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The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high-throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here, we investigate just how prevalent is the \"few articles - many proteins\" phenomenon. We examine the experimentally validated annotation of proteins provided by several groups in the GO Consortium, and show that the distribution of proteins per published study is exponential, with 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation. Since each of the dominant articles describes the use of an assay that can find only one function or a small group of functions, this leads to substantial biases in what we know about the function of many proteins. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments. Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways. For some organisms, the information provided by different studies overlap by a large amount. We also show that the information provided by high throughput experiments is less specific than those provided by low throughput experiments. Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments.

The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high-throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here, we investigate just how prevalent is the \"few articles - many proteins\" phenomenon. We examine the experimentally validated annotation of proteins provided by several groups in the GO Consortium, and show that the distribution of proteins per published study is exponential, with 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation. Since each of the dominant articles describes the use of an assay that can find only one function or a small group of functions, this leads to substantial biases in what we know about the function of many proteins. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments. Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways. For some organisms, the information provided by different studies overlap by a large amount. We also show that the information provided by high throughput experiments is less specific than those provided by low throughput experiments. Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments.

The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high-throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here we investigate just how prevalent is the \"few articles -- many proteins\" phenomenon. We examine the experimentally validated annotation of proteins provided by several groups in the GO Consortium, and show that the distribution of proteins per published study is exponential, with 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation. Since each of the dominant articles describes the use of an assay that can find only one function or a small group of functions, this leads to substantial biases in what we know about the function of many proteins. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments. Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways. For some organisms, the information provided by different studies overlap by a large amount. We also show that the information provided by high throughput experiments is less specific than those provided by low throughput experiments. Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments.

Motivation: Gene blocks are genes co-located on the chromosome. In many cases, genes blocks are conserved between bacterial species, sometimes as operons, when genes are co-transcribed. The conservation is rarely absolute: gene loss, gain, duplication, block splitting, and block fusion are frequently observed. An open question in bacterial molecular evolution is that of the formation and breakup of gene blocks, for which several models have been proposed. These models, however, are not generally applicable to all types of gene blocks, and consequently cannot be used to broadly compare and study gene block evolution. To address this problem we introduce an event-based method for tracking gene block evolution in bacteria. Results: We show here that the evolution of gene blocks in proteobacteria can be described by a small set of events. Those include the insertion of genes into, or the splitting of genes out of a gene block, gene loss, and gene duplication. We show how the event-based method of gene block evolution allows us to determine the evolutionary rate, and to trace the ancestral states of their formation. We conclude that the event-based method can be used to help us understand the formation of these important bacterial genomic structures. Availability: The software is available under GPLv3 license on http://github.com/reamdc1/gene_block_evolution.git Supplementary online material: http://iddo-friedberg.net/operon-evolution Contact: Iddo Friedberg i.friedberg@miamioh.edu

The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced reward behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction. Al-Hasani, Gowrishankar et al. show that long-range GABAergic projections from the ventral tegmental area to the ventral nucleus accumbens shell inhibit cholinergic activity to promote reward reinforcement.

Background Serum troponin levels correlate with the extent of myocyte necrosis in acute myocardial infarction (AMI) and predict adverse outcomes. However, thresholds of cardiac troponin elevation that could portend to poor outcomes have not been established. Methods In this cohort study, we characterized all cardiac troponin elevations > 0.04 ng/mL (upper limit of normal [ULN]) from patients hospitalized with an ICD-9/10 diagnosis of AMI across our health system from 2012–2019. We grouped events into exponential categories of peak cardiac troponin and evaluated the association of these troponin categories with all-cause mortality, heart transplants, or durable left ventricular assist devices (LVAD). Patients with cardiac troponin > 10,000 × ULN were manually chart reviewed and described. Results There were 18,194 AMI hospitalizations with elevated cardiac troponin. Peak troponin was 1–10 × ULN in 21.1%, 10–100 × ULN in 34.8%, 100–1,000 × ULN in 30.1%, 1,000–10,000 × ULN in 13.1%, and > 10,000 × ULN in 0.9% of patients. One-year mortality was 17–21% across groups, except in > 10,000 × ULN group where it was 33% (adjusted hazard ratio (99%CI) for > 10,000 × ULN group compared to all others: 1.86 (1.21, 2.86)). Hazards of one-year transplant and MCS were also significantly elevated in the > 10,000 × ULN group. Conclusions Elevation in cardiac troponin levels post AMI that are > 10,000 × ULN was rare but identified patients at particularly high risk of adverse events. These patients may benefit from clarification of goals of care and early referral for advanced heart failure therapies. These data have implications for conversion to newer high-sensitivity cardiac troponin assays whose maximum assay limit is often lower than traditional assays.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors ( N =1167) with opioid misusers who never progressed to daily injection ( N =161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P =4.30E-9; odds ratio 0.64 (95% confidence interval 0.55–0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study ( N =312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

The functional role of long-range ventral tegmental area (VTA) to nucleus accumbens (NAc) GABAergic projections in regulating reward reinforcement remains unknown. Using ex vivo and in vivo approaches, including fiber photometry, optogenetics, and electrophysiology, we identify VTA-NAc GABAergic-cholinergic interactions serving a specialized function in modulating reinforced reward behavior through their targeted inhibition of ventral accumbens shell cholinergic interneurons.

PurposeFor more than half of Crohn’s disease patients, strictures will cause bowel obstructions that require surgery within 10 years of their initial diagnosis. This study utilizes computed tomography imaging and clinical data obtained at the initial emergency room visit to create a prediction model for progression to surgery in Crohn’s disease patients with acute small bowel obstructions.MethodsA retrospective chart review was performed for patients who presented to the emergency room with an ICD-10 diagnosis for Crohn’s disease and visit diagnosis of small bowel obstruction. Two expert abdominal radiologists evaluated the CT scans for bowel wall thickness, maximal and minimal luminal diameters, length of diseased segment, passage of oral contrast, evidence of penetrating disease, bowel wall hyperenhancement or stratification, presence of a comb sign, fat hypertrophy, and small bowel feces sign. The primary outcome was progression to surgery within 6 months of presentation. The secondary outcome was time to readmission.ResultsForty patients met the inclusion criteria, with 78% receiving medical treatment alone and 22% undergoing surgery within 6 months of presentation to the emergency room. Multivariable analysis produced a model with an AUC of 92% (95% CI 0.82–1.00), 78% sensitivity, and 97% specificity, using gender, body mass index, and the radiographic features of segment length, penetrating disease, and bowel wall hyperenhancement.ConclusionsThe model demonstrates that routine clinical and radiographic data from an emergency room visit can predict progression to surgery, and has the potential to risk stratify patients, guide management in the acute setting, and predict readmission.