential “effectors” of subtype-specific morphological and functional traits. More specifically, we identified the upregulation of centrosome-associated, microtubule-stabilizing/bundling proteins and extracellular matrix proteins and axon guidance cues as part of a single intrinsic regulatory program that might underlie the unique polarization of the ddNs, the only descending MG neurons that cross the midline.
Composition of estuarine sediment microbiome from a chronosequence of restored urban salt marshes
Authors: Morris Nathan , Alldred Mary , Zarnoch Chester , Alter Elizabeth
Published: May 2019

Salt marshes play an important role in the global nutrient cycle. The sediments in these systems harbor diverse and complex bacterial communities possessing metabolic capacities that provide ecosystem services such as nutrient cycling and removal. On the East Coast of the United States, salt marshes have been experiencing degradation due to anthropogenic stressors. Salt marsh islands within Jamaica Bay, New York City (USA), are surrounded by a large highly urbanized watershed and have declined in area. Restoration efforts have been enacted to reduce further loss, but little is known about how microbial communities develop following restoration activities, or how processes such as nitrogen cycling are impacted. Sediment samples were collected at two sampling depths from five salt marsh islands to characterize the bacterial communities found in marsh sediment including a post-restoration chronosequence of 3-12 years. We used 16s rRNA amplicon sequencing to define alpha and beta diversity, taxonomic composition, and predicted metabolic profile of each sediment sample. We found significant differences in alpha diversity between sampling depths, and significant differences in beta diversity, taxonomic composition, and predicted metabolic capacity among the five sampling locations. The youngest restored site and the degraded natural sampling site exhibited the most distinct communities among the five sites. Our findings suggest that while the salt marsh islands are located in close proximity to each other, they harbor distinct bacterial communities that can be correlated with the post-restoration age, marsh health, and other environmental factors such as availability of organic carbon.

IMPORTANCE

Salt marshes play a critical role in the global nutrient cycle due to sediment bacteria and their metabolic capacities. Many East Coast salt marshes have experienced significant degradation over recent decades, thought largely to be due to anthropogenic stressors such as nitrogen loading, urban development, and sea-level rise. Salt marsh islands in Jamaica Bay (Queens/Brooklyn NY) are exposed to high water column nitrogen due to wastewater effluent. Several receding marsh islands have been subjected to restoration efforts to mitigate this loss. Little is known about the effect marsh restoration has on bacterial communities, their metabolic capacity, or how they develop post-restoration. Here we describe the bacterial communities found in marsh islands including a post-restoration chronosequence of 3-12 years and one degraded marsh island that remains unrestored.