bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acyltransferases in the first step of glycerophospholipid synthesis have redundant and non-redundant roles insn-1 acyl chain regulation, ether lipid levels, and cell survival
Authors: Salame Sarah , Qasmaoui Hasna , Jose Gregor P , Fleuriot Lucile , Debayle Delphine , Harayama Takeshi 
Published: January 2024

AbstractThe increased use of lipidomics analyses in biomedical research made it crucial to understand correctly how lipid compositions are regulated. Lipid acyl chains are important regulators of membrane physicochemical properties, and are incorporated by various acyltransferases. The acyltransferases implicated in the first step of glycerophospholipid synthesis, the GPATs and GNPAT, have distinct localizations and substrate preferences. This suggests that they have distinct roles on lipid regulation, but a complete understanding of their redundant and non-redundant functions is missing. We report here a comprehensive analysis of cells having mutations in GPATs and GNPAT, either alone or in combinations. Our results suggest that the balance between GPATs and GNPAT affect the levels of ether lipids, together with glycerophospholipid acyl chain length and unsaturation. In addition, we found that lipid synthesis initiated at peroxisomes, but not mitochondria, is sufficient to provide the lipid synthesis flux required for normal cell growth. Our study unveils the multifaceted roles of the first step of de novo glycerophospholipid synthesis, thus leading to a better understanding of how lipidomes are shaped.
MetaCompare 2.0: Differential ranking of ecological and human health resistome risks
Authors: Rumi Monjura Afrin , Oh Min , Davis Benjamin C. , Juvekar Adheesh , Brown Connor L. , Vikesland Peter J. , Pruden Amy , Zhang Liqing 
Published: January 2024

AbstractBackgroundWhile there is increasing recognition of numerous environmental contributions to the spread of antibiotic resistance, quantifying the relative contributions of various sources remains a fundamental challenge. Similarly, there is a need to differentiate acute human health risks corresponding to exposure to a given environment, versus broader ecological risk of evolution and spread of antibiotic resistance genes (ARGs) across microbial taxa. Recent studies have proposed various methods of harnessing the rich information housed by metagenomic data for achieving such aims. Here, we introduce MetaCompare 2.0, which improves upon the original MetaCompare pipeline by differentiating indicators of human health resistome risk (i.e., potential for human pathogens to acquire ARGs) from ecological resistome risk (i.e., overall mobility of ARGs across a given microbiome).ResultsTo demonstrate the sensitivity of the MetaCompare 2.0 pipeline, we analyzed publicly available metagenomes representing a broad array of environments, including wastewater, surface water, soil, sediment, and human gut. We also assessed the effect of sequence assembly methods on the risk scores. We further evaluated the robustness of the pipeline to sequencing depth, contig count, and metagenomic library coverage bias through comparative analysis of a range of subsamples extracted from a set of deeply sequenced wastewater metagenomes. The analysis utilizing samples from different environments demonstrated that MetaCompare 2.0 consistently produces lower risk scores for environments with little human influence and higher risk scores for human contaminated environments affected by pollution or other stressors. We found that the ranks of risk scores were not measurably affected by different assemblers employed. The Meta-Compare 2.0 risk scores were remarkably consistent despite varying sequencing depth, contig count, and coverage.ConclusionMetaCompare 2.0 successfully ranked a wide array of environments according to both human health and ecological resistome risks, with both scores being strongly impacted by anthropogenic stress. We packaged the improved pipeline into a publicly-available web service that provides an easy-to-use interface for computing resistome risk scores and visualizing results. The web service is available athttp://metacompare.cs.vt.edu/
Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing
Authors: Konishi Colin T , Mulaiese Nancy , Butola Tanvi , Zhang Qinkun , Kagan Dana , Yang Qiaoyan , Pressler Mariel , Dirvin Brooke G , Devinsky Orrin , Basu Jayeeta , Long Chengzu 
Published: January 2024

AbstractAltered protein conformation can cause incurable neurodegenerative disorders. Mutations inSERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenicSERPINI1variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy which may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer’s and Huntington’s diseases.
Microfluidic platform enables shear-less aerosolization of lipid nanoparticles for messenger RNA inhalation
Authors: Kim Jeonghwan , Jozic Antony , Bloom Elissa , Jones Brian , Marra Michael , Murthy Namratha Turuvekere Vittala , Eygeris Yulia , Sahay Gaurav 
Published: January 2024

