bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort
Authors: Zucco Adrian G. , Bennedbæk Marc , Ekenberg Christina , Gabrielaite Migle , Leung Preston , Polizzotto Mark N. , Kan Virginia , Murray Daniel D. , Lundgren Jens D. , MacPherson Cameron R. 
Published: April 2023

Objective:
Human leucocyte antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort.

Design:
Cohort from the Strategic Timing of AntiRetroviral Treatment (START) study.

Methods:
We imputed HLA class I alleles from host genetic data (2546 HIV+ participants) and sampled immunopeptidomes from 2079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL.

Results:
We identified four clades totaling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B∗57:01 and B∗57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β −0.25; adj. P-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies

Conclusion:
The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data.
A novel, evidence-based, comprehensive clinical decision support system improves outcomes for patients with traumatic rib fractures
Authors: Jones Emma K. , Ninkovic Ivana , Bahr Matthew , Dodge Sarah , Doering Michael , Martin David , Ottosen Julie , Allen Tadashi , Melton Genevieve B. , Tignanelli Christopher J. 
Published: April 2023

BACKGROUND
Traumatic rib fractures are associated with high morbidity and mortality. Clinical decision support systems (CDSS) have been shown to improve adherence to evidence-based (EB) practice and improve clinical outcomes. The objective of this study was to investigate if a rib fracture CDSS reduced hospital length of stay (LOS), 90-day and 1-year mortality, unplanned ICU transfer, and the need for mechanical ventilation. The independent association of two process measures, an admission EB order set and a pain-inspiratory-cough score early warning system, with LOS were investigated.

METHODS
The CDSS was scaled across nine US trauma centers. Following multiple imputation, multivariable regression models were fit to evaluate the association of the CDSS on primary and secondary outcomes. As a sensitivity analysis, propensity score matching was also performed to confirm regression findings.

RESULTS
Overall, 3,279 patients met inclusion criteria. Rates of EB practices increased following implementation. On risk-adjusted analysis, in-hospital LOS preintervention versus postintervention was unchanged (incidence rate ratio [IRR], 1.06; 95% confidence interval [CI], 0.97–1.15, p = 0.2) but unplanned transfer to the ICU was reduced (odds ratio, 0.28; 95% CI, 0.09–0.84, p = 0.024), as was 1-year mortality (hazard ratio, 0.6; 95% CI, 0.4–0.89, p = 0.01). Provider utilization of the admission order bundle was 45.3%. Utilization was associated with significantly reduced LOS (IRR, 0.87; 95% CI, 0.77–0.98; p = 0.019). The early warning system triggered on 34.4% of patients; however, was not associated with a significant reduction in hospital LOS (IRR, 0.76; 95% CI, 0.55–1.06; p = 0.1).

CONCLUSION
A novel, user-centered, comprehensive CDSS improves adherence to EB practice and is associated with a significant reduction in unplanned ICU admissions and possibly mortality, but not hospital LOS.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Funding the war in America: A look in the mirror
Authors: Hynes Allyson M. , Weaver Jessica L. , Hatchimonji Justin S. , Sperry Jason L. , Sanchez Sabrina E. , Seamon Mark J. , Kheirbek Tareq , Scantling Dane R. 
Published: April 2023

BACKGROUND
Health care political action committees (HPACs) historically contribute more to candidates opposing firearm restrictions (FRs), clashing with their affiliated medical societies. These societies have increasingly emphasized the prevention of firearm violence and it is not known if recent contributions by their HPACs have aligned with their stated goals. We hypothesized that such HPACs still contribute similar amounts toward legislators up for reelection opposing FR.

METHODS
We identified HPACs of medical societies endorsing one or both calls-to-action against firearm violence published in the Annals of Internal Medicine (2015, 2019). House of Representatives (HOR) votes on H.R.8, a background checks bill, were characterized from GovTrack. We compiled HPAC contributions between the H.R.8 vote and election to HOR members up for re-election from the National Institute on Money in Politics. Our primary outcome was total campaign contributions by H.R.8 stance. Secondary outcomes included percentage of politicians funded and total contributions.

