bluuebunny/crossref_metadata_2025 huggingface dataset:
Extending Inherited Metabolic Disorder diagnostics with Biomarker Interaction Visualizations
Authors: Slenter Denise N. , Hemel Irene M.G.M. , Evelo Chris T. , Bierau Jörgen , Willighagen Egon L. , Steinbusch Laura K.M.
Published: February 2022

Background

Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype-phenotype correlation, andde novomutations, complicating diagnosis. Furthermore, products of one metabolic conversion can be the substrate of another pathway obscuring biomarker identification and causing overlapping biomarkers for different disorders. Visualization of the connections between metabolic biomarkers and the enzymes involved might aid in the diagnostic process. The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. This framework was tested on two groups of well-studied and related metabolic pathways (the urea cycle and pyrimidine de-novo synthesis). The lessons learned from our approach will help to scale up the framework and support the diagnosis of other less understood IMDs.

Methods

Our framework integrates literature and expert knowledge into machine-readable pathway models, including relevant urine biomarkers and their interactions. The clinical data of 16 previously diagnosed patients with various pyrimidine and urea cycle disorders were visualized on the top 3 relevant pathways. Two expert laboratory scientists evaluated the resulting visualizations to derive a diagnosis.

Results

The proof-of-concept platform resulted in varying numbers of relevant biomarkers (five to 48), pathways and pathway interactions for each patient. The two experts reached the same conclusions for all samples with our proposed framework as with the current metabolic diagnostic pipeline. For nine patient samples the diagnosis was made without knowledge about clinical symptoms or sex. For the remaining seven cases, four interpretations pointed in the direction of a subset of disorders, while three cases were found to be undiagnosable with the available data. Diagnosing these patients would require additional testing besides biochemical analysis.

Conclusion

The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. Several challenges were identified during the development of this framework, which should be resolved before this approach can be scaled up and implemented to support the diagnosis of other (less understood) IMDs. The framework could be extended with other OMICS data (e.g. genomics, transcriptomics), phenotypic data, as well as linked to other knowledge captured as Linked Open Data.
ORFanID: A Web-Based Search Engine for the Discovery and Identification of Orphan and Taxonomically Restricted Genes
Authors: Gunasekera Richard S. , Raja Komal K. B. , Hewapathirana Suresh , Tundrea Emanuel , Gunasekera Vinodh , Galbadage Thushara , Nelson Paul A.
Published: February 2022

With the numerous genomes sequenced today, it has been revealed that a noteworthy percentage of genes in a given taxon of organisms in the phylogenetic tree of life do not have orthologous sequences in other taxa. These sequences are commonly referred to as orphans or ORFans if found as single occurrences in a single species or as taxonomically restricted genes (TRGs) when found at higher taxonomic levels. Quantitative and collective studies of these genes are necessary for understanding their biological origins. However, the current software for identifying orphan genes is limited in its functionality, database search range, and very complex algorithmically. Thus, researchers studying orphan genes must harvest their data from many disparate sources. ORFanID is a graphical web-based search engine that facilitates the efficient identification of both orphan genes and TRGs at all taxonomic levels, from DNA or amino acid sequences in the NCBI database cluster and other large bioinformatics repositories. The software allows users to identify genes that are unique to any taxonomic rank, from species to domain, using NCBI systematic classifiers. It provides control over NCBI database search parameters, and the results are presented in a spreadsheet as well as a graphical display. The tables in the software are sortable, and results can be filtered using the fuzzy search functionality. The visual presentation can be expanded and collapsed by the taxonomic tree to its various branches. Example results from searches on five species and gene expression data from specific orphan genes are provided in the Supplementary Information. Availability and Implementation: The ORFanID web application and database can be accessed at http://www.orfangenes.com/. The website provides textual and video instructions on how to use the tool. The Source Code for ORFanID is available at https://github.com/orfanid.
Plasma ST6Gal1 is Dispensable for IgG Sialylation
Authors: Oswald Douglas M , Lehoux Sylvain D , Zhou Julie Y , Glendenning Leandre M , Cummings Richard D , Cobb Brian A
Published: February 2022

The glycosylation of IgG has attracted increased attention due to the impact of N-glycan modifications at N297 on IgG function, acting primarily through modulation of Fc domain conformation and Fcγ receptor binding affinities and signaling. However, the mechanisms regulating IgG glycosylation and especially α2,6-sialylation of its N-glycan remain poorly understood. We observed previously that IgG is normally sialylated in mice with B cells lacking the sialyltransferase ST6Gal1. This supported the hypothesis that IgG may be sialylated outside of B cells, perhaps through the action of hepatocyte-released plasma ST6Gal1. Here we demonstrate that this model is incorrect. Animals lacking hepatocyte expressed ST6Gal1 retain normal IgG α2,6-sialylation, despite the lack of detectable ST6Gal1 in plasma. Moreover, we confirmed that B cells were not a redundant source of IgG sialylation. Thus, while α2,6-sialylation is lacking in IgG from mice with germline ablation of ST6Gal1, IgG α2,6-sialylation is normal in mice lacking ST6Gal1 in either hepatocytes or B cells. These results indicate that IgG α2,6-sialylation arises after release from a B cell, but is not dependent on plasma-localized ST6Gal1 activity.
Poor matching of action codes challenges ‘mirroring’ in macaque F5 mirror neurons
Authors: Pomper Joern K. , Shams-Ahmar Mohammad , Wen Shengjun , Bunjes Friedemann , Thier Peter
Published: February 2022

