bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Antiretroviral Therapy Reduces Severity but Does Not Eliminate Neurodevelopmental Compromise in Children With HIV
Authors: Benki-Nugent Sarah , Tamasha Nancy , Mueni Alice , Laboso Tony , Wamalwa Dalton C. , Njuguna Irene , Gómez Laurén , Tapia Kenneth , Bangirana Paul , Maleche-Obimbo Elizabeth , Boivin Michael J. , John-Stewart Grace C. 
Published: January 2023

Background:
Early antiretroviral therapy (ART) during infancy reduces cognitive impairment due to HIV, but the extent of benefit is unclear.

Setting:
Children were recruited from hospital and health centers providing HIV care and treatment in Nairobi, Kenya.

Methods:
Cognitive, behavioral, and motor outcomes were assessed in children with HIV and early ART (<1 year), children with HIV and late ART (1.5–6 years), and children HIV–unexposed uninfected (CHUU). Domain z scores and odds neurobehavioral impairment (≤15th percentile in CHUU) were compared in adjusted analyses.

Results:
Children with HIV initiated ART at median ages 0.4 (early ART) and 3.5 years (late ART). Children were assessed at median ages 6.9 (CHUU, N = 61), 6.9 (early ART, N = 54), and 13.5 (late ART; N = 27) years. Children with late ART vs. children with early ART had significantly lower z scores in 7 domains, specifically global cognition, short-term memory, visuospatial processing, learning, nonverbal test performance, executive function, and motor skills (adjusted mean differences, −0.42 to −0.62, P values ≤ 0.05), and had higher odds impairment in 7 domains (adjusted odds ratios [aORs], 2.87 to 16.22, P values ≤ 0.05). Children with early ART vs. CHUU had lower z scores in 5 domains (global cognition, short-term memory, delayed memory, processing speed, and behavioral regulation [adjusted mean differences, −0.32 to −0.88, P values < 0.05]) and higher impairment for 2 domains (short-term memory [aOR, 3.88] and behavioral regulation [aOR 3.46], P values < 0.05). Children with late ART vs. CHUU had lower z scores in 8 domains (adjusted mean differences, −0.57 to −1.05, P values ≤ 0.05), and higher impairment in 7 domains (aORs 1.98 to 2.32, P values ≤ 0.05).

Conclusion:
Early ART in the first year of life attenuates but does not eliminate the neurodevelopmental compromise of HIV.
Diagnostic accuracy of screening tools for pediatric blunt cerebrovascular injury: An ATOMAC multicenter study
Authors: Nickoles Todd A. , Lewit Ruth A. , Notrica David M. , Ryan Mark , Johnson Jeremy , Maxson Robert Todd , Naiditch Jessica A. , Lawson Karla A. , Temkit M'hamed , Padilla Benjamin , Eubanks James W. 
Published: January 2023

BACKGROUND
Blunt cerebrovascular injury (BCVI) is rare but significant among children. There are three sets of BCVI screening criteria validated for adults (Denver, Memphis, and Eastern Association for the Surgery of Trauma criteria) and two that have been validated for use in pediatrics (Utah score and McGovern score), all of which were developed using retrospective, single-center data sets. The purpose of this study was to determine the diagnostic accuracy of each set of screening criteria in children using a prospective, multicenter pediatric data set.

METHODS
A prospective, multi-institutional observational study of children younger than 15 years who sustained blunt trauma to the head, face, or neck and presented at one of six level I pediatric trauma centers from 2017 to 2020 was conducted. All patients were screened for BCVI using the Memphis criteria, but criteria for all five were collected for analysis. Patients underwent computed tomography angiography of the head or neck if the Memphis criteria were met at presentation or neurological abnormalities were detected at 2-week follow-up.

RESULTS
A total of 2,284 patients at the 6 trauma centers met the inclusion criteria. After excluding cases with incomplete data, 1,461 cases had computed tomography angiography and/or 2-week clinical follow-up and were analyzed, including 24 cases (1.6%) with BCVI. Sensitivity, specificity, positive predictive value, and negative predictive value for each set of criteria were respectively 75.0, 87.5, 9.1, and 99.5 for Denver; 91.7, 71.1, 5.0, and 99.8 for Memphis; 79.2, 82.7, 7.1, and 99.6 for Eastern Association for the Surgery of Trauma; 45.8, 95.8, 15.5, and 99.1 for Utah; and 75.0, 89.5, 10.7, and 99.5 for McGovern.