RESULTS
Nineteen societies endorsed one or both call-to-action articles. Three hundred eighty-five of 430 HOR members ran for reelection in 2020. Those endorsing H.R.8 (n = 226, 59%) received $2.8 M for $4,750 (interquartile range [IQR], $1000–$15,500) per candidate. Those opposing (n = 159, 41%) received $1.5 M for $2,500 (IQR, $0–$11,000) per candidate (p = 0.0057). Health care political action committees donated toward a median of 20% (IQR, 7–28) of candidates endorsing H.R.8 and 9% (IQR, 4–22) of candidates opposing H.R.8 (p = 0.0014). Those endorsing H.R.8 received 1,585 total contributions for a median of 3 (IQR, 1–10) contributions per candidate, while those opposing received 834 total contributions for a median of 2 (IQR, 0–7) contributions per candidate (p = 0.0029).

CONCLUSION
Politicians voting against background checks received substantial contributions toward reelection from the HPACs of societies advocating for firearm restrictions. However, this is the first study to suggest that HPAC's contributions have become more congruent with their respective societies. Further alignment of medical society goals and their HPAC political contributions could have a profound impact on firearm violence.

LEVEL OF EVIDENCE
Prognostic and Epidemiological; Level III.
The mechanisms of siRNA selection by plant Argonaute proteins triggering DNA methylation
Authors: Liu Wei , Shoji Keisuke , Naganuma Masahiro , Tomari Yukihide , Iwakawa Hiro-oki 
Published: April 2023

ABSTRACTThe model plantArabidopsis thalianaencodes as many as ten Argonaute proteins (AGO1–10) with different functions. Each AGO selectively loads a set of small RNAs by recognizing their length and 5′ nucleotide identity to properly regulate target genes. Previous studies showed that AGO4 and AGO6, key factors in DNA methylation, incorporate 24-nt small-interfering RNAs with 5′ adenine (24A siRNAs). However, it has been unclear how these AGOs specifically load 24A siRNAs. Here, we biochemically investigated the siRNA preference of AGO4, AGO6 and their chimeric mutants. We found that AGO4 and AGO6 use distinct mechanisms to preferentially load 24A siRNAs. Moreover, we showed that the 5′ A specificity of AGO4 and AGO6 is not determined by the previously known nucleotide specificity loop in the MID domain but rather by the coordination of the MID and PIWI domains. These findings advance our mechanistic understanding of how small RNAs are accurately sorted into different AGO proteins in plants.
Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC
Authors: Liu Songlei , Li Li , Zhang Fan , van Sambeek Björn , Appleton Evan , Ng Alex H. M. , Khoshakhlagh Parastoo , Chen Yuting , Garcia-Corral Mariana , Wu Chun-Ting , Huang Jeremy Y. , Tan Yuqi , Chao George , Aach John , Tam Jenny , Lim Elaine T. , Raychaudhuri Soumya , Church George M. 
Published: April 2023

AbstractThe ability to differentiate stem cells into human cell types is essential to define basic mechanisms and therapeutics, especially for cell types not routinely accessible by biopsies. But while engineered expression of transcription factors (TFs) identified through TF screens has been found to rapidly and efficiently produce some cell types, generation of other cell types that require complex combinations of TFs has been elusive. Here we develop an iterative, pooled single-cell TF screening method that improves the identification of effective TF combinations using the generation of human microglia-like cells as a testbed: Two iterations identified a combination of SPI1, CEBPA, FLI1, MEF2C, CEBPB, and IRF8 as sufficient to differentiate human iPSC into microglia-like cells in 4 days. Characterization of TF-induced microglia demonstrated molecular and functional similarity to primary microglia. We explore the use of single-cell atlas reference datasets to confirm identified TFs and how combining single-cell TF perturbation and gene expression data can enable the construction of causal gene regulatory networks. We describe what will be needed to fashion these methods into a generalized integrated pipeline, further ideas for enhancement, and possible applications.
Fusarium culmorumproduces NX-2 toxin simultaneously with deoxynivalenol and 3-acetyl-deoxynivalenol or nivalenol (submitted to Toxins)
Authors: Schiwek Simon , Alhussein Mohammad , Rodemann Charlotte , Budragchaa Tuvshinjargal , Beule Lukas , Tiedemann Andreas von , Karlovsky Petr 
Published: April 2023

