bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective Effects of Butyrate on Retinal Neovascularization in Preclinical Retinopathy of Prematurity Models
Authors: Oxenrider Allston , Bui Tommy , Lester John , Thounaojam Menaka C. , Martin Pamela M. , Jadeja Ravirajsinh N. 
Published: June 2024

AbstractRetinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide, necessitating new therapeutic strategies. Current interventions targeting advanced disease stages often fail to prevent long-term visual impairment. This study investigates the potential of sodium butyrate (NaB), an orally administered short-chain fatty acid, in preclinical models of ROP. Using the oxygen-induced retinopathy (OIR) mouse model, we demonstrate that daily oral NaB supplementation significantly protects against pathological angiogenesis, impacting not only vascular but also neuronal and microglial pathology in the inner retina. Notably, NaB shows efficacy in early-phase ROP intervention, as evidenced by studies in post-natal day 9 (P9) OIR mice and a novel hyperglycemia-associated retinopathy (HAR) model, which mimics the hyperglycemic conditions of many premature infants. These findings highlight NaB as a promising alternative or adjunct therapy to current anti-VEGF treatments, offering protection across multiple retinal cell types and stages of ROP development. The study underscores the need for further research to elucidate the specific mechanisms of NaB’s action, paving the way for its potential clinical application in ROP management. This research marks the first exploration of butyrate as a preventative and therapeutic agent for ROP, setting the stage for additional preclinical evaluations and optimization.HighlightsSodium butyrate (NaB) shows significant protection against pathological angiogenesis in the oxygen-induced retinopathy (OIR) mouse model.NaB impacts not only vascular but also neuronal and microglial pathology in the inner retina.The study highlights NaB’s potential as an early-phase intervention therapy for retinopathy of prematurity (ROP).This research is the first to investigate butyrate as a preventative and therapeutic agent for ROP.
Student self-assessment: feasibility, advantages and limitations Example of a workshop for trainee surgeons using a suture score
Authors: Riquin Elise , Le Nerzé Thomas , Goulin Jeanne , Rony Louis , Boucher Sophie , Martin Ludovic , Schmitt Françoise 
Published: June 2024

AbstractIntroductionEvaluating skills requires developing relevant grading tools that could potentially be used for self-assessments. The goal of our study was to assess the relevance of a self-assessment (SA) grid used for a skin suture exercise as compared to an evaluation carried out at the same time by an expert (EE), while also identifying any factors likely to influence it.Materials and methodsBetween 2018 and 2022, an assessment grid for a skin suture exercise was used during skills assessment sessions with first-year trainee surgeons. The students were given a self-assessment grid to fill out at the same time. The results of the SA and the EE in this grid were analyzed and compared, then set against the anxiety scores of the trainees based on the STAI Y-A. A comparative analysis of trainees with a tendency to over- or underestimate themselves was carried out to identify the factors that could contribute to them misjudging their skills.FindingsThe data for 70 trainee doctors was analyzed. The mean of the difference in score between the SA and the EE was 2 points lower for SA than EE (p < 0.001). The mean score for the STAI Y-A was 36.2 +/- 8.9 and the learner’s anxiety had no effect on the EE but did affect the SA. When learners showed low self-confidence, they underestimated themselves, but examiners also had a tendency to give them lower grades. In multivariate analysis, the less experience a learner had, the more they tended to overestimate their abilities.ConclusionAnxiety and self-confidence affect self-assessment, but external assessment does not seem to be affected by the learner’s stress levels. Formative self-reflection based on the use of SA grids should be introduced during medical studies so as to adjust the level of technical skill perceived by trainees and to make simulation-based training more effective.
Reproducibility and Robustness of Localized Mortality Prediction
Authors: Nitch-Griffin Evelyn , Peterson Amy , Skaf Yara , Brunson Jason Cory 
Published: June 2024

