bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fecal bile acid profiles predict recurrence in patients with primary Clostridioides difficile infection
Authors: Mullish Benjamin H. , Martinez-Gili Laura , Chekmeneva Elena , Correia Gonçalo D. S. , Lewis Matthew R. , Der Sluis Verena Horneffer-Van , McDonald Julie A. K. , Pechlivanis Alexandros , Walters Julian R. F. , McClure Emma L , Marchesi Julian R. , Allegretti Jessica R. 
Published: June 2022

1.AbstractBackgroundFactors that influence recurrence risk in primary Clostridioides difficile infection (CDI) are poorly understood, and tools to predict recurrence are lacking. Perturbations in microbial-derived bile acids (BAs) contribute to CDI pathogenesis and may be relevant to primary disease prognosis.AimsTo define stool bile acid profiles and microbial bile-metabolising functionality in primary CDI patients, and explore signatures predicting recurrence.MethodsWeekly stool samples were collected from primary CDI patients from the last day of anti-CDI therapy until recurrence, or through eight weeks post-completion otherwise. Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to profile bile acids, and bacterial bile salt hydrolase (BSH) activity was measured to determine primary BA deconjugation capacity. Multivariate and univariate models were used to define differential BA trajectories in recurrers versus non-recurrers, and assess fecal bile acids as predictive markers for recurrence.ResultsTwenty (36%) out of 56 patients (median age 57, 64% male) recurred, with 80% of recurrence occurring within the first nine days post-antibiotic treatment. Principal component analysis (PCA) of stool bile acid profiles demonstrated clustering of samples by recurrence status and post-treatment time point. Longitudinal fecal bile acid trajectories in non-recurrers showed a recovery of secondary bile acids and their derivatives in non-recurring patients that was not observed in recurrers. BSH activity increased over time amongst patients who did not relapse (β= 0.056; likelihood ratio test p=0.018). A joint longitudinal-survival model identified five stool bile acids with AUROC > 0.73 for prediction of recurrence within nine days post-CDI treatment.ConclusionsGut bile acid metabolism dynamics differ in primary CDI patients between those who develop recurrence versus those who do not. Individual bile acids show promise in primary CDI patients as potential novel biomarkers to predict CDI recurrence.
Out-of-hospital Cardiac Arrest Before and During the COVID-19 Pandemic in the South Bronx
Authors: Biskupski Patrick , Heraud Sebastian Ocrospoma , Khalil Mahmoud , Horoub Ali , Maqsood Muhammad , Ong Kenneth , Cemalovic Nail , Menon Vidya 
Published: June 2022

AbstractBackgroundOut-of-hospital cardiac arrest (OHCA) is a major health challenge; the impact of the COVID-19 pandemic on OHCA in the South Bronx is unknown. The aim of this study was to determine differences between return of spontaneous circulation(ROSC), witnessed arrest, bystander CPR and survival to discharge, prior to and during the COVID-19 pandemic to improve ROSC and survival.MethodsSingle-center retrospective study of non-traumatic OHCA adult patients admitted to Lincoln Medical Center between 8/2019 to 6/2021, 3/2020 being the first established date of the COVID-19 pandemic in New York City. International Classification of Diseases (ICD) coding was used to identify cardiac arrests and collect information. Statistical analysis was performed using IBM-SPSS.ResultsROSC time pre COVID-19 was 26 minutes, during the COVID-19 pandemic it was 25 minutes 54 seconds. A significant difference in witnessed arrests in the pre COVID-19 period compared to the COVID-19 period (86% vs 55% p = 0.03). Bystander CPR occurred 36% of the time in the pre COVID-19 period contrasting to 19% during. Prior to the COVID-19 pandemic the overall survival to discharge in OHCA ROSC cases was 28.5% comparing to 29% during the pandemic. ROSC was 18 minutes among survivors during the pandemic, compared to 21 minutes in survivors prior to COVID (p = 0.2).ConclusionThere was a non-significant difference in ROSC, bystander CPR and survival to discharge in non-traumatic OHCA prior to and during the COVID-19 pandemic in the South Bronx. There was a significant difference in witnessed vs unwitnessed OHCA prior to and during the COVID-19 pandemic.
Estimating the within-person change in dental service access measures during the COVID-19 Pandemic
Authors: Semprini Jason 
Published: June 2022