The discharge of F5 mirror neurons of a monkey observing another individual performing an action has been interpreted as a motor representation, stimulated by sensory input, ultimately serving action understanding. This hypothesis requires mirror neurons to exhibit an action tuning that is matched between action observation and execution. However, the evidence for this is insufficient, mainly because previous work has suffered from a limited exploration of action space tuning and an object vs. action vision confound. To overcome these limitations, we conducted an experiment in which identical objects had to be manipulated in three different ways in order to serve distinct action goals. We show that the population of F5 mirror neurons can dissociate the three actions almost perfectly, during both observation and execution. However, the population code for action execution was only poorly matched to the code for observation. Just a few neurons exhibited only matched codes, yet, always confined to short, varying segments of the overall action. These findings challenge the hypothesis that an observer understands the actions of others by the activation of motor representations of the observed actions. Rather they support the alternative notion that F5 might use information on observed actions to select behavioral responses.
Artificial soils reveal individual factor controls on microbial processes
Authors: Valle Ilenne Del , Gao Xiaodong , Ghezzehei Teamrat A. , Silberg Jonathan J. , Masiello Caroline A.
Published: February 2022

Soil matrix properties influence microbial behaviors that underlie nutrient cycling, greenhouse gas production, and soil formation. However, the dynamic and heterogeneous nature of soils makes it challenging to untangle the effects of different matrix properties on microbial behaviors. To address this challenge, we developed a tunable artificial soil recipe and used these materials to study the abiotic mechanisms driving soil microbial growth and communication. When we used standardized matrices with varying textures to culture gas-reporting biosensors, we found that Gram-negative bacteria grew best in synthetic silt soils, remaining active over a wide range of soil matric potentials, while Gram-positive bacteria preferred sandy soils, sporulating at a low water potentials. Soil texture, mineralogy, and alkalinity all attenuated the bioavailability of an acyl-homoserine lactone (AHL) signaling molecule that controls community-level microbial behaviors. Texture controlled the timing of AHL sensing, while AHL bioavailability was decreased ∼105-fold by mineralogy and ∼103-fold by alkalinity. Finally, we built artificial soils with a range of complexities that converge on the properties of one Mollisol. As artificial soil complexity increased to more closely resemble the Mollisol, microbial behaviors approached those occurring in the natural soil, with the notable exception of organic matter. Properties that behaved additively were soil texture, pH, and mineralogy, while organic matter did not, suggesting that its soil behavior is an emergent property.

IMPORTANCE

Understanding environmental controls on soil microbes is difficult because many abiotic parameters vary simultaneously and uncontrollably when different natural soils are compared, preventing mechanistic determination of any individual soil parameter’s effect on microbial behaviors. We describe how soil texture, mineralogy, pH, and organic matter content can be varied individually within artificial soils to study their effects on soil microbes. Using microbial biosensors that report by producing a rare indicator gas, we identify soil properties that control microbial growth and attenuate the bioavailability of a diffusible chemical used to control community-level behaviors. We find that artificial soils differentially affect signal bioavailability and the growth of Gram-negative and Gram-positive microbes. We show that some soil properties have additive effects on signal bioavailability, while others exhibit emergent properties. These artificial soils are useful for studying the mechanisms that underlie soil controls on microbial fitness, signaling, and gene transfer.
Accurate and robust inference of genetic ancestry from cancer-derived molecular data across genomic platforms
Authors: Belleau Pascal , Deschênes Astrid , Tuveson David A. , Krasnitz Alexander
Published: February 2022

Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust genetic ancestry inference from existing cancer-derived data, including whole exomes, transcriptomes and targeted gene panels, very often in the absence of matching cancer-free genomic data. Here we examine the feasibility and accuracy of such computation. In order to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile, we have developed a data synthesis framework. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. Data synthesis is applicable to multiple profiling platforms and makes it possible to assess the performance of inference specifically for a given molecular profile, and separately for each continental-level ancestry. This ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. We further show that our inference procedure is accurate and robust in a wide range of sequencing depths. Testing our approach for three representative cancer types, and across three molecular profiling modalities, we demonstrate that global, continental-level ancestry of the patient can be inferred with high accuracy, as quantified by its agreement with the golden standard of the ancestry derived from matching cancer-free molecular data. Our study demonstrates that vast amounts of existing cancer-derived molecular data potentially are amenable to ancestry-oriented studies of the disease, without recourse to matching cancer-free genomes or patients’ self-identification by ancestry.
Why Are Alzheimer’s Disease Patients Unaware of their Memory Deficits?
Authors: Razafimahatratra Solofo , Guieysse Thomas , Lejeune François-Xavier , Houot Marion , Medani Takfarinas , Dreyfus Gérard , Klarsfeld André , Villain Nicolas , Pereira Filipa Raposo , La Corte Valentina , George Nathalie , Pantazis Dimitrios , Andrade Katia
Published: February 2022

Anosognosia, or the lack of awareness of one’s own impairment, is frequent for memory deficits in patients with Alzheimer’s disease (AD). Although often related to frontal dysfunctions, the neural mechanisms of anosognosia remain largely unknown. We hypothesized that anosognosia in AD may result from a failure in the error-monitoring system, thus preventing patients from being aware of and learning from their own errors. We therefore investigated the event-related potentials evoked by erroneous responses during a memory task in two groups of amyloid positive individuals who had only subjective memory complaints at study entry: 1) those who progressed to AD; and 2) those who remained cognitively normal after five years of follow-up. Our findings revealed direct evidence of a failure in the error-monitoring system at early stages of AD, suggesting that it may be the critical neural substrate of anosognosia in this neurodegenerative disorder.
Using a Computational Cognitive Model to Simulate the Effects of Personal and Social Network Experiences on Seasonal Influenza Vaccination Decisions
Authors: Walsh Matthew M. , Parker Andrew M. , Vardavas Raffaele , Nowak Sarah A. , Kennedy David P. , Gidengil Courtney A.
Published: February 2022

The substantial societal costs of seasonal influenza include illness, loss of lives, and loss of work productivity. Vaccination is the most effective means for averting the disease, yet fewer than half of adults in the United States are vaccinated annually. In this research, we focus on how personal experience and the experiences of close social contacts contribute to vaccination decisions. The results of a multi-year longitudinal survey study revealed the significant effects of personal and social network experiences on vaccination. We develop a memory-based model of vaccination decisions using the Adaptive Control of Thought – Rational (ACT-R) integrated cognitive architecture. The model accounts for the effects of personal and social experience on vaccination, and suggests interventions that may be effective in increasing vaccination uptake.
Inference of causal relationships based on the genetics of cardiometabolic traits and conditions unique to females in >50,000 participants
Authors: Xiao Brenda , Velez Edwards Digna R. , Lucas Anastasia , Drivas Theodore , Gray Kathryn , Keating Brendan , Weng Chunhua , Jarvik Gail P. , Hakonarson Hakon , Kottyan Leah , Elhadad Noemie ,   Regeneron Genetics Center, Wei Wei-Qi , Luo Yuan , Kim Dokyoon , Ritchie Marylyn , Verma Shefali Setia
Published: February 2022

Background

Cardiometabolic diseases are highly comorbid and associated with poor health outcomes. However, the investigation of the relationship between the genetic predisposition to cardiometabolic diseases with the risk of conditions unique to females such as breast cancer, endometriosis and pregnancy-related complications is highly understudied. This study aimed to estimate the cross-trait genetic overlap and influence of genetic burden of cardiometabolic traits on health conditions unique to females.

Methods

We obtained data for female participants in the Penn Medicine BioBank (PMBB; 21,837 samples) and the electronic MEdical Records and GEnomics (eMERGE; 49,171 samples) network. We examined the relationship between four cardiometabolic phenotypes (body mass index (BMI), coronary artery disease (CAD), type 2 diabetes (T2D) and hypertension (through blood pressure measurements)) and 23 female health conditions by performing four analyses: 1) Cross-trait genetic correlation analyses to compare genetic architecture. 2) Polygenic risk scores (PRS)-based association tests to characterize shared genetic effects on disease risk. 3) Mendelian randomization (MR) for significant associations to assess cross-trait causal relationships. 4) Chronology analyses to visualize the timeline of events unique to groups of females with high and low genetic burden for cardiometabolic traits and highlight the disease prevalence in risk groups by age.

Results

We observed high genetic correlation among cardiometabolic and female health conditions. PRS meta-analysis identified 29 significant associations reflecting potential shared biology among common cardiometabolic phenotypes and female health conditions. Significant associations include PRSBMIwith endometrial cancer and polycystic ovarian syndrome (PCOS), PRSCADwith breast cancer, and the PRST2Dwith gestational diabetes and PCOS. Mendelian randomization provided additional evidence of independent causal effects between T2D and gestational diabetes and CAD and with breast cancer. Our results reflected inverse association between PRSCADand breast cancer. Lastly, as visualized from chronology analyses, individuals with high PRS are also more likely to develop conditions such as PCOS and gestational hypertension at earlier ages.

