bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategy for identifying insulin pump use in Clinical Practice Research Datalink GOLD
Authors: Persson Rebecca , Sponholtz Todd , Baak Brenda N , Jick Susan S 
Published: February 2024

AbstractBackgroundClinical Practice Research Datalink (CPRD) GOLD is an invaluable resource for clinical research. However, some exposures are difficult to capture, including continuous subcutaneous insulin infusion pump systems (“insulin pumps”). We present a strategy we developed to classify insulin pump users and to estimate the duration of pump use in CPRD GOLD. This was done to study adverse skin events in new adult pump users.MethodsInsulin pump users were defined as patients who had a specific insulin pump code (prescription for an insulin pump cartridge or clinical code for continuous insulin infusion) in their record. Duration of use was defined as the continuous use of any insulin formulation commonly used in pump systems before and after the insulin pump specific code. Each patient’s pump start and end dates were calculated programmatically and then confirmed by manual review of the patient’s CPRD record.ResultsThere were 1032 patients with an insulin pump specific code recorded in CPRD GOLD through December 2018, of which 302 met the inclusion criteria for our safety study. Due to high variability in the patterns of insulin use, programmatic determination of pump start and end dates was insufficient. The start and/or end dates of >50% of patients required adjustment upon manual review.ConclusionsInsulin pump users in CPRD GOLD could be easily identified using this strategy, but we may have missed additional insulin pump users without specific pump codes. The duration of pump use, however, was difficult to capture. This strategy, though time intensive, is a useful tool for the study of insulin pumps.FundingThis study was funded by AbbVie.Conflicts of Interest StatementBoston Collaborative Drug Surveillance Program (BCDSP) received funding from AbbVie for this study. Susan Jick and Rebecca Persson are employees of BCDSP. Todd Sponholtz and Brenda Baak were interns at BCDSP. Authors retain full and scientific control over the content of this manuscript.DisclosuresThis manuscript has not been peer-reviewed. We provide this information as a reference for other users of Clinical Practice Research Datalink GOLD.This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the NHS as part of their care and support. The interpretation and conclusions contained in this study are those of the authors alone. This study was approved by the Independent Scientific Advisory Committee (ISAC) for Medicines and Healthcare products Regulatory Agency (protocol no: 19_216R).
Characteristics and Determinants of Pulmonary Long COVID
Authors: Patton Michael John , Benson Donald , Robison Sarah W. , Dhaval Raval , Locy Morgan L. , Patel Kinner , Grumley Scott , Levitan Emily B. , Morris Peter , Might Matthew , Gaggar Amit , Erdmann Nathaniel 
Published: February 2024

ABSTRACTRATIONALEPersistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed ’Long COVID’); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined.OBJECTIVESUsing longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID.METHODSThe University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection. Longitudinal PFTs including total lung capacity (TLC) and diffusion limitation of carbon monoxide (DLCO) were used to evaluate restriction and diffusion impairment over time in this cohort. Analysis of chest CT imaging was used to phenotype the pulmonary Long COVID pathology. Risk factors linked to development of pulmonary Long COVID were estimated using univariate and multivariate logistic regression models.MEASUREMENTS AND MAIN RESULTSLongitudinal evaluation 929 patients with post-COVID pulmonary symptoms revealed diffusion impairment (DLCO ≤80%) and restriction (TLC ≤80%) in 51% of the cohort (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impaired restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified evidence of fibrosis in this population.CONCLUSIONSPersistent diffusion impaired restriction was identified as a key feature of pulmonary Long COVID. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.
Mitral annular plane systolic excursion to left atrial volume ratio – a strainless relation with left ventricular filling pressures
Authors: Lindow Thomas , Tureli Hande Oktay , Eklund Gustafsson Charlotte , Manna Daniel , Wieslander Björn , Lindqvist Per , Venkateshvaran Ashwin 
Published: February 2024