AbstractBackgroundAmerican adults delay dental care more than any other healthcare service. Unfortunately, the COVID-19 pandemic may have stalled efforts to address dental service delays. Early evidence has suggested substantial declines in dental service visits in the early phase of the pandemic, however our study is among the first to measure within-person changes from 2019 to 2020 and conduct subgroup analyses to examine if changing dental patterns were mediated by exposure to the pandemic, risk of adverse COVID-19 outcomes, or dental insurance.MethodsWe analyzed a National Health Interview Survey panel of individuals initially surveyed in 2019, with subsequent follow up in 2020. The outcomes included dental service access measures and the interval of a most recent dental visit. By constructing a probability weighted linear regression model with fixed-effects, we estimated the average within-person change from 2019 to 2020. Robust standard errors were clustered within each respondent.ResultsOverall, adults in 2020 were 4.6%-points less likely to visit the dentist compared to 2019 (p < 0.001). Significantly higher declines were found in Northeast/West regions compared to Midwest/South. We find no evidence that declining dental services in 2020 were associated with more chronic diseases, older age, or lack of dental insurance coverage. Adults did not report more financial or non-financial access barriers to dental care in 2020 compared to 2019.ConclusionsThe long-term effects of the COVID-19 pandemic on delayed dental care warrants continued monitoring as policymakers aim to mitigate the pandemic’s negative consequences on oral health equity.
Linear discriminant analysis reveals hidden patterns in NMR chemical shifts of intrinsically disordered proteins
Authors: Romero Javier A. , Putko Paulina , Urbańczyk Mateusz , Kazimierczuk Krzysztof , Zawadzka-Kazimierczuk Anna 
Published: June 2022

AbstractNMR spectroscopy is key in the study of intrinsically disordered proteins (IDPs). Yet, even the first step in such an analysis—the assignment of observed resonances to particular nuclei—is often problematic due to low peak dispersion in the spectra of IDPs. We show that the assignment process can be aided by finding “hidden” chemical shift patterns specific to the amino acid residue types. We find such patterns in the training data from the Biological Magnetic Resonance Bank using linear discriminant analysis, and then use them to classify spin systems in an alfa-synuclein sample prepared by us. We describe two situations in which the procedure can greatly facilitate the analysis of NMR spectra. The first involves the mapping of spin systems chains onto the protein sequence, which is part of the assignment procedure—a prerequisite for any NMR-based protein analysis. In the second, the method supports assignment transfer between similar samples. We conducted experiments to demonstrate these cases, and both times the majority of spin systems could be unambiguously assigned to the correct residue types.Author summaryIntrinsically disordered proteins dynamically change their conformation, which allows them to fulfil many biologically significant functions, mostly related to process regulation. Their relation to many civilization diseases makes them essential objects to study. Nuclear magnetic resonance spectroscopy (NMR) is the method for such research, as it provides atomic-scale information on these proteins. However, the first step of the analysis – assignment of experimentally measured NMR chemical shifts to particular atoms of the protein – is more complex than in the case of structured proteins. The methods routinely used for these proteins are no more sufficient. We have developed a method of resolving ambiguities occurring during the assignment process.In a nutshell, we show that an advanced statistical method known as linear discriminant analysis makes it possible to determine chemical shift patterns specific to different types of amino acid residues. It allows assigning the chemical shifts more efficiently, opening the way to a plethora of structural and dynamical information on intrinsically disordered proteins.
The crosstalk between DNA-PK and cGAS drives tumor immunogenicity
Authors: Taffoni Clara , Marines Johanna , Chamma Hanane , Saccas Mathilde , Bouzid Amel , Guha Soumyabrata , Valadao Ana-Luiza Chaves , Polak Katarzyna , Del Rio Maguy , Gongora Celine , Pineau Donovan , Hugnot Jean-Philippe , Kissa Karima , Fontenille Laura , Blanchet Fabien P. , Vila Isabelle K. , Laguette Nadine 
Published: June 2022

SUMMARYCytosolic DNAs promote inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been thus suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that lack cGAS to question whether alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex drives cGAS independent inflammatory responses but that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment, a process that impaired early tumorigenesis but correlated with poor outcome. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.
Genomic analysis in Entamoeba reveals intron gain and unbiased intron loss, transformed splicing signals, and a coevolved snRNA
Authors: Roy Scott William , Bowser Bradley A. 
Published: June 2022