CONCLUSION
In this large multicenter pediatric cohort, the Memphis criteria demonstrated the highest sensitivity at 91.7% and would have missed the fewest BCVI, while the Utah score had the highest specificity at 95.8% but would have missed more than half of the injuries. Development of a tool, which narrows the Memphis criteria while maintaining its sensitivity, is needed for application in pediatric patients.

LEVEL OF EVIDENCE
Diagnostic Test/Criteria; Level II.
The Role of AI Model Documentation in Translational Science: A Scoping Review
Authors: Brereton Tracey A. , Malik Momin , Lifson Mark A. , Greenwood Jason D. , Peterson Kevin J. , Overgaard Shauna M. 
Published: January 2023

AbstractBackgroundTranslation of artificial intelligence/machine learning (AI/ML)-based medical modeling software (MMS) into clinical settings requires rigorous evaluation by interdisciplinary teams and across the AI lifecycle. The fragmented nature of available resources to support MMS documentation limits the transparent reporting of scientific evidence to support MMS, creating barriers and impeding the translation of software from code to bedside.ObjectiveThe aim of this paper is to scope AI/ML-based MMS documentation practices and define the role of documentation in facilitating safe and ethical MMS translation into clinical workflows.MethodsA scoping review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. MEDLINE (PubMed) was searched using MeSH key concepts of AI/ML, ethical considerations, and explainability to identify publications detailing AI/ML-based MMS documentation, in addition to snowball sampling of selected reference lists. To include the possibility of implicit documentation practices not explicitly labeled as such, we did not use “documentation “ as a key concept but rather as an inclusion criterion. A two-stage screening process (title and abstract screening and full-text review) was conducted by an independent reviewer. A data extraction template was utilized to record publication-related information, barriers to developing ethical and explainable MMS, available standards, regulations, frameworks, or governance strategies related to documentation, and recommendations for documentation for papers that met inclusion criteria.ResultsOf the total 115 papers, 21 (18%) articles met the requirements for inclusion. Data regarding the current state and challenges of AI/ML-based documentation was synthesized and themes including bias, accountability, governance, and interpretability were identified.ConclusionsOur findings suggest that AI/ML-based MMS documentation practice is siloed across the AI life cycle and there exists a gray area for tracking and reporting of non-regulated MMS. Recommendations from the literature call for proactive evaluation, standards, frameworks, and transparency and traceability requirements to address ethical and explainability barriers, enhance documentation efforts, provide support throughout the AI lifecycle, and promote translation of MMS. If prioritized across multidisciplinary teams and across the AI lifecycle, AI/ML-based MMS documentation may serve as a method of coordinated communication and reporting toward resolution of AI translation barriers related to bias, accountability, governance, and interpretability.
Identification of a mitochondrial targeting sequence in cathepsin D and its localization in mitochondria
Authors: Ikari Naoki , Arakawa Hirofumi 
Published: January 2023

AbstractCathepsin D (CTSD) is a major lysosomal protease harboring an N-terminal signal peptide (amino acids 1–20) to enable vesicular transport from endoplasmic reticulum to lysosomes. Here, we report the possibility of a mitochondrial targeting sequence and mitochondrial localization of CTSD in cells. Live-cell imaging analysis with enhanced green fluorescent protein (EGFP)-CTSD indicated that CTSD localizes to mitochondria. CTSD amino acids 21–35 are responsible for its mitochondrial localization, which exhibit typical features of mitochondrial targeting sequences, and are evolutionarily conserved. A proteinase K protection assay and sucrose gradient analysis showed that a small population of endogenous CTSD molecules exists in mitochondria. These results suggest that CTSD is a dual-targeted protein that may localize in both lysosomes and mitochondria.
Nanocrystalline silver layer of knitted polyester outperforms other silver-containing wound dressings in an in vitro wound model
Authors: Hus Jonathan , Frausto Ricardo F. , Grunhut Joel , Hus Nir J. 
Published: January 2023