Conclusions

Polygenic susceptibility to cardiometabolic traits is associated with conditions unique to females. Several of these associations are likely to result from the complex pathophysiology of cardiometabolic risk, and others may reflect potential pleiotropic effects that go beyond cardiometabolic health in females.
Alpha globin gene copy number and hypertension risk among Black Americans
Authors: Ruhl A. Parker , Jeffries Neal , Yang Yu , Gutierrez Orlando M. , Muntner Paul , Naik Rakhi P. , Pecker Lydia H. , Mott Bryan T. , Zakai Neil A. , Safford Monika M. , Lange Leslie A. , Winkler Cheryl A. , Irvin Marguerite R. , Cushman Mary , Ackerman Hans C.
Published: February 2022

BACKGROUND

Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension.

METHODS

Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression.

RESULTS

Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07).

CONCLUSIONS

There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that variation in alpha globin gene copy number does not modify the risk of hypertension among Black American adults.
Severe hospital events following symptomatic infection with Sars-CoV-2 Omicron and Delta variants in France, December 2021 – January 2022: a retrospective, population-based, matched cohort study
Authors: Auvigne Vincent , Vaux Sophie , Le Strat Yann , Schaeffer Justine , Fournier Lucie , Tamandjou Cynthia , Montagnat Charline , Coignard Bruno , Levy-Bruhl Daniel , du Châtelet Isabelle Parent
Published: February 2022

Background

A rapid increase in incidence of the SARS-CoV-2 Omicron variant occurred in France in December 2021, while the Delta variant was prevailing since July 2021. We aimed to determine whether the risk of a severe hospital event following symptomatic SARS-CoV-2 infection differs for Omicron versus Delta.

Methods

We conducted a retrospective cohort study to compare severe hospital events (admission to intensive care unit or death) between Omicron and Delta symptomatic cases matched according to week of virological diagnosis and age. The analysis was adjusted for age, sex, vaccination status, presence of comorbidities and region of residence, using Cox proportional hazards model.

Findings

Between 06/12/2021-28/01/2022, 184 364 cases were included, of which 931 had a severe hospital event (822 Delta, 109 Omicron). The risk of severe event was lower among Omicron versus Delta cases; the difference in severity between the two variants decreased with age (aHR=0·11 95%CI: 0·07-0·17 among 40-64 years, aHR=0·51 95%CI: 0·26-1·01 among 80+ years). The risk of severe event increased with the presence of comorbidities (for very-high-risk comorbidity, aHR=4·18 95%CI: 2·88-6·06 among 40-64 years) and in males (aHR=2·29 95%CI: 1·83-2·86 among 40-64 years) and was higher in unvaccinated compared to primo-vaccinated (aHR=6·90 95%CI: 5·26-9·05 among 40-64 years). A booster dose reduced the risk of severe hospital event in 80+ years infected with Omicron (aHR=0·27; 95%CI: 0·11-0·65).

Interpretation

This study confirms the lower severity of Omicron compared to Delta. However, the difference in disease severity is less marked in the elderly.
MatchMiner: An open source platform for cancer precision medicine
Authors: Klein Harry , Mazor Tali , Siegel Ethan , Trukhanov Pavel , Ovalle Andrea , Vecchio Fitz Catherine Del , Zwiesler Zachary , Kumari Priti , Van Der Veen Bernd , Marriott Eric , Yu Joyce , Albayrak Adem , Barry Susan , Keller Rachel B. , MacConaill Laura E. , Lindeman Neal , Johnson Bruce E. , Rollins Barrett J. , Do Khanh T. , Beardslee Brian , Shapiro Geoffrey , Hector-Barry Suzanne , Methot John , Sholl Lynette , Lindsay James , Hassett Michael J. , Cerami Ethan
Published: February 2022

The systematic deployment of next generation sequencing means patient tumors can be genomically profiled and specific genetic alterations can be targeted with precision medicine (PM) drugs. More therapeutic clinical trials are needed to test new PM drugs to advance precision medicine, however, the availability of comprehensive patient sequencing data coupled with complex clinical trial eligibility has made it challenging to match patients to PM trials. To facilitate enrollment onto PM trials, we developed MatchMiner. MatchMiner is an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner’s capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. MatchMiner’s two primary goals are to (1) facilitate PM trial options for all patients, and (2) accelerate trial enrollment onto PM trials. MatchMiner has 3 main modes of use: (1) patient-centric, where a clinician looks up trial options for an individual patient, (2) trial-centric, where a trial team identifies candidate patients for their trial by setting up a filter, and (3) trial search, where a clinician can find trial options for patients that have external genomic reports. From the time MatchMiner was first deployed at DFCI in March 2016 through March 2021, we curated 354 PM trials containing a broad range of genomic and clinical eligibility criteria and MatchMiner facilitated 166 trial consents (MatchMiner consents, MMC) for 159 patients. To quantify MatchMiner’s impact on trial consent, we retrospectively measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment decision making process.
Integrating Human Brain Proteomic Data with Genome-Wide Association Study Findings Identifies Novel Brain Proteins in Substance Use Traits
Authors: Toikumo Sylvanus I , Xu Heng , Kember Rachel L , Kranzler Henry R
Published: February 2022