AbstractThe intron-exon structures of nuclear genes show striking diversity across eukaryotes. Several independent lineages have undergone convergent evolution including widespread loss of introns and transformed cis splicing signals. The causes and mechanisms of these changes remain mysterious: (i) transformation of splicing signals could reflect either selective loss of suboptimal introns or coevolution of introns and splicing machinery; and (ii) corresponding changes in the splicing machinery remain poorly characterized. A promising model to study these questions is Entamoeba. Analysis of five Entamoeba species revealed low intron densities, nearly universal atypical 5’ splice sites and 3’ intronic sequences. A flexible search for U1 snRNA genes revealed a modified 5’-AACAAAC-3’ recognition sequence, affording complete Watson-Crick basepairing potential with the atypical 5’ splice site and extended basepairing potential. A U1 candidate in the related species Mastigamoeba balumuthi revealed a separate modification complimenting a different atypical consensus splice site. Genome-wide study of intron loss and gain revealed that introns with suboptimal splicing motifs were no more likely to be lost, suggesting against genome-wide homogenization of intron splicing motifs by selective intron loss. Unexpectedly, this analysis also revealed widespread intron gain in Entamoeba invadens. In total, the current analyses: (i) provide the most direct available evidence of coevolution of spliceosomal introns and splicing machinery; (ii) illuminate the evolutionary forces responsible for concerted intron loss and splicing motif transformation; and (iii) reveal widespread intron gain in an otherwise highly reduced lineage.
Targeting ATP12A, a non-gastric proton pump alpha subunit, for idiopathic pulmonary fibrosis treatment
Authors: Abdelgied Mohamed , Uhl Katie , Chen Oliver G , Schultz Chad , Tripp Kaylie , Peraino Angela M , Paithankar Shreya , Chen Bin , Kakazu Maximiliano Tamae , Bahena Alicia Castillo , Jager Tara E , Lawson Cameron , Chesla Dave W , Pestov Nikolay , Modyanov Nikolai N. , Prokop Jeremy , Neubig Richard R , Uhal Bruce D , Girgis Reda E , Li Xiaopeng 
Published: June 2022

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in cystic fibrosis patients. We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened the bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan (VON). This data supports the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.
Large-scale identification of phospho-modulated motif-based protein-protein interactions
Authors: Kliche Johanna , Garvanska Dimitriya Hristoforova , Simonetti Leandro , Badgujar Dilip , Dobritzsch Doreen , Nilsson Jakob , Davey Norman , Ivarsson Ylva 
Published: June 2022

AbstractPhosphorylation is an extensively studied post-translation modification that regulates protein function by promoting, inhibiting or modulating protein-protein interactions. Deciphering which of the hundreds of thousands of phosphosites in the proteome that regulate interactions remains challenging. We generated a proteomic peptide-phage display (ProP-PD) library to screen for phosphosites that regulate short linear motif-based interactions. The phage peptidome covers 13,500 phospho-serine/threonine sites found in the intrinsically disordered regions of the human proteome, each phosphosite being represented as a wildtype and a phosphomimetic variant. We screened 73 modular domains and identified 252 putative phospho-modulated interactions. Affinity measurements confirmed the phosphomodulation of 16 out of 21 tested interactions. We discovered a novel phospho-dependent interaction between clathrin and the mitotic spindle protein hepatoma-upregulated protein (HURP). We validated the phospho-dependent clathrin interaction in a cellular context and found it to be essential for the mitotic function of HURP. Structural characterisation elucidated the molecular basis for the phospho-dependency of the clathrin-HURP interaction. Collectively, our work showcases the power of phosphomimetic ProP-PD to discover novel phospho-modulated SLiM-based interactions required for cellular function.
Multiplexed protein detection and parallel binding kinetics analysis with label-free digital single-molecule counting
Authors: Zhou Xinyu , Wang Rui , Wan Zijian , Zhang Pengfei , Wang Shaopeng 
Published: June 2022

AbstractMultiplexed protein detection is critical for improving the drug and biomarkers screening efficiency. Here we show that multiplexed protein detection and parallel protein interaction analysis can be realized by evanescent scattering microscopy with label-free digital single-molecule counting. We implemented an automatic single-molecule counting strategy with high temporal resolution to precisely determine the binding time, which improves the counting efficiency and accuracy. We show that digital single-molecule counting can recognize proteins with different molecular weights, thus making it possible to monitor the protein binding processes in the solution by real time tracking the numbers of free and bound proteins landing on the sensor surface. Furthermore, we show that this strategy can simultaneously analyze the kinetics of two different protein interaction processes on the surface and in the solution. This work may pave a way to investigate complicated protein interactions, such as the competition of biomarker-antibody binding in biofluid with biomarker-protein binding on the cellular membrane.
Emergent Actin Flows Explain Diverse Parasite Gliding Modes
Authors: Hueschen Christina L. , Zarko Li-av Segev , Chen Jian-Hua , LeGros Mark A. , Larabell Carolyn A. , Boothroyd John C. , Phillips Rob , Dunn Alexander R. 
Published: June 2022