ABSTRACTBackgroundSilver possesses cytotoxic properties against many microorganisms and is regularly used in wound care. Current evidence supporting the use of one type of silver-containing wound dressing (SCWD) is insufficient.MethodsTo examine the ability of selected SCWDs to inhibit the growth of two strains of bacteria (E. coli and S. aureus) commonly found in wounds, an in vitro wound model was used. Bacteria were applied to the surface of nutrient agar and a piece of each SCWD was applied to the bacteria. The plates were incubated at 37°C overnight. The zone of inhibition (ZI) around each SCWD was measured in cm2.ResultsThe mean ZI for Acticoat Flex-3 onE. coliwas 1.59 ± 0.15 cm2, which was significantly greater than that observed for Aquacel Ag (p<0.001), Mepilex Ag (p<0.0001), Mepitel Ag (p<0.001), Optifoam (p<0.0001) and Tegaderm Alginate Ag (p<0.01), but statistically indistinguishable from Maxorb II Ag. The mean ZI onS.aureuswas 1.21 ± 0.16 cm2, which was greater than Aquacel Ag (p<0.05), Mepilex (p<0.0001), Optifoam (p<0.0001) and Tegaderm Alginate Ag (p<0.05), but statistically indistinguishable from Maxorb II Ag or Mepitel Ag.ConclusionsOf the SCWDs tested, Acticoat Flex-3 demonstrated the most robust antimicrobial effect. Herein we show that Acticoat Flex-3 may provide the most wound protection against bacterial infection. In conclusion, these data provide clinicians with additional independent evidence to inform their clinical practice on the use of specific wound dressings.PRECISThe antimicrobial properties of Acticoat Flex-3, a dressing composed of nanocrystalline silver layer of knitted polyester, outperformed other silver-containing dressings againstE. coliandS. aureus.
Zika virus dumbbell-1 structure is critical for sfRNA presence and cytopathic effect during infection
Authors: Graham Monica E. , Merrick Camille , Akiyama Benjamin M. , Szucs Matthew , Leach Sarah , Kieft Jeffery S. , Beckham J. David 
Published: January 2023

AbstractZika virus (ZIKV) contains multiple conserved RNA structures in the viral 3’ untranslated region (UTR), including the structure known as dumbbell-1 (DB-1). Previous research has shown that the DB-1 structure is important for flavivirus genome replication and cytopathic effect (CPE). However, the role of the DB structure and the mechanism by which it contributes to viral pathogenesis is not known. Using recently solved flavivirus DB RNA structural data, we designed two DB-1 mutant ZIKV infectious clones termed ZIKV-TL.PK, which disrupts DB-1 tertiary folding and ZIKV-p.2.5’, which alters DB-1 secondary structure formation. In cell culture, we found that viral genome replication of both mutant clones is not significantly affected compared to ZIKV-WT, but viral CPE is considerably decreased. We investigated sub-genomic flaviviral RNA (sfRNA) formation by both DB-1 mutants following A549 infection and found both mutant clones have decreased levels of all sfRNA species compared to ZIKV-WT during infection. To investigate the mechanism of decreased CPE in our DB-1 mutant clones, we assayed ZIKV DB mutant-infected A549 cells for cell viability and caspase activation. We found that cell viability is significantly increased in DB-1 mutant-infected cells compared to ZIKV-WT due to reduced caspase 3 activation. We also show that replication of the ZIKV-P.2.5’ mutant was significantly restricted by type I interferon treatment without altering interferon stimulated gene expression. Using a murine model of ZIKV infection, we show that both ZIKV-DB-1 mutants exhibit reduced morbidity and mortality compared to ZIKV-WT virus due to tissue specific attenuation in ZIKV-DB viral replication in the brain tissue. Overall, our data show that the flavivirus DB-1 RNA structure is important for maintaining sfRNA levels during infection which supports caspase-3 dependent, viral cytopathic effect, type 1 interferon resistance, and viral pathogenesis in a mouse model.
PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle
Authors: Benzarti Mohaned , Oudin Anais , Viry Elodie , Gargiulo Ernesto , Schmoetten Maryse , Neises Laura , Pulido Coralie , Lorenz Nadia I. , Ronellenfitsch Michael W. , Sumpton David , Warmoes Marc , Jaeger Christian , Lesur Antoine , Moussay Etienne , Paggetti Jerome , Niclou Simone P. , Letellier Elisabeth , Meiser Johannes 
Published: January 2023