AbstractFusarium culmorumis a major pathogen of grain crops. Infected plants accumulate deoxynivalenol (DON), 3-acetyl-deoxynivalenol (3-ADON), or nivalenol (NIV), which are mycotox-ins of the trichothecene B group. These toxins are also produced byF. graminearumspecies complex. New trichothecenes structurally similar to trichothecenes B but lacking the carbonyl group on C-8, designated NX toxins, were recently discovered in atypical isolates ofF. graminearumfrom North America. Only these isolates and a few strains of a yet to be characterizedFusariumspecies from South Africa are known to produce NX-2 and other NX toxins. Here we report that among 20F. culmorumstrains isolated from maize, wheat, and oat in Europe and Asia over a period of 70 years, 18 strains produced NX-2 simultaneously with 3-ADON and DON or NIV. Rice cultures of strains producing 3-ADON accumulated NX-2 in amounts corresponding to 2-8% of 3-ADON (1.2 - 36 mg/kg). A strain producing NIV accumulated NX-2 and NIV at comparable amounts (13.6 and 10.3 mg/kg, respectively). InF. graminearum, producers of NX-2 possess a special variant of cytochrome P450 monooxygenase encoded byTRI1that is unable to oxidize C-8. InF. culmorum, producers and non-producers of NX-2 possess identicalTRI1; the reason for the production of NX-2 is unknown. Our results indicate that production of NX-2 simultaneously with trichothecenes B is a common feature ofF. culmorum.Key resultIsolates ofFusarium culmorumobtained from different hosts at different locations over several dec-ades produced NX-2, which is a type A trichothecene structurally related to 3-ADON.
Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Pneumonia
Authors: Carvalho Neuenschwander Fernando , Barnett-Griness Ofra , Piconi Stefania , Maor Yasmin , Sprinz Eduardo , Assy Nimer , Khmelnitskiy Oleg , Lomakin Nikita , Goloshchekin Boris Mikhailovich , Nahorecka Ewelina , Calvacante Adilson Joaquim Westheimer , Ivanova Anastasia , Zhuravel Sergey Vladimirovich , Trufanova Galina Yurevna , Bonora Stefano , Saffoury Amer , Mayo Ami , Shvarts Yury , Rizzardini Giuliano , Sobroza de Mello Rogerio , Pilau Janaina , Klinov Alexey , Valente-Acosta Benjamin , Burlaka Oleg Olegovich , Bakhtina Natalia , Bar-Meir Maskit , Shishimorov Ivan Nikolaevich , Oñate-Gutierrez Jose , Rincon Cristian Ivan Garcia , Martynenko Tatiana Ivanovna , Abrahão Hajjar Ludhmila , Procopio Ana Carolina Nazare de Mendonca , Simon Krzystof , Santiago Walter Gabriel Chaves , Fronczak Adam , Filho Conrado Roberto Hoffmann , Hussein Osama , Martynov Vladimir Aleksandrovich , Chichino Guido , Blewaska Piotr , Wroblewski Jacek , Santana Sergio Saul Irizar , Agudelo Andres Felipe Ocampo , Barczyk Adam , Gerlach Rachael L. , Campbell Eppie , Bibliowicz Aida , Fathi Reza , Anderson Patricia , Raday Gilead , Klein Michal , Fehrmann Clara , Eagle Gina , Katz Ben-Yair Vered , Levitt Mark L. 
Published: April 2023