Background: Despite the growing number of genetic risk loci identified for substance use traits (SUTs), the impact of these loci on protein abundance and their potential as therapeutic targets are unknown. Methods: To address this, we performed a proteome-wide association study (PWAS) by integrating human brain proteomes from discovery (Banner; N = 152) and validation (ROSMAP; N = 376) datasets with genome-wide association study (GWAS) summary statistics for 4 SUTs. The sample comprised 4 GWAS of European-ancestry individuals for smoking initiation [Smk] (N = 1,232,091), alcohol use disorder [AUD] (N = 313,959), cannabis use disorder [CUD] (N = 384,032), and opioid use disorder [OUD] (N = 302,585). We conducted transcriptome-wide association studies (TWAS) with human brain transcriptomic data to examine the overlap of genetic effects at the proteomic and transcriptomic levels and tested significant genes for causality through Colocalization analysis. Results: Twenty-seven genes (Smk=21, AUD=3, CUD=2, OUD=1) were significantly associated with cis-regulated brain protein abundance. There was evidence for causality in 6 genes (Smk: NT5C2, GMPPB, NQO1, SRR, and ACTR1B; AUD: CTNND1), which act by regulating brain protein abundance. Cis-regulated transcript levels for 8 genes (Smk=6, CUD=1, OUD=1) were associated with SUTs, indicating that genetic loci could confer risk for these SUTs by modulating both gene expression and proteomic abundance. Conclusions: Functional studies of the high-confidence risk proteins (SRR for Smk and CTNND1 for AUD) identified here are needed to determine whether they are modifiable targets and useful in developing medications and biomarkers for these SUTs.
Reduction in postoperative opioid requirement associated with use of the NSS-2® Bridge device, a disposable auriculo-nerve field stimulator, and factors affecting the response in cancer patients undergoing abdominal surgical procedures
Authors: Chelly Jacques E. , Holtzman Matthew P. , Bartlett David L. , Choudry Haroon A. , Pingpank James F. , Zureikat Amer H. , Norton Brittany E. , Sadhasivam Senthilkumar K. , Vogt Keith M.
Published: February 2022

Objective

Determine the effect on opioid use after surgery with use of the NSS-2® Bridge device (NBD®) as a field nerve stimulator of the nerves innervating the ear for 5 days.

Methods

This was a prospective, randomized, double-blind, placebo-controlled trial investigating the effectiveness of the NBD® in reducing opioid (expressed as oral morphine equivalent; OME, mg) requirement in subjects undergoing abdominal surgery for cancer. A total of 53 subjects randomly assigned to either an active NBD® group or placebo group were included in the analysis. Secondary endpoints included pain using a verbal analogue scale (VAS, 0 = no pain to 10 = worst possible pain), time to ambulation, oral intake, first bowel movement, discharge from the hospital, and tolerability of the NBD®. Lastly, functional recovery rated using the 12-item Short Form Survey (SF12) assessed at three months.

Results

Use of the NBD® resulted in a 26% overall reduction in OME with no difference in pain level expressed as the area under the curve between postoperative day 1 to 5. respectively). This overall reduction accounts for a 6% reduction in OME in the patients undergoing laparoscopic surgery and a 39% reduction in OME and 25% reduction in pain in patients undergoing open surgery. The tolerability of the device was reported as excellent.

Conclusions

Cancer patients have been identified as a population at risk of developing opioid use disorders. This prospective, randomized, double-blind, placebo-controlled study, demonstrated that NBD® may be an effective alternative to the use of opioid postoperatively in patients undergoing abdominal surgery for cancer, especially in especially in patients undergoing open surgery and in elderly.
Developing and validating a multivariable prediction model for predicting costs of colon surgery
Authors: Taha Anas , Taha-Mehlitz Stephanie , Ochs Vincent , Enodien Bassey , Honaker Michael Drew , Frey Daniel M. , Cattin Philippe C.
Published: February 2022