AbstractThroughout the metastatic cascade, cancer cells are faced with harsh metabolic environments and nutritional stresses which apply selection pressure leaving only the most metabolically resilient cells to survive and form metastases. Metabolic characterisation of such cell populationsin vitrois currently challenging. Using galactose as a tool compound to mimic glycolytic limitation within the tumour microenvironment of primary and secondary neoplastic sites, we were able to uncover metabolic flexibility and plasticity of cancer cellsin vitro. In contrast to the established idea that high glycolytic flux and expression of dimeric PKM2 redirects carbons towards anabolic routes such as the pentose phosphate pathway and serine synthesis pathway (SSP), we have discovered by using stable-isotope tracing that also glycolytic limitation results in metabolic rewiring. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near complete block of pyruvate kinase isozyme M2 (PKM2) to divert carbons towards SSP. Simultaneously, TCA cycle flux is sustained and oxygen consumption is increased, both supported by glutamine. Glutamine not only supports TCA cycle flux but also SSP via distinct mechanisms. Due to PKM2 block, malic enzyme exclusively supports TCA cycle flux while mitochondrial phosphoenolpyruvate carboxykinase supports SSP. Moreover, by using genetic modifications of different one-carbon (1C) cycle enzymes, we are able to reverse the PKM2 block suggesting a link between mitochondrial 1C cycle and pyruvate kinase. Thus we show that PKM2 inhibition acts as a branching point to direct glycolytic and glutamine carbons into distinct routes, overall supporting the metabolic plasticity and flexibility of cancer cells.
Formate Promotes Invasion and Metastasis by Activating Fatty Acid Synthesis and Matrix Metalloproteinases
Authors: Delbrouck Catherine , Kiweler Nicole , Pozdeev Vitaly I. , Neises Laura , Oudin Anaïs , Schuster Anne , d’Hérouël Aymeric Fouquier , Shen Ruolin , Halder Rashi , Lesur Antoine , Ogris Christoph , Lorenz Nadia I. , Jaeger Christian , Ronellenfitsch Michael W. , Piraud Marie , Skupin Alexander , Niclou Simone P. , Letellier Elisabeth , Meiser Johannes 
Published: January 2023

ABSTRACTMetabolic rewiring is essential to enable cancer onset and progression. One important metabolic pathway that is often hijacked by cancer cells is the one-carbon cycle, in which the third carbon of serine is oxidized to formate. We have previously shown that formate production in cancer cells often exceeds the anabolic demand, resulting in formate overflow. Furthermore, we observed that high extracellular formate promotes thein vitroinvasiveness of glioblastoma (GBM) cells. However, additional data supporting thisin vitroobservation and mechanistic details remained elusive so far.In the present study, we now demonstrate that inhibition of formate overflow results in a decreased invasiveness of GBM cellsex vivoandin vivo. Additionally, we observed that exposure to exogeneous formate can induce a transiently stable pro-invasive phenotype that results in increased metastasis formationin vivo. All in all, these results suggest that a local formate increase within the tumor microenvironment may be one factor that can promote cancer cell motility and dissemination.Mechanistically, we uncover a previously undescribed interplay where formate acts as a trigger to alter fatty acid metabolism and matrix metalloproteinase (MMP) activity which in turn impacts cancer cell invasiveness. We thus highlight the role of formate as a pro-invasive metabolite. Gaining a deeper understanding of formate overflow and how it promotes invasion in cancer, may open new therapeutic opportunities to prevent cancer cell dissmination.
In silico Antibody-Peptide Epitope prediction for Personalized cancer therapy
Authors: Jacobs Ivan , Ming Lim Chwee , Mong Jamie , Emmanoil Maragkoudakis , Malik Nishant 
Published: January 2023