ABSTRACTRationaleThere are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation.ObjectiveEvaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia.MethodsA randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021.Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days.Main Outcome MeasurementsPrimary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days.Main ResultsPre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2levels at or below the median value (≤60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with ≤60% FIO2 at baseline that no longer required supplemental oxygen (≥24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed.ConclusionsPost-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen (≤60% FiO2). Further studies are warranted.Trial registration numberNCT04467840
From silence to song: Testosterone triggers extensive transcriptional changes in the female canary HVC
Authors: Ko Meng-Ching , Frankl-Vilches Carolina , Bakker Antje , Sohnius-Wilhelmi Nina , Alcami Pepe , Gahr Manfred 
Published: April 2023

AbstractSeasonal song production in canaries, influenced by gonadal hormones, is a well-documented phenomenon. We explored testosterone-induced song development in adult female canaries—a behavior rarely exhibited naturally. Gene regulatory networks in the song-controlling brain area HVC were compared at multiple time points (1 hour to 14 days) post-treatment with those of placebo-treated controls, paralleling HVC and song development. Females began vocalizing within four days of testosterone treatment, with song complexity and HVC volume increasing progressively over two weeks. Rapid transcriptional changes involving 2,739 genes preceded song initiation. Over two weeks, 9,913 genes—approximately 64% of the canary’s protein-coding genome—were differentially expressed, with 98% being transiently regulated. These genes are linked to various biological functions, with early changes at the cellular level and later changes affecting the nervous system level after prolonged hormone exposure. Our findings suggest that testosterone-induced song development is accompanied by extensive and dynamic transcriptional changes in the HVC, implicating widespread neuronal involvement. The data reveal extensive transcriptomic changes, including alterations in steroid receptor expression and numerous transcription factors, coinciding with significant neural transformations. These changes underpin the gradual emergence of singing behavior, providing insights into the neural basis of seasonal behavioral patterns.
Preventive small-quantity lipid-based nutrient supplements reduce severe wasting and severe stunting among young children: an individual participant data meta-analysis of randomized controlled trials
Authors: Dewey Kathryn G. , Arnold Charles D. , Wessells K. Ryan , Prado Elizabeth L. , Abbeddou Souheila , Adu-Afarwuah Seth , Ali Hasmot , Arnold Benjamin F. , Ashorn Per , Ashorn Ulla , Ashraf Sania , Becquey Elodie , Brown Kenneth H. , Christian Parul , Colford John M. , Dulience Sherlie J. L. , Fernald Lia C.H. , Galasso Emanuela , Hallamaa Lotta , Hess Sonja Y. , Humphrey Jean H. , Huybregts Lieven , Iannotti Lora L. , Jannat Kaniz , Lartey Anna , Port Agnes Le , Leroy Jef L. , Luby Stephen P. , Maleta Kenneth , Matias Susana L. , Mbuya Mduduzi NN , Mridha Malay K. , Nkhoma Minyanga , Null Clair , Paul Rina R. , Okronipa Harriet , Ouédraogo Jean-Bosco , Pickering Amy J. , Prendergast Andrew J. , Ruel Marie , Shaikh Saijuddin , Weber Ann M. , Wolff Patricia , Zongrone Amanda , Stewart Christine P. 
Published: April 2023

ABSTRACTBackgroundMeta-analyses show that small-quantity lipid-based nutrient supplements (SQ- LNS) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting.ObjectiveWe aimed to identify the effect of SQ-LNS on severe wasting (weight-for-length z- score < −3) and severe stunting (length-for-age z-score < −3).MethodsWe conducted a two-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNS provided to children 6 to 24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS vs. control and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons.ResultsQ-LNS provision led to a relative reduction of 31% in severe wasting (Prevalence Ratio, PR 0.69 (0.55, 0.86), n=34,373) and 17% in severe stunting (PR 0.83 (95% CI: 0.78, 0.90), n=36,795). Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded: PR 0.74 (0.57, 0.96), n=26,327 for severe wasting and PR 0.88 (0.81, 0.95), n=28,742 for severe stunting. Study-level characteristics generally did not significantly modify the effects of SQ-LNS, but results suggested greater effects of SQ-LNS in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation.ConclusionsIncluding SQ-LNS in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. Registered atwww.crd.york.ac.uk/PROSPEROas CRD42019146592.
Nanopore Fingerprinting of Supramolecular DNA Nanostructures
Authors: Confederat Samuel , Sandei Ilaria , Mohanan Gayathri , Wälti Christoph , Actis Paolo 
Published: April 2023