ABSTRACTLeveraging the extensive surface area of the lungs for gene therapy, inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a novelmicrofluidic aerosolization platform(MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient mRNA delivery to the respiratory system. Our results demonstrated the superiority of the novel MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines.In vivoexperiments with mice that inhaled these aerosolized nanoparticles revealed successful, lung-specific mRNA transfection without observable signs of toxicity. This pioneering MAP represents a significant advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.
Gut Analysis Toolbox: Automating quantitative analysis of enteric neurons
Authors: Sorensen Luke , Humenick Adam , Poon Sabrina S.B. , Han Myat Noe , Mahdavian Narges Sadat , Hamnett Ryan , Gómez-de-Mariscal Estibaliz , Neckel Peter H. , Saito Ayame , Mutunduwe Keith , Glennan Christie , Haase Robert , McQuade Rachel M. , Foong Jaime P.P. , Brookes Simon J.H. , Kaltschmidt Julia A. , Muñoz-Barrutia Arrate , King Sebastian K. , Veldhuis Nicholas A. , Carbone Simona E. , Poole Daniel P. , Rajasekhar Pradeep 
Published: January 2024

AbstractThe enteric nervous system (ENS) plays an important role in coordinating gut function. The ENS consists of an extensive network of neurons and glial cells within the wall of the gastrointestinal tract. Alterations in neuronal distribution, function, and type are strongly associated with enteric neuropathies and gastrointestinal (GI) dysfunction and can serve as biomarkers for disease. However, current methods for assessing neuronal counts and distribution suffer from undersampling. This is partly due to challenges associated with imaging and analyzing large tissue areas, and operator bias due to manual analysis. Here, we present the Gut Analysis Toolbox (GAT), an image analysis tool designed for characterization of enteric neurons and their neurochemical coding using 2D images of GI wholemount preparations. GAT is developed for the Fiji distribution of ImageJ. It has a user-friendly interface and offers rapid and accurate cell segmentation. Custom deep learning (DL) based cell segmentation models were developed using StarDist. GAT also includes a ganglion segmentation model which was developed using deepImageJ. In addition, GAT allows importing of segmentation generated by other software. DL models have been trained using ZeroCostDL4Mic on diverse datasets sourced from different laboratories. This captures the variability associated with differences in animal species, image acquisition parameters, and sample preparation across research groups. We demonstrate the robustness of the cell segmentation DL models by comparing them against the state-of-the-art cell segmentation software, Cellpose. To quantify neuronal distribution GAT applies proximal neighbor-based spatial analysis. We demonstrate how the proximal neighbor analysis can reveal differences in cellular distribution across gut regions using a published dataset. In summary, GAT provides an easy-to-use toolbox to streamline routine image analysis tasks in ENS research. GAT enhances throughput allowing unbiased analysis of larger tissue areas, multiple neuronal markers and numerous samples rapidly.
Using variable data independent acquisition for capillary electrophoresis-based untargeted metabolomics
Authors: Kiuchi Saki , Otoguro Yasuhiro , Nitta Tomoaki , Chung Mi Hwa , Nakaya Taiki , Matsuzawa Yuki , Oobuchi Katsuya , Sasaki Kazunori , Yamamoto Hiroyuki , Tsugawa Hiroshi 
Published: January 2024

ABSTRACTCapillary electrophoresis coupled with tandem mass spectrometry (CE-MS/MS) offers advantages in peak capacity and sensitivity for metabolic profiling, owing to the electroosmotic flow-based separation. However, the utilization of data-independent MS/MS acquisition (DIA) is restricted due to the absence of an optimal procedure for analytical chemistry and its related informatics framework. We assessed the mass spectral quality using two DIA techniques, namely, all-ion fragmentation (AIF) and variable DIA (vDIA), to isolate 60∼800 Da precursor ions with respect to annotation rates. Our findings indicate that vDIA, coupled with the updated MS-DIAL chromatogram deconvolution algorithm, yields higher spectral matching scores and annotation rates compared to AIF. Additionally, we evaluated a linear migration time (MT) correction method using internal standards to accurately align chromatographic peaks in a dataset. After the correction, the peaks exhibited less than 0.1 min MT drifts, a difference mostly equivalent to that of conventional reverse-phase liquid chromatography techniques. Moreover, we conducted MT prediction for metabolites recorded in mass spectral libraries and metabolite structure databases containing a total of 469,870 compounds, achieving an accuracy of less than 1.5 min root mean squares. Thus, our platform provides a peak annotation platform utilizing MT information, accurate precursorm/z, and the MS/MS spectrum recommended by the metabolomics standards initiative. Applying this procedure, we investigated metabolic alterations in lipopolysaccharide (LPS)-induced macrophages, characterizing 170 metabolites. Furthermore, we assigned metabolite information to unannotated peaks using anin-silicostructure elucidation tool, MS-FINDER. The results were integrated into the nodes in the molecular spectrum network based on the MS/MS similarity score. Consequently, we identified a significantly increased amount of metabolites in the LPS-administration group, glycinamide ribonucleotide, not present in any spectral libraries. Additionally, we retrieved metabolites of false-negative hits in the initial spectral annotation procedure. Overall, our study underscores the potential of CE-MS/MS with DIA and computational mass spectrometry techniques for metabolic profiling.
Behavioral economic strategies to increase naloxone acquisition and carrying
Authors: Feuerstein-Simon Rachel , Dolan Abby , Sharma Meghana , Lowenstein Margaret W. , Buttenheim Alison M. , Meisel Zachary F. , Cannuscio Carolyn C. 
Published: January 2024