ABSTRACTThe human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encodes cell-surface proteins responsible for regulating the immune system. Viral peptides presented to cancer cell surfaces by the HLA trigger the immune system to kill the cells, creating Antibody-peptide epitopes (APE). This study proposes an in-silico approach to identify patient-specific APEs by applying complex networks diagnostics on a novel multiplex data structure as input for a deep learning model. The proposed analytical model identifies patient and tumor-specific APEs with as few as 20 labeled data points. Additionally, the proposed data structure employs complex network theory and other statistical approaches that can better explain and reduce the black box effect of deep learning. The proposed approach achieves an F1-score of 80% and 93% on patients one and two respectively and above 90% on tumor-specific tasks. Additionally, it minimizes the required training time and the number of parameters.
Combined KRASG12Cand SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance
Authors: Thatikonda Venu , Lu Hengyu , Jurado Sabine , Kostyrko Kaja , Bristow Christopher A. , Bosch Karin , Feng Ningping , Gao Sisi , Gerlach Daniel , Gmachl Michael , Lieb Simone , Jeschko Astrid , Machado Annette A. , Marszalek Ethan D. , Mahendra Mikhila , Jaeger Philipp A. , Sorokin Alexey , Strauss Sandra , Trapani Francesca , Kopetz Scott , Vellano Christopher P. , Petronczki Mark , Kraut Norbert , Heffernan Timothy P. , Marszalek Joseph R. , Pearson Mark , Waizenegger Irene , Hofmann Marco H. 
Published: January 2023

AbstractEfforts to improve the anti-tumor response to KRASG12Ctargeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12Cinhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12Cplus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.
BRWD1 orchestrates chromatin topology by converting static to dynamic cohesin complexes
Authors: Mandal Malay , Maienschein-Cline Mark , Hu Yeguang , Mohsin Azam , Veselits Margaret L. , Wright Nathaniel E. , Okoreeh Michael K. , me Yoon Young , Veselits Jacob , Georgopoulos Katia , Clark Marcus R. 
Published: January 2023

AbstractLymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination1. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs2,3. How this occurs remains unclear. Herein, we demonstrate that in small pre-B cells, the lineage and stagespecific epigenetic reader Bromodomain and WD Repeating Containing Protein 1 (BRWD1)2,4reorders three-dimensional chromatin topology to affect transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters and coordinated this withIgklocus contraction. BRWD1 did so by converting chromatin-bound static cohesin to dynamic complexes competent to mediate long-range looping. Remarkably, ATP depletion recapitulated cohesin distributions observed inBrwd1-/-cells. Therefore, in small pre-B cells, cohesin conversion is the main energetic mechanism dictating where dynamic looping occurs in the genome. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be dictated by lineage contextual mechanisms to facilitate specific cell fate transitions.
Soybean and cotton spermosphere soil microbiome shows dominance of soil-borne copiotrophs
Authors: Olofintila Oluwakemisola E. , Noel Zachary A. 
Published: January 2023

AbstractThe spermosphere is the transient, immediate zone of soil around imbibing and germinating seeds. It represents a habitat where there is contact between seed-associated microbes and soil microbes, but is studied less compared to other plant habitats. Previous studies on spermosphere microbiology were primarily culture-based or did not sample the spermosphere soil as initially defined in space and time. Thus, the objectives of this study were to develop an efficient strategy to collect spermosphere soils around imbibing soybean and cotton in non-sterile soil and investigate changes in microbial communities. The method employed sufficiently collected spermosphere soil as initially defined in space by constraining the soil sampled with a cork borer and confining the soil to a 12-well microtiter plate. Spermosphere prokaryote composition changed over time and depended on the crop within six hours after seeds were sown. By 12 to 18 hours, crops had unique microbial communities in spermosphere soils. Prokaryote evenness dropped following seed imbibition with the proliferation of copiotrophic soil bacteria. Due to their long history of plant growth promotion, prokaryote OTUs inBacillus, Paenibacillus, Burkholderia, Massilia, Azospirillum, andPseudomonaswere notable genera enriched. Fungi and prokaryotes were hub taxa in cotton and soybean spermosphere networks. Additionally, the enriched taxa were not hubs in networks, suggesting other taxa besides those enriched may be important for spermosphere communities. Overall, this study advances knowledge in the assembly of the plant microbiome early in a plant’s life, which may have plant health implications in more mature plant growth stages.