SummaryDuring host infection, single-celled apicomplexan parasites like Plasmodium and Toxoplasma use a motility mechanism called gliding, which differs fundamentally from other known mechanisms of eukaryotic cell motility. Gliding is thought to be powered by a thin layer of flowing filamentous (F)-actin1–3 sandwiched between the plasma membrane and a myosin-coated4,5 inner membrane complex. How this surface actin layer drives the diverse apicomplexan gliding modes observed experimentally - helical, circular, and twirling6,7, and patch8, pendulum9, or rolling2 – presents a rich biophysical puzzle. Here, we use single-molecule imaging to track individual actin filaments and myosin complexes in live Toxoplasma gondii. Based on these data, we hypothesize that F-actin flows arise by self-organization, rather than following a microtubule-based template as previously believed. We develop a continuum model of emergent F-actin flow within the unusual confines provided by parasite geometry. In the presence of F-actin turnover, our model predicts the emergence of a steady-state mode in which actin transport is largely rearward. Removing actin turnover leads to actin patches that recirculate up and down the cell, a “cyclosis” that we observe experimentally for drug-stabilized actin bundles in live parasites. These findings provide a mechanism by which actin turnover governs a transition between distinct self-organized F-actin states, whose properties can account for the diverse gliding modes known to occur. More broadly, we illustrate how different forms of gliding motility can emerge as an intrinsic consequence of the self-organizing properties of F-actin flow in a confined geometry.
Mechanistic insights into the activation of lecithin-cholesterol acyltransferase in therapeutic nanodiscs composed of apolipoprotein A-I mimetic peptides and phospholipids
Authors: Giorgi Laura , Niemelä Akseli , Kumpula Esa-Pekka , Natri Ossi , Parkkila Petteri , Huiskonen Juha T. , Koivuniemi Artturi 
Published: June 2022

AbstractThe mechanistic details behind the activation of lecithin-cholesterol acyltransferase (LCAT) by apolipoprotein A-I (apoA-I) and its mimetic peptides are still enigmatic. Resolving the fundamental principles behind the LCAT activation will facilitate the design of advanced HDL-mimetic therapeutic nanodiscs for LCAT deficiencies and coronary heart disease, and for several targeted drug delivery applications. Here, we have combined coarse-grained molecular dynamics simulations with complementary experiments to gain mechanistic insight into how apoA-I mimetic peptide 22A and its variants attune LCAT activity in peptide-lipid nanodiscs. Results highlight that peptide 22A forms transient antiparallel dimers in the rim of nanodiscs. The dimerization tendency considerably decreases with the removal of C-terminal lysine K22, which has also been shown to reduce the cholesterol esterification activity of LCAT. In addition, our simulations revealed that LCAT prefers to localize to the rim of nanodiscs in a manner that shields the membrane-binding domain (MBD), αA-αA’, and the lid amino acids from the water phase, following the previous experimental evidence. Meanwhile, the location and conformation of LCAT in the rim of nanodisc are spatially more restricted when the active site covering lid of LCAT is in the open form. The average location and spatial dimensions of LCAT in its open form were highly compatible with the electron microscopy images. All peptide 22A variants studied here had a specific interaction site in the open LCAT structure flanked by the lid and MBD domain. The bound peptides showed different tendencies to form antiparallel dimers and, interestingly, the temporal binding site occupancies of the peptide variants affected their in vitro ability to promote LCAT-mediated cholesterol esterification.
Design advancements for an integrated mission management system for small air transport vehicles in the COAST project
Authors: Di Vito Vittorio , Grzybowski Piotr , Rogalski Tomasz , Maslowski Piotr 
Published: June 2022

Purpose
This paper aims to describe the activities that are ongoing, in the Cost Optimized Avionics SysTem (COAST) project, to design an integrated mission management system (IIMS) to be used as support to the pilot and/or to act as a backup in case of pilot incapacitation onboard on small air transport (SAT) vehicles, under single-pilot operations.

Design/methodology/approach
The COAST project, funded by Clean Sky 2 programme, is developing enabling technologies for single-pilot operations in the European Aviation Safety Agency CS-23 category vehicles. Such technologies include specific tools that are designed as individual enablers for single-pilot operations and specifically address: the real-time support to pilot’s decision making in maintaining the vehicle self-separation (this technology is the tactical separation system [TSS]); the real-time support to pilot’s situational awareness about observed and forecasted weather conditions (this technology is the advanced weather awareness system [AWAS]); and the real-time management of emergency conditions due to pilot’s incapacitation under single-pilot operations (this technology is the flight reconfiguration system [FRS]). Based on the outcomes of the design activities of such individual tools, in the COAST project emerged the opportunity to proceed with the design of a further system, leveraging the individual tools and benefitting from their integration.

Findings
The IMMS design started in the year 2020 and the activities carried out up to mid-2021 allowed to define the concept of operations of the system, its high-level requirements (functional, interface and operational requirements) and the preliminary system architecture.

Originality/value
The IMMS contributes enabling the implementation of single-pilot operations in CS-23 category vehicles, thanks to the possibility to support, in normal operational conditions, the pilot’s decision-making and, in emergency conditions due to pilot’s incapacitation, the automatic flight management up to the safe destination.