AbstractBackgroundWhile localized modeling—the use of predictive models to perform the adaptation step in case-based reasoning—has been evaluated in several experimental settings, its reported successes have infrequently been independently and externally validated.ObjectiveWe aimed to extend and validate an experimental study of mortality prediction in a critical care population and to assess the importance of several methodological factors to predictive performance.MethodsWe reproduced the workflow of Lee, Maslove, and Dubin (2015) using an updated database. We evaluated performance as area under the receiver operating characteristic curve and under the precision–recall curve and calibration as weakness of evidence in Hosmer– Lemeshow tests. We compared the effects of several modeling choices, including how relevance is quantified, and how relevance cohorts are retrieved, and the choice of model. We compared ours to previous results and used linear regression to quantify the role of each modeling choice on performance.ResultsOverall performance and its relationship to cohort size validated previous results. These relationships varied by model family as expected, though we observed no advantage of decision trees over a model-free approach and poor performance by random forests. An alternate choice of unlearned similarity measure yielded marginal and inconsistent performance differences. Denominating cohorts by similarity threshold rather than by cardinality yielded marginal but consistent performance losses. A temporal validation exercise enabled by a change of information system before the recent upgrade corroborated performance estimates from cross-validation. In all, cohort denomination mattered more to performance than any other methodological choice.DiscussionThe greater impact of retrieval than of adaptation suggests a weakness with the strategy of localized modeling. Additional research to deconstruct the varieties of this approach and quantify the relative benefits of its components is needed to resolve this question.
Clinical prediction with localized modeling using similarity-based cohorts: A scoping review
Authors: Cohen Adi , McCall-Junkin Patti , Brunson Jason Cory 
Published: June 2024

AbstractBackgroundApplications of classical case-based reasoning (CBR) have given rise to a family of techniques we call “localized models”, in which a statistical model is fitted to a neighborhood of labeled cases matched by similarity to a target case. We aim to describe clinical and health applications of localized models to date and propose a general framework for their design and evaluation.MethodsWe searched four bibliographic platforms during 2021 July 19–22, updated 2024 January 24. We set four eligibility criteria to identify applications of localized models to clinical and health tasks. Two authors divided title/abstract screening and reviewed screened entries for inclusion. We discussed settings, tasks, and tools; identified and tabulated themes; and synthesized the methods into a general framework.ResultsOf 1,657 search results, 360 were reviewed, then combined with 43 publications that seeded the review and 1 obtained by citation tracking. 27 were included, published 1997–2022. The specificity of search terms was poor, and inter-rater reliability was low. Almost all models were predictive, the most common tasks being prognosis and diagnosis. Most studies used clinical, occasionally laboratory and image, data. Several addressed memory and runtime costs. A general technique that specializes to most of those reviewed involved matching, retrieval, fitting, and evaluation steps that could optionally be supervised, optimized, or recursively performed.ConclusionsLocalized models have potential to improve the performance of clinical decision support tools while maintaining interpretability, but rigorous comparisons to competing methods must be conducted and computational hurdles must be overcome. We hope that our review will spur future work on efficiency, reproducibility, and user needs.
Association of Endovascular Thrombectomy Volume and Outcomes in Acute Ischemic Stroke: A National Inpatient Sample Study
Authors: Fry Lane , Brake Aaron , Heskett Cody , De Stefano Frank A. , Williams Ari , Majo Nashaat , Lei Catherine , Alkiswani Abdul-Rahman , Le Kevin , Rouse Adam G. , Peterson Jeremy , Ebersole Koji 
Published: June 2024

AbstractBackgroundPrevious studies have reported a positive relationship between higher hospital endovascular thrombectomy (EVT) volume and shorter procedures, higher revascularization rates, and improved functional outcomes. We investigated the association between hospital EVT volume and clinical outcomes using the National Inpatient Sample (NIS) database from 2016-2020.MethodsA cross-sectional analysis of the NIS examining the relationship of hospital EVT volume and outcomes was performed. All relevant clinical and demographic information was collected. The outcomes were favorable functional outcome (home without assistance), inpatient mortality, and intracerebral hemorrhage (ICH). Centers were classified as high-volume if they were in the top quintile of annual EVT volume. We performed univariate, multivariate, nearest neighbor matched analysis, and an exploratory annual case volume cutoff analysis.ResultsThere were 114,640 patients who underwent EVT included in the sample. Of these, 24,415 (21.3%) were in the high-volume group. High-volume centers had higher rates of favorable functional outcome in univariate (OR 1.20, p < 0.001), multivariate (aOR 1.19, p = 0.003), and matched analysis (OR 1.14, p = 0.028). Prior to matching, lower rates of inpatient mortality (OR 0.83, p < 0.001). However, in univariate and matched analysis there were no differences between high and low-volume centers. There were no differences in ICH across all analyses. Functional benefit was first noted at ≥ 50 EVTs, but centers performing ≥ 175 EVTs had substantially higher functional benefit (aOR 1.42, p = 0.002).ConclusionsOur analysis demonstrates increased hospital case volume is associated with a modest improvement in favorable functional outcomes in patients undergoing EVT for AIS. Attempts to identify procedural cut off values reveal likely improved functional outcomes beginning at 50 EVT per year, while this benefit seems to increase with increasing case volumes. These higher levels of case volumes do not lead to higher rates of inpatient mortality or ICH.
Noncanonical roles of chemokine regions in CCR9 activation revealed by structural modeling and mutational mapping
Authors: Pinheiro Ines De Magalhaes , Dawson John R.D. , Calo Nicolas , Paolini-Bertrand Marianne , Akondi Kalyana Bharati , Tan Gavin , Handel Tracy M. , Kufareva Irina , Hartley Oliver 
Published: June 2024