Hospitals are burdened with predicting, calculating and managing various cost-affecting parameters regarding patients and their treatments. Accuracy in cost prediction is further affected if a patient suffers from other health issues which hinder the traditional prognosis. This can lead to an unavoidable deficit in the final revenue of medical centers. This study aims to determine whether machine learning (ML) algorithms can predict cost factors based on patients undergoing colon surgery. For the forecasting, multiple predictors will be taken into the model to provide a tool that can be helpful for hospitals to manage their costs which ultimately will lead to operating more cost-efficiently.. This proof of principle will lay the groundwork for an efficient ML-based prediction tool based on multicenter data from a range of international centers in the subsequent phases of the study. With a % MAPE result of 18 – 25.6, our model’s prediction showed decent results to forecast the costs regarding various diagnosed factors and surgical approaches. There is an urgent need for further studies on predicting cost factors, especially for cases with anastomotic leakage, to minimize unnecessary costs for hospitals.
Macrophages and glia are the dominant P2X7-expressing cell types in the gut nervous system – no evidence for a role of neuronal P2X7 receptors in colitis
Authors: Jooss Tina , Zhang Jiong , Rezzonico-Jost Tanja , Rissiek Björn , Koch-Nolte Friedrich , Magnus Tim , Zierler Susanna , Schemann Michael , Grassi Fabio , Nicke Annette
Published: February 2022

Blockade or deletion of the pro-inflammatory P2X7 receptor channel has been shown to reduce tissue damage and symptoms in models of inflammatory bowel disease (IBD) and P2X7 receptors on enteric neurons were suggested to mediate neuronal death and associated motility changes. Here we used P2X7-specific antibodies and nanobodies as well as a BAC transgenic P2X7-EGFP reporter mouse model and P2rx7−/− controls to perform a detailed analysis of cell type-specific P2X7 expression and possible overexpression effects in the enteric nervous system. In contrast to previous studies, we did not detect P2X7 in neurons but found dominant expression in glia and macrophages which closely interact with the neurons. P2X7 overexpression per se did not induce significant pathological effects. Our data indicate that macrophages and/or glia account for P2X7-mediated neuronal damage in IBD and provide a refined basis for the exploration of P2X7-based therapeutic strategies.
Bergerac Strains of C. elegans Revisited: Expansion of Tc1 elements Impose a Significant Genomic and Fitness Cost
Authors: Daigle Austin T. , Deiss Thaddeus C. , Melde Robert H. , Bergthorsson Ulfar , Katju Vaishali
Published: February 2022

The DNA transposon Tc1 was the first transposable element (TE) to be characterized in Caenorhabditis elegans and to date, remains the best-studied TE in Caenorhabditis worms. While Tc1 copy-number is regulated at approximately 30 copies in the laboratory N2/Bristol and the vast majority of C. elegans strains, the Bergerac strain and its derivatives have experienced a marked Tc1 proliferation. Given the historical importance of the Bergerac strain in the development of the C. elegans model, we implemented a modern genomic analysis of three Bergerac strains (CB4851, RW6999, and RW7000) in conjunction with multiple phenotypic assays to better elucidate the (i) genomic distribution of Tc1, and (ii) phenotypic consequences of TE deregulation for the host organism. The median estimates of Tc1 copy-number in the Bergerac strains ranged from 451 to 748, which is both (i) greater than previously estimated, and (ii) likely to be an underestimate of the actual copy-numbers since coverage-based estimates and ddPCR results both suggest higher Tc1 numbers. All three Bergerac strains had significantly reduced trait means compared to the N2 control for each of four fitness-related traits, with specific traits displaying significant differences between Bergerac strains. Tc1 proliferation was genome-wide, specific to Tc1, and particularly high on chromosomes V and X. There were fewer Tc1 insertions in highly expressed chromatin environments than expected by chance. Furthermore, Tc1 integration motifs were also less frequent in exon than non-coding sequences. The source of the proliferation of Tc1 in the Bergerac strains is specific to Tc1 and independent of other TEs. The Bergerac strains contain none of the alleles that have previously been found to derepress TE activity in C. elegans. However, the Bergerac strains had several Tc1 insertions near or within highly germline-transcribed genes which could account for the recent germline proliferation.
An integrative approach: using transcriptomic data and network analysis of transcriptional reprogramming in tomato response to PSTVd variants
Authors: Aviña-Padilla Katia , Zambada-Moreno Octavio , Herrera-Oropeza Gabriel Emilio , Jimenez-Limas Marco A. , Abrahamian Peter , Hammond Rosemarie W. , Hernández-Rosales Maribel
Published: February 2022