ABSTRACTBackgroundThe opioid overdose crisis claimed over 80,000 American lives in 2019, with opioids implicated in the majority of these deaths. The COVID-19 pandemic has exacerbated the crisis, with challenges arising from the increased use of fentanyl, synthetic opioids, and combined opioid-stimulant substances. Urgent strategies are required to mitigate drug-related harms in the context of an unsafe drug supply.ObjectiveThis paper presents the findings of two consecutive randomized controlled trials conducted in Philadelphia, aiming to assess the effectiveness of behavioral economic interventions in promoting naloxone acquisition and carrying among adults.MethodsThe trials focused on increasing naloxone acquisition (Study A) and promoting naloxone carrying (Study B) among participants who completed community-based overdose recognition and reversal training. Participants were randomized into three arms: those receiving text message nudges, those signing commitment contracts, and a control group receiving only in-person overdose reversal training. Data collection utilized a web-based platform, and participants were compensated upon study completion.ResultsIn Study A, participants were encouraged to acquire naloxone, and the primary endpoint was naloxone acquisition within four weeks post-training. Results showed that around one in five participants acquired naloxone, regardless of the intervention arm, indicating limited effectiveness of behavioral strategies in promoting naloxone acquisition.In Study B, where all participants received naloxone by default, the primary endpoint was the consistency of naloxone carrying. Participants had naloxone on hand at approximately half of the eight unannounced check-ins, with no significant differences between intervention groups and the control group.ConclusionNaloxone distribution by default emerges as a promising strategy to increase naloxone possession and save lives amidst the opioid overdose crisis. Addressing structural barriers, including cost and pharmacy availability, is essential. Additionally, interventions should consider leveraging motivations such as altruism and regret aversion to encourage naloxone carrying.
UPTAKE OF REPRODUCTIVE, MATERNAL AND NEWBORN HEALTH IN THE CONTEXT OF COVID-19 PANDEMIC IN KENYA
Authors: Jebet Joyce , Muia Ruth , Ongeso Abednego , Omuga Blasio , Omoni Grace , Wagoro Miriam 
Published: January 2024

AbstractBackgroundThe outbreak of COVID 19 in 2019 lead to destabilization of all sectors globally including access to health care. The strain on the health care system as a result of the disease outbreak led to a shift in operations in the health care system. Maternal and neonatal care was affected as women and their families could not freely access health care owing to the restrictions to curb the spread of COVID 19. This led to a risk of a reversal in the gains made in maternal and neonatal health, prompting the need to strengthen community midwifery.AimThe aim of this study was to strengthen community reproductive, maternal and newborn health in the context of COVID-19 pandemic in Kenya.Materials and methodsThis is part of an interventional study that sought to strengthen community maternal and neonatal health services. A baseline survey was conducted to assess the uptake of reproductive, maternal and neonatal care services in one sub-county in Kilifi and Kitui, where five wards in each sub-county were selected. An interviewer administered questionnaire was used to collect data. The sample size for the two Counties was 414.ResultsThere was a total of 378 respondents mostly comprising a rural population 75.7% (n=286). Outpatient and COVID 19 services (tests and vaccine) were most sought 37.5% (n= 137) and 29.9% (n=109) respectively. Antenatal care services were sought by 26% (n=95) of the respondents, postnatal care 9% (n=33) and skilled birth attendance 8.8% (n=32).ConclusionThe most utilized health facility services were outpatient and COVID 19 services. Antenatal care was also sought, however skilled birth attendance and postnatal care services were least sought.
Evaluation of the impact of concentration and extraction methods on the targeted sequencing of human viruses from wastewater
Authors: Jiang Minxi , Wang Audrey L.W. , Be Nicholas A. , Mulakken Nisha , Nelson Kara L. , Kantor Rose S. 
Published: January 2024