AbstractThe G protein-coupled CC chemokine receptor 9 (CCR9) plays a major role in inflammatory bowel disease and has been implicated in cancer. Despite its importance as a drug target, there is limited mechanistic understanding of how CCR9 engages and is activated by its endogenous chemokine agonist CCL25. Here, by combining structural modeling with multimodal pharmacological assessment of receptor mutants, we generated a functional map of the CCR9-CCL25 interaction interface and delineated key determinants of binding, agonism, constitutive activity, and G protein vs arrestin signaling. In contrast to all complexes studied to date, where chemokines drive receptor activation through their N-termini, we determined that CCL25 activates CCR9 via a distinct region, its 30s loop. In support of this non-canonical mechanism, CCR9 signaling is tolerant to alanine mutations in the N-terminus of CCL25 but strongly affected by modifications to the 30s loop. Through molecular evolution of the CCL25 N-terminus, we identified chemokine analogs with enhanced binding properties. However, in contrast to other receptor-chemokine systems, these analogs remained full agonists, consistent with the localization of CCL25 signaling determinants outside of the N-terminus. The non-canonical signature of CCR9 activation provides new insights to aid CCR9 drug discovery and may also inform structure-based design of drugs targeting other chemokine receptors.
Nonsymmetric formation of Δ1-piperideine from lysine in plants via a bacterial-like PLP-dependent enzyme
Authors: Wood Catharine X. , Daza Oriana Serna , Newling Katherine , James Sally , Unsworth William P. , Lichman Benjamin R. 
Published: June 2024

AbstractPiperidine alkaloids in plants derive from lysine via Δ1-piperideine. We investigated the alkaloid biosynthesis inFlueggea suffruticosa, a plant that produces diverse piperidine alkaloids, including securinine. Until now, pathways leading to the formation of Δ1-piperideine have involved two enzymatic steps: a decarboxylase and an oxidase, proceeding via free cadaverine. We discovered Δ1-piperideine synthase (PS), a PLP-dependent enzyme that forms Δ1-piperideine directly from lysine via an oxidative deamination. We demonstrate that PS catalyses this transformation in a non-symmetric manner, and show it is positioned within the group III decarboxylase family, which is typically associated with prokaryotes. We also identified a paralog gene exhibiting decarboxylase activity. This work delineates the first enzymatic step in the biosynthesis of securinine as an unprecedented oxidative deamination of lysine. It also marks the identification of the first eukaryotic group III decarboxylase and resolves the longstanding question of non-symmetric nitrogen incorporation in piperidine alkaloids.
Imperfect hairpins formed by CTG trinucleotide repeats are heteroduplex DNA molecules in living cells
Authors: Viterbo David , Dupaigne Pauline , Kaminski Pierre Alexandre , Dejardin François , Petres Stéphane , Cam Eric Le , Richard Guy-Franck 
Published: June 2024

AbstractThere are over fifty microsatellite expansion disorders, often neurodegenerative pathologies, due to large expansions of tandem repeat sequences. These microsatellites vary in motif composition, size and copy number in the genome. The ability of these repeats to form secondary structuresin vitrois strongly suspected to trigger the expansion process and therefore, the pathology. However, there is no formal proof that similar structures are formedin vivo, in living and replicating cells.We are focused on the CTG trinucleotide repeat whose expansion is responsible for myotonic dystrophy type 1 (DM1 or Steinert disease), affecting 1 in 8,000 people worldwide.A series of llama nanobodies (VHH) were selected to bind to the secondary structure formed by a synthetic imperfect CTG hairpin. Yeast one-hybrid was used to identify VHH that were able to activate a reporter genein vivo. One of them was shown to be very specific since it binds a CTG hairpin but not a CAG hairpin or a GC-rich sequence. This nanobody also bind to long CTG trinucleotide repeats carried by plasmidic or genomic DNAs, proportionally to the number of repeats, suggesting that longer repeats tend to form more frequently imperfect hairpins. Finally, the VHH was bound to a protein G column and used to selectively enrich structure-containing DNA molecules, that were further observed by electron microscopy. They exhibit different kinds of structures in which only one strand is folded into an imperfect hairpin.Our results unambiguously show that alternative DNA structures are transiently formed by CTG trinucleotide repeats in living bacterial and yeast cells and suggest that imperfect CTG hairpins mainly existin vivomainly as heteroduplex DNA molecules.
CircPVT1 sponges miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer
Authors: Palcau Alina Catalina , Pulito Claudio , De Pascale Valentina , Casadei Luca , Valerio Maria Cristina , Sacconi Andrea , Rutigliano Daniela , Donzelli Sara , Auciello Romana Francesca , Pimpinelli Fulvia , Muti Paola , Botti Claudio , Strano Sabrina , Blandino Giovanni 
Published: June 2024