AbstractPurposeLeft atrial reservoir strain (LASr) offers diagnostic and prognostic value in patients with heart failure. However, LASr may be technically challenging and is not available to all clinical echocardiographers. Since LASr is a consequence of left atrial (LA) stretch during apical descent of the mitral annulus, we hypothesized that a ratio between mitral annular plane systolic excursion (MAPSE) and LA volume (LAV) may offer similar diagnostic value as LASr. We aimed to investigate the relationship between MAPSE/LAV and LASr and evaluate the diagnostic performance of MAPSE/LAV to identify patients with elevated LV filling pressure.MethodsMAPSE/LAV and LA strain measures were obtained in patients referred for echocardiography due to aortic stenosis, and in patients who had undergone clinically indicated right heart catheterization (RHC) with simultaneous echocardiography.ResultsIn 93 patients with moderate aortic stenosis, MAPSE/LAV was moderately correlated with LASr (r=0.57) but was lower in patients with elevated compared to normal LV filling pressure by echocardiography (0.11 vs. 0.16 mm/mL, p<0.001). In 72 patients who had undergone RHC and simultaneous echocardiography, MAPSE/LAV and LASr correlated weakly with pulmonary artery wedge pressure (PAWP) (r=-0.44 and r=0.37). MAPSE/LAV was lower in patients with elevated (>15 mmHg) vs. normal PAWP (0.14 mm/mL vs. 0.27 mm/mL). Accuracy for detection of elevated PAWP was similar for MAPSE/LAV (area under the curve MAPSE/LAV: 0.75 [0.58–0.92] and LASr: 0.75 [0.57–0.90]).ConclusionsDespite a moderate correlation with LASr, MAPSE/LAV provided similar diagnostic value as LASr regarding LV filling pressures as determined by echocardiography and RHC.
Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9
Authors: Li Yan , Usman Muhammad , Sapp Ellen , Ke Yuting , Wang Zejian , Boudi Adel , DiFiglia Marian , Li Xueyi 
Published: February 2024

AbstractLoss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). The abrogation of trappc9 in mice has been shown to alter the density of neurons containing dopamine receptor D2 (DRD2) and/or DRD1 in the striatum. Here, we report that trappc9 deficiency in mice resulted in disruption of systemic glucose homeostasis and onset of obesity and NAFLD, which were relieved upon chronic treatment combining DRD2 agonist quinpirole and DRD1 antagonist SCH23390. The homeostasis of systemic glucose in trappc9-deficient mice was restored upon administrating quinpirole alone. Transcriptomic and proteomic analyses revealed signs of impairments in neurotransmitter secretion in trappc9-deficient mice. Brain examinations showed that trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine transmission.
Chromatin structure andvar2csa– a tango in regulation ofvargene expression in the human malaria parasite,Plasmodium falciparum?
Authors: Lenz Todd , Zhang Xu , Chakraborty Abhijit , Ardakany Abbas Roayaei , Prudhomme Jacques , Ay Ferhat , Deitsch Kirk , Le Roch Karine G. 
Published: February 2024

ABSTRACTOver the last few decades, novel methods have been developed to study how chromosome positioning within the nucleus may play a role in gene regulation. Adaptation of these methods in the human malaria parasite,Plasmodium falciparum, has recently led to the discovery that the three-dimensional structure of chromatin within the nucleus may be critical in controlling expression of virulence genes (vargenes). Recent work has implicated an unusual, highly conservedvargene calledvar2csain contributing to coordinated transcriptional switching, however how this gene functions in this capacity is unknown. To further understand howvar2csainfluencesvargene switching, targeted DNA double-strand breaks (DSBs) within the sub-telomeric region of chromosome 12 were used to delete the gene and the surrounding chromosomal region. To characterize the changes in chromatin architecture stemming from this deletion and how these changes could affectvargene expression, we used a combination of RNA-seq, Chip-seq and Hi-C to pinpoint epigenetic and chromatin structural modifications in regions of differential gene expression. We observed a net gain of interactions in sub-telomeric regions and internalvargene regions followingvar2csaknockout, indicating an increase of tightly controlled heterochromatin structures. Our results suggest that disruption ofvar2csaresults not only in changes invargene transcriptional regulation but also a significant tightening of heterochromatin clusters thereby disrupting coordinated activation ofvargenes throughout the genome. Altogether our result confirms a strong link between thevar2csalocus, chromatin structure andvargene expression.AUTHOR SUMMARYMalaria remains one of the deadliest parasite-borne diseases, causing not only over a half million deaths annually, but also infecting hundreds of millions more.Plasmodium falciparum,the protozoan parasite that is responsible for the most virulent form of human malaria, is transmitted to humans by infected female mosquitoes during a blood meal. Due to a growing resistance to all existing antimalarials, there is a need to identify novel targets to design new antimalarial strategies. Our research builds on the growing body of evidence that supports the role of genome organization or chromatin structure within the nucleus in controlling the parasite development as well as virulence factors designed to circumvent the host immune response. This study identifies genes and structural elements within thePlasmodium falciparumgenome that are controlled, at least partially, by the expression of a single unique and highly conserved virulence gene.
Spatial top-down proteomics for the functional characterization of human kidney
Authors: Zemaitis Kevin J. , Fulcher James M. , Kumar Rashmi , Degnan David J. , Lewis Logan A. , Liao Yen-Chen , Veličković Marija , Williams Sarah M. , Moore Ronald J. , Bramer Lisa M. , Veličković Dušan , Zhu Ying , Zhou Mowei , Paša-Tolić Ljiljana 
Published: February 2024