Viroids are minimal pathogens of angiosperms, consisting of non-coding RNAs that cause severe diseases in agronomic crops. Symptoms associated with viroid infection are linked to developmental alterations due to genetic regulation. To understand the global molecular mechanisms of host response, we implemented an omics approach to identify master transcription regulators (MTRs) and their differentially expressed targets in tomato infected with mild and severe variants of PSTVd. Our approach integrates root and leaf transcriptomic data, gene regulatory network analysis, and identification of affected biological processes. Overall, our results reveal that specific bHLH, MYB, and ERF transcription factors regulate genes involved in molecular mechanisms underlying critical signaling pathways. Functional enrichment of regulons shows that bHLH-MTRs are linked to metabolism and plant defense, while MYB-MTRs are involved in signaling regulation and hormone-related processes. Strikingly, a member of the bHLH-TF family have a potential specific role as a microprotein involved in the post-translational regulation of hormone signaling events. For the severe variant, ERF-MTRs are characteristic, while ZNF-TF, tf3a-TF, BZIP-TFs, and NAC-TF act as unique MTRs. Altogether, our results lay a foundation for further research on the PSTVd and host genome interaction, providing evidence for identifying potential key genes that influence symptom development in tomato plants.
Deepwater Horizoncrude oil reduces aerobic capacity of birds
Authors: Goodchild Christopher G. , Krall Jeffrey B. , Santhanakrishnan Arvind , DuRant Sarah E.
Published: February 2022

Crude oil spills can have catastrophic effects on marine and inland ecosystems, yet it is difficult to accurately quantify the extent of ecological damage caused by oil spills. For instance, avian population damage assessments conducted after large oil spills (e.g.,Deepwater Horizonspill) often focus on the number of visibly oiled birds. However, birds without visible oiling can exhibit hematological damage from oil ingestion. If such hematological responses limit oxygen deliver to tissues and impair aerobic performance, then energy-mediated effects from oil ingestion may ultimately affect endpoints of demographic significance (e.g., survival and reproduction). We investigated whether oil ingestion affects aerobic performance in birds by orally dosing zebra finches (Taeniopygia guttata) with 2 or 6 mL/kg of weathered MC252 crude oil for 28 days. After 14 and 28 days of dosing, we measured hematological indices (oxidative damage, packed cell volume [PCV], hemoglobin, reticulocytes), maximum metabolic rate (MMR), resting metabolic rate (RMR), and short-distance flight performance. Finches exposed to oil exhibited lower hemoglobin and PCV, higher reticulocyte counts, and greater oxidative damage. Shifts in these hematological indices appeared to alter organismal energetics, resulting in reduced MMR, RMR, and aerobic scope. Short-distance burst-flight was not negatively impacted by oil ingestion. Collectively, these results suggest oil ingestion impairs metabolic performance, which may negatively impact a bird’s ability to perform sustained energetically expensive activities (e.g., migration).

Significance

The 2010Deepwater Horizonoil spill released an unprecedented volume of crude oil (MC252) into the northern Gulf of Mexico and contaminated 2100 km of shoreline habitat that serves as critical breeding grounds and migratory stop-over sites for birds. Here we describe the impact of oil ingestion on the aerobic capacity of zebra finches, a model songbird. Oil ingestion reduced maximum metabolic rate and aerobic scope, which may be caused in part by hematological damage. These data suggest oil ingestion limits the ability of birds to perform essential energetically demanding activities (e.g., migration, nest incubation), thus quantification of avian injury based on external oiling alone may underestimate the true impact of oil spills on avian populations.
IDSL.UFA assigns high confidence molecular formula annotations for untargeted LC/HRMS datasets in metabolomics and exposomics
Authors: Baygi Sadjad Fakouri , Banerjee Sanjay K , Chakraborty Praloy , Kumar Yashwant , Barupal Dinesh Kumar
Published: February 2022

Untargeted LC/HRMS assays in metabolomics and exposomics aim to characterize the small molecule chemical space in a biospecimen. To gain maximum biological insights from these datasets, LC/HRMS peaks should be annotated with chemical and functional information including molecular formula, structure, chemical class and metabolic pathways. Among these, molecular formulas may be assigned to LC/HRMS peaks through matching theoretical and observed isotopic profiles (MS1) of the underlying ionized compound. For this, we have developed the Integrated Data Science Laboratory for Metabolomics and Exposomics – United Formula Annotation (IDSL.UFA) R package. In the untargeted metabolomics validation tests, IDSL.UFA assigned 54.31%-85.51% molecular formula for true positive annotations as the top hit, and 90.58%-100% within the top five hits. Molecular formula annotations were also supported by MS/MS data. We have implemented new strategies to 1) generate formula sources and their theoretical isotopic profiles 2) optimize the formula hits ranking for the individual and the aligned peak lists and 3) scale IDSL.UFA-based workflows for studies with larger sample sizes. Annotating the raw data for a publicly available pregnancy metabolome study using IDSL.UFA highlighted hundreds of new pregnancy related compounds, and also suggested presence of chlorinated perfluorotriether alcohols (Cl-PFTrEAs) in human specimens. IDSL.UFA is useful for human metabolomics and exposomics studies where we need to minimize the loss of biological insights in untargeted LC/HRMS datasets. The IDSL.UFA package is available in the R CRAN repository https://cran.r-project.org/package=IDSL.UFA. Detailed documentation and tutorials are also provided at www.ufa.idsl.me.
Heroin Self-Administration Induces Altered Dopamine Terminal Dynamics in the Nucleus Accumbens
Authors: George Brianna E. , Dawes Monica H. , Peck Emily G. , Jones Sara R.
Published: February 2022