AbstractSequencing human viruses in wastewater is challenging due to their low abundance compared to the total microbial background. This study compared the impact of four virus concentration/extraction methods (Innovaprep, Nanotrap, Promega, Solids extraction) on probe-capture enrichment for human viruses followed by sequencing. Different concentration/extraction methods yielded distinct virus profiles. Innovaprep ultrafiltration (following solids removal) had the highest sequencing sensitivity and richness, resulting in the successful assembly of most near-complete human virus genomes. However, it was less sensitive in detecting SARS-CoV-2 by dPCR compared to Promega and Nanotrap. Across all preparation methods, astroviruses and polyomaviruses were the most highly abundant human viruses, and SARS-CoV-2 was rare. These findings suggest that sequencing success can be increased by using methods that reduce non-target nucleic acids in the extract, though the absolute concentration of total extracted nucleic acid, as indicated by Qubit, and targeted viruses, as indicated by dPCR, may not be directly related to targeted sequencing performance. Further, using broadly targeted sequencing panels may capture viral diversity but risks losing signals for specific low-abundance viruses. Overall, this study highlights the importance of aligning wet lab and bioinformatic methods with specific goals when employing probe-capture enrichment for human virus sequencing from wastewater.SynopsisFour concentration/extraction methods combined with probe-capture sequencing of human viruses in raw wastewater were compared. Innovaprep ultrafiltration with solids removal had the best performance for human virus detection sensitivity, richness, and recovery of near-complete genomes.
Bifidobacterium longummodifies a nutritional intervention for stunting in Zimbabwean infants
Authors: Gough Ethan K , Edens Thaddeus J , Carr Lynnea , Robertson Ruairi C , Mutasa Kuda , Ntozini Robert , Chasekwa Bernard , Geum Hyun Min , Baharmand Iman , Gill Sandeep K , Mutasa Batsirai , Mbuya Mduduzi N N , Majo Florence D , Tavengwa Naume , Francis Freddy , Tome Joice , Evans Ceri , Kosek Margaret , Prendergast Andrew J , Manges Amee R ,   the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial Team
Published: January 2024

SummaryChild stunting is an indicator of chronic undernutrition and reduced human capital. Small-quantity lipid-based nutrient supplements (SQ-LNS) has been widely tested to reduce stunting, but has modest effects. The infant intestinal microbiome may contribute to stunting, and is partly shaped by mother and infant histo-blood group antigens (HBGA). We investigated whether mother-infant fucosyltransferase status, which governs HBGA, and the infant gut microbiome modified the impact of SQ-LNS on stunting at age 18 months among Zimbabwean infants in the SHINE Trial (NCT01824940). We found that mother-infant fucosyltransferase discordance andBifidobacterium longummodified SQ-LNS efficacy. Infant age-related microbiome shifts inB. longumsubspecies dominance frominfantis, a proficient human milk oligosaccharide utilizer, tosuisorlongum, proficient plant-polysaccharide utilizers, were partly influenced by discordance in mother-infant FUT2+/FUT3-phenotype, suggesting that a “younger” microbiome at initiation of SQ-LNS reduces its benefits on stunting in areas with a high prevalence of linear growth restriction.
Effectiveness of a bedaquiline, linezolid, clofazimine “core” for multidrug-resistant tuberculosis
Authors: Zeng Chengbo , Hernán Miguel A. , Trevisi Letizia , Sauer Sara , Mitnick Carole D. , Hewison Catherine , Bastard Mathieu , Khan Palwasha , Seung Kwonjune J. , Rich Michael L. , Law Stephanie , Kikvidze Marina , Kirakosyan Ohanna , Miankou Alexey , Thit Phone , Mamsa Shahid , Janmohamed Aleeza , Melikyan Nara , Ahmed Saman , Vargas Dante , Binegdie Amsalu Bekele , Temirova Kulbaram , Oyewusi Lawrence , Philippe Kerline , Vilbrun Stalz C. , Khan Uzma , Huerga Helena , Franke Molly F. ,   endTB Observational Study Team
Published: January 2024

AbstractRationaleTreatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients.ObjectivesWe compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline.MethodsWe emulated a target trial to compare the effectiveness of initiating and remaining on the core regimen to one of five regimens reinforced with (1) bedaquiline for ≥9 months, (2) bedaquiline for ≥9 months and delamanid, (3) imipenem, (4) a second-line injectable, or (5) delamanid and imipenem. We included patients in whom a fluoroquinolone was unlikely to be effective based on drug susceptibility testing and/or prior exposure. Our analysis consisted of cloning, censoring, and inverse-probability weighting to estimate the probability of successful treatment.Measurements and Main ResultsAdjusted probabilities of successful treatment were high across regimens, ranging from 0.75 (95%CI:0.61, 0.89) to 0.84 (95%CI:0.76, 0.91). We found no substantial evidence that any of the reinforced regimens improved effectiveness of the core regimen, with ratios of treatment success ranging from 1.01 for regimens reinforced with bedaquiline ≥9 months (95%CI:0.79, 1.28) and bedaquiline ≥9 months plus delamanid (95%CI:0.81, 1.31) to 1.11 for regimens reinforced by a second-line injectable (95%CI:0.92, 1.39) and delamanid and imipenem (95%CI:0.90, 1.41).ConclusionsHigh treatment success underscores the effectiveness of regimens comprised of bedaquiline, linezolid, and clofazimine, highlighting the need for expanded access to these drugs.