AbstractBackgroundThe Human Proteome Project has credibly detected nearly 93% of the roughly 20,000 proteins which are predicted by the human genome. However, the proteome is enigmatic, where alterations in amino acid sequences from polymorphisms and alternative splicing, errors in translation, and post-translational modifications result in a proteome depth estimated at several million unique proteoforms. Recently mass spectrometry has been demonstrated in several landmark efforts mapping the human proteoform landscape in bulk analyses. Herein, we developed an integrated workflow for characterizing proteoforms from human tissue in a spatially resolved manner by coupling laser capture microdissection, nanoliter-scale sample preparation, and mass spectrometry imaging.ResultsUsing healthy human kidney sections as the case study, we focused our analyses on the major functional tissue units including glomeruli, tubules, and medullary rays. After laser capture microdissection, these isolated functional tissue units were processed with microPOTS (microdroplet processing in one-pot for trace samples) for sensitive top-down proteomics measurement. This provided a quantitative database of 616 proteoforms that was further leveraged as a library for mass spectrometry imaging with near-cellular spatial resolution over the entire section. Notably, several mitochondrial proteoforms were found to be differentially abundant between glomeruli and convoluted tubules, and further spatial contextualization was provided by mass spectrometry imaging confirming unique differences identified by microPOTS, and further expanding the field-of-view for unique distributions such as enhanced abundance of a truncated form (1-74) of ubiquitin within cortical regions.ConclusionsWe developed an integrated workflow to directly identify proteoforms and reveal their spatial distributions. Where of the 20 differentially abundant proteoforms identified as discriminate between tubules and glomeruli by microPOTS, the vast majority of tubular proteoforms were of mitochondrial origin (8 of 10) where discriminate proteoforms in glomeruli were primarily hemoglobin subunits (9 of 10). These trends were also identified within ion images demonstrating spatially resolved characterization of proteoforms that has the potential to reshape discovery-based proteomics because the proteoforms are the ultimate effector of cellular functions. Applications of this technology have the potential to unravel etiology and pathophysiology of disease states, informing on biologically active proteoforms, which remodel the proteomic landscape in chronic and acute disorders.
Engineering multi-degrading bacterial communities to bioremediate soils contaminated with pesticides residues
Authors: Thieffry Sylvia , Aubert Julie , Devers-Lamrani Marion , Martin-Laurent Fabrice , Romdhane Sana , Rouard Nadine , Siol Mathieu , Spor Aymé 
Published: February 2024

AbstractParallel to the important use of pesticides in conventional agriculture there is a growing interest for green technologies to clear contaminated soil from pesticides and their degradation products. One specific technique, the inoculation of degrading micro-organisms in polluted soil, known as bioaugmentation, is a promising method still in needs of further developments. Specifically, improvements in the understanding of how degrading microorganisms must overcome abiotic filters and interact with the autochthonous microbial communities are needed in order to efficiently design bioremediation strategies. Here we designed a protocol aiming at studying the degradation of two herbicides, glyphosate (GLY) and isoproturon (IPU),viaexperimental modifications of two source bacterial communities. We used statistical methods stemming from genomic prediction to link community composition to herbicides degradation potentials. Our approach proved to be efficient with correlation estimates over 0.8 - between model predictions and measured pesticide degradation values. OTUs significantly associated with the degradation ability, and therefore identified as relevant by the models were confronted to the literature. Next, multi-degrading bacterial communities were obtained by coalescing bacterial communities with high GLY or IPU degradation ability based on their community-level properties. Finally, we evaluated the efficiency of constructed multi-degrading communities to remove pesticide contamination in a different soil. While results are less clear in the case of GLY, we showed an efficient transfer of degrading capacities towards the receiving soil even at relatively low inoculation levels in the case of IPU. Altogether, we developed an innovative protocol for building multi-degrading simplified bacterial communities with the help of genomic prediction tools and coalescence, and proved their efficiency in a contaminated soil.
FakA impacts antiseptic susceptibility inStaphylococcus aureusandEnterococcus faecalis
Authors: Gaya Maria Solsona , Felgate Heather , Siani Harsha , Whitchurch Cynthia B , Webber Mark A 
Published: February 2024