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-hrs, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. After one day of withdrawal, male rats exhibited lower basal extracellular levels of dopamine as well as reduced dopaminergic responses to a heroin challenge (0.1 mg/kg/inf, IV). Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats have reduced stimulated dopamine release during tonic-like, single-pulse stimulations but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor activity was increased following heroin self-administration. These results reveal a marked low dopamine state following heroin-exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.
Identification and Functional Characterization of Bicaudal-D2 As A Candidate Disease Gene in Autosomal Recessive Consanguineous Family with Dilated Cardiomyopathy
Authors: Luo Kai , Zheng Chenqing , Luo Rong , Cao Xin , Sun Huajun , Ma Huihui , Huang Jichang , Yang Xu , Wu Xiushan , Li Xiaoping
Published: February 2022

Familial Dilated cardiomyopathy (DCM) is a genetic cardiomyopathy with reduced left ventricle function or systolic function. Fifty-one DCM genes have been reported, most of which are inherited in an autosomal dominant manner, while those caused by a recessive manner are rarely observed. Here we identified an autosome recessive and evolutionarily conserved missense variant, c.2429G>A: p.Arg810His, in bicaudal D homolog 2 (BICD2), which was segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 of 210 sporadic cases, highlighting its candidate causative role. Interestingly, we discovered that BICD2 expressed higher in cardiomyocytes from DCM than that from control by reanalyzing published scRNA-seq dataset, implicating its possible involvement in cardiac function. We next explored BICD2 function in zebrafish model at both embryonic and adult stages. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. We performed zebrafish echocardiography to detect indices of ventricular size at the adult zebrafish stage. Intriguingly, dilated hearts, decreased ejection fraction, cardiac output and stroke volume were observed, suggesting a phenotype similar to human DCM in bicd2-knockout homozygotes. Furthermore, RNA-seq confirmed the largest transcriptome shift in bicd2 homozygotes. Gene Set Enrichment Analysis(GSEA) of bicd2-deficient fish showed altered gene expression enriched in cardiac pathways and mitochondrial energy metabolism. In conclusion, we found for the first time that an autosomal recessive BICD2 variant is associated with familial DCM, providing further insight into the molecular pathological mechanism of DCM.
Humoral Antibody Kinetics with ChAdOx1-nCOV (CovishieldTM) and BBV-152 (CovaxinTM) Vaccine among Indian Healthcare workers: A 6-month Longitudinal Cross-sectional Coronavirus Vaccine-induced Antibody Titre (COVAT) Study
Authors: Singh Awadhesh Kumar , Phatak Sanjeev Ratnakar , Singh Ritu , Bhattacharjee Kingshuk , Singh Nagendra Kumar , Gupta Arvind , Sharma Arvind
Published: February 2022

Background and Aims

There is limited data available on longitudinal humoral antibody dynamics following two doses of ChAdOx1-nCOV (CovishieldTM) and BBV-152 (CovaxinTM) vaccine against SARS-CoV-2 among Indians.

Methods

We conducted a 6-month longitudinal study in vaccinated healthcare workers by serially measuring quantitative anti-spike antibody at 3-weeks, 3-months and 6- months after the completion of second dose. Geometric mean titer (GMT) and linear mixed models were used to assess the dynamics of antibody levels at 6 months.

Results

Of the 481 participants, GMT of anti-spike antibody decreased by 56% at 6- months regardless of demographics and comorbidities in 360 SARS-CoV-2 naive individuals, significantly in hypertensives. Participants with past infection had significantly higher GMT at all time points compared to naive individuals. Among SARS-CoV-2 naive cohorts, a significantly higher GMT was noted amongst the Covishield recipients at all time points, but there was a 44% decline in GMT at 6- month compared to peak titer period. Decline in GMT was insignificant (8%) in Covaxin recipients at 6-month despite a lower GMT at all time points vs. Covishield. There was 5.6-fold decrease in seropositivity rate at 6-month with both vaccines. Participants with type 2 diabetes mellitus have a lower seropositivity rate at all the time points. While seropositivity rate was significantly higher with Covishield vs. Covaxin at all time points except at 6-month where Covaxin recipients had a higher seropositivity, although no difference in seropositivity was noted in propensity-matched analysis.

Conclusions

There is waning humoral antibody response following two doses of either vaccine at six months.

Highlights:

We assessed humoral antibody dynamics following two doses of the two vaccines used in India until 6 months.

Our study of 481 health care workers showed a significant decrease in the anti-spike antibody at 6-months.

Reduction in antibody was regardless of demographics, comorbidities and the vaccine type.

T2DM cohorts had lowest seropositivity, while hypertensive had significant antibody decline at 6-month.