ABSTRACTDNA nanotechnology has paved the way for new generations of programmable nanomaterials. Utilising the DNA origami technique, various DNA constructs can be designed, ranging from single tiles to the self-assembly of large-scale complex multi-tile arrays. These DNA nanostructures have enabled new applications in biosensing, drug delivery and other multifunctional materials. In this study, we demonstrate real-time, non-destructive and label-free fingerprinting of higher-order assemblies of DNA origami nanostructures using solid-state nanopores. Using this approach, we quantify the assembly yields for each DNA origami nanostructure with single-entity resolution using the nanostructure-induced charge introduced in the nanopore as a discriminant. We compare the assembly yield of the supramolecular DNA nanostructures obtained with the nanopore with agarose gel electrophoresis and AFM imaging and demonstrate that the nanopore system can provide enhanced information about the nanostructures. We envision that this nanopore detection platform can be applied to a range of nanomaterial designs and enable the analysis and manipulation of large DNA assemblies in real-time with single-molecule resolution.STATEMENT OF SIGNIFICANCEWe demonstrate a single molecule high-throughput approach for the analysis of higher-order DNA origami assemblies with a crowded nanopore. The technique enables the characterisation of DNA origami nanostructures at statistically relevant numbers in real-time and at single-molecule resolution while being non-destructive and label-free, and without the requirement of lengthy sample preparations or use of expensive reagents. We exemplify the technique by demonstrating the quantification of the assembly yield of DNA origami nanostructures based on their equivalent charge surplus computed from the ion current signals recorded. Compared to the standard analysis methods of AFM and agarose gel electrophoresis, the nanopore measurements provides enhanced information about the nanostructures.
Detailed profiling with MaChIAto reveals various genomic and epigenomic features affecting the efficacy of knock-out, short homology-based knock-in and Prime Editing
Authors: Nakamae Kazuki , Takenaga Mitsumasa , Nakade Shota , Awazu Akinori , Sakamoto Naoaki , Yamamoto Takashi , Sakuma Tetsushi 
Published: April 2023

AbstractHighly efficient gene knock-out and knock-in have been achieved by harnessing CRISPR-Cas9 and its advanced technologies such as Prime Editor. In addition, various bioinformatics resources have become available to quantify and qualify the efficiency and accuracy of CRISPR edits, which significantly increased the user-friendliness of the general next-generation sequencing (NGS) analysis in the context of genome editing. However, there is no specialized and integrated software for investigating the preference in the genomic context involved in the efficiency and accuracy of genome editing using CRISPR-Cas9 and beyond. Here, we address this issue by establishing a novel analysis platform of NGS data for profiling the outcome of template-free knock- out and short homology-based editing, named MaChIAto (Microhomology-associatedChromosomalIntegration/editingAnalysistools) (https://github.com/KazukiNakamae/MaChIAto). MaChIAto accommodates the classification and profiling of the NGS reads to uncover the tendency of the corresponding method of genome editing. In the profiling function, MaChIAto can summarize the mutation patterns along with the editing efficiency, and > 70 kinds of feature analysis, e.g., correlation analysis with thermodynamics and secondary structure parameters, are available. Additionally, the classifying function of MaChIAto is based on, but much stricter than, that of the existing tool, which is achieved by implementing a novel method of parameter adaptation utilizing Bayesian optimization. To demonstrate the functionality of MaChIAto, we analyzed the NGS data of knock- out, short homology-based knock-in, and Prime Editing. We confirmed that some features of (epi-)genomic context affected the efficiency and accuracy. These results show that MaChIAto is a helpful tool for understanding the best design for CRISPR edits. More importantly, it is the first tool for discovering features in the short homology-based knock-in outcomes. MaChIAto would help researchers profile editing data and generate prediction models for CRISPR edits, further contributing to revealing a “black box” process to produce a variety of CRISPR and Prime Editing outcomes.