ABSTRACTBiocides are widely used to control and prevent healthcare-associated infections and understanding how nosocomial pathogens respond to biocidal agents is key to improving infection prevention and control products and practices.An evolution model was used to study howStaphylococcus aureusandEnterococcus faecalisresponded after repeated exposure to sub-lethal concentrations of chlorhexidine digluconate (CHX) and octenidine dihydrochloride (OCT) when grown planktonically and as biofilms.Both pathogens were able to adapt to grow at concentrations above the MIC of both biocides with planktonic lineages surviving at higher concentrations of both agents than biofilm lineages. Exposure to CHX was linked with lower biofilm biomass production inE. faecalisalthough biofilm biomass increased forS. aureusisolates after exposure to both agents. Evolved isolates had no major fitness deficit and only low-level changes to susceptibility to antibiotics were observed after biocide exposure.Sequencing of biocide adapted mutants repeatedly identified mutations withinfakAencoding a fatty acid kinase in independent lineages ofS. aureusafter exposure to both biocides in all conditions. Analogous changes were observed within the homologous gene in parallel experiments withEnterococcus faecalis. Further assays to study the mechanistic basis and relationship to phospholipid production showed that evolved isolates withfakAmutations accumulated less ethidium bromide than parent strains, exhibited altered cell envelope morphology and decreased susceptibility to daptomycin.This data shows important pathogens can evolve limited tolerance to two common biocides but that this has collateral impacts on biofilm formation, colony morphology and fitness. FakA appears to play an important role in biocide tolerance.
The N-terminal helix of MarA as a key element in the mechanism of DNA binding
Authors: Corbella Marina , Moreira Cátia , Bello-Madruga Roberto , Torrent Marc , Kamerlin Shina C.L. , Blair Jessica M.A. , Sancho-Vaello Enea 
Published: February 2024

AbstractEfflux is one of the mechanisms employed by Gram-negative bacteria to become resistant to routinely used antibiotics. The inhibition of efflux by targeting their regulators is a promising strategy to re-sensitise bacterial pathogens to antibiotics. AcrAB-TolC is the main Resistance-Nodulation-Division efflux pump in Enterobacteriaceae. MarA is an AraC/XylS family global regulator that regulates more than 40 genes related to the antimicrobial resistance phenotype, includingacrAB. The aim of this work was to understand the role of the N-terminal helix of MarA in the mechanism of DNA binding. An N-terminal deletion of MarA showed that the N-terminal helix has a role in the recognition of the functional marboxes. By engineering two double cysteine variants of MarA, and combiningin vitroelectrophoretic mobility assays andin vivomeasurements ofacrABtranscription with molecular dynamic simulations, it was shown that the immobilization of the N-terminal helix of MarA prevents binding to DNA. This new mechanism of inhibition seems to be universal for the monomeric members of the AraC/XylS family, as suggested by additional molecular dynamics simulations of the two-domain protein Rob. These results point to the N-terminal helix of the AraC/XylS family monomeric regulators as a promising target for the development of inhibitors.
Neural codes track prior events in a narrative and predict subsequent memory for details
Authors: Collin Silvy H.P. , Kempner Ross P. , Srivatsan Sunita , Norman Kenneth A. 
Published: February 2024

AbstractThroughout our lives, we learn schemas that specify what types of events to expect in particular contexts and the temporal order in which these events usu- ally occur. Here, our first goal was to investigate how such context-dependent temporal structures are represented in the brain during processing of temporally- extended events. To accomplish this, we ran a 2-day fMRI study in which we exposed participants to many unique animated videos of weddings composed of sequences of rituals; each sequence originated from one of two fictional cultures (North and South), where rituals were shared across cultures, but the transition structure between these rituals differed across cultures. The results, obtained using representational similarity analysis, revealed that context-dependent tem- poral structure is represented in multiple ways in parallel, including distinct neural representations for the culture, for particular sequences, and for past and current events within the sequence. Our second goal was to test the hypothe- sis that neural schema representations scaffold memory for specific details. In keeping with this hypothesis, we found that the strength of the neural represen- tation of the North/South schema for a particular wedding predicted subsequent episodic memory for the details of that wedding.
Applying an automated NMR-based metabolomic workflow to unveil strawberry molecular mechanisms in vernalization
Authors: Fernández-Veloso Andrea , Hiniesta-Valero Jaime , Guerra-Castellano Alejandra , Tomás Laura , De la Rosa Miguel A. , Díaz-Moreno Irene 
Published: February 2024

AbstractMetabolomics is the discipline that aims to determine the whole metabolic profile of a complex mixture. These studies are useful to capture the physiological status of an organism at a given moment. Even though the main technique used in metabolomics is Mass Spectrometry coupled to chromatography, in recent years, interest in Nuclear Magnetic Resonance (NMR) is increasing because of some benefits of NMR, i.e., it is a non-invasive, highly reproducible, and inherently quantitative technique. However, difficulties in data analysis comprise one of the main reasons that hinder the standardization of NMR for metabolomic analysis in research. In this work, we applied an automated workflow for NMR-based metabolomic analysis for the study of vernalization in strawberry. Vernalization is a key process in obtaining a successful strawberry crop, however, the molecular mechanisms behind it remain still unknown. We expect this work to improve the knowledge of crop metabolism —specifically the vernalization process— while promoting the use of NMR in conjunction with computational tools for agriculture studies.