AbstractAltered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is still unexplored. Herein, we initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity which promotes transcriptionally glutaminase, which converts glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids. In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.
The dominance of global phase dynamics in human cortex, from delta to gamma
Authors: Alexander David M. , Dugué Laura 
Published: June 2024

AbstractThe organization of the phase of electrical activity in the cortex is critical to inter-site communication, but the balance of this communication across macroscopic (>15cm), mesoscopic (1 to 15cm) and microscopic (<1cm) ranges is an open question. Traveling waves in the cortex are spatial phase gradients, such that phase values change smoothly through the cortical sheet over time. Macroscopic cortical traveling waves have been understudied compared to micro- or mesoscopic waves. The spatial frequencies (i.e., the characteristic scales) of cortical waves have been characterized in the grey-matter for micro- and mesoscopic scales of cortex and show decreasing spatial power with increasing spatial frequency. This research, however, has been limited by the size of the measurement array, thus excluding macroscopic traveling waves. Obversely, poor spatial resolution of extra-cranial measurements prevents incontrovertible macroscopic estimates of spatial power via electroencephalogram and magnetoencephalogram. We apply a novel method to estimate the spatial frequency spectrum of phase dynamics in order to quantify the uncertain macroscopic scale. Stereotactic electroencephalogram is utilized to leverage measurements of local-field potentials within the grey matter, while also taking advantage of the sometimes large extent of spatial coverage. Irregular sampling of the cortical sheet is offset by use of linear algebra techniques to empirically estimate the spatial frequency spectrum. We find the spatial power of the phase is highest at the lowest spatial frequencies (longest wavelengths), consistent with the power spectra ranges for micro- and meso-scale dynamics, but here shown up to the size of the measurement array (15-25cm), i.e., approaching the entire extent of cortex. Low spatial frequencies dominate the cortical phase dynamics. This has important functional implications as it means that the phase measured at a single contact in the grey-matter is more strongly a function of global phase organization than local. This result arises across a wide range of temporal frequencies, from the delta band (2Hz) through to the high gamma range (100Hz).
Machine learning guided rational design of a non-heme iron-based lysine dioxygenase improves its total turnover number
Authors: Wilson R. Hunter , Damodaran Anoop R. , Bhagi-Damodaran Ambika 
Published: June 2024

AbstractHighly selective C-H functionalization remains an ongoing challenge in organic synthetic methodologies. Biocatalysts are robust tools for achieving these difficult chemical transformations. Biocatalyst engineering has often required directed evolution or structure-based rational design campaigns to improve their activities. In recent years, machine learning has been integrated into these workflows to improve the discovery of beneficial enzyme variants. In this work, we combine a structure-based machine-learning algorithm with classical molecular dynamics simulations to down select mutations for rational design of a non-heme iron-dependent lysine dioxygenase, LDO. This approach consistently resulted in functional LDO mutants and circumvents the need for extensive study of mutational activity before-hand. Our rationally designed single mutants purified with up to 2-fold higher yields than WT and displayed higher total turnover numbers (TTN). Combining five such single mutations into a pentamutant variant, LPNYI LDO, leads to a 40% improvement in the TTN (218±3) as compared to WT LDO (TTN = 160±2). Overall, this work offers a low-barrier approach for those seeking to synergize machine learning algorithms with pre-existing protein engineering strategies.
Tafazzin regulates neutrophil maturation and inflammatory response
Authors: Zakrzewski Przemysław , Rice Christopher M. , Fleming Kathryn , Cela Drinalda , Groves Sarah J. , Ponce Fernando , Gibbs Willem , Roberts Kiran , Pike Tobias , Strathdee Douglas , Anderson Eve , Nobbs Angela H. , Toye Ashley , Steward Colin , Amulic Borko 
Published: June 2024

ABSTRACTBarth syndrome (BTHS) is a rare genetic disease caused by mutations in theTAFAZZINgene. It is characterized by neutropenia, cardiomyopathy and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet there is little understanding of the molecular and physiological causes of this phenomenon. We combined bone marrow analysis, CRISPR/Cas9 genome editing in hematopoietic stem cells and functional characterization of circulating BTHS patient neutrophils to investigate the role ofTAFAZZINin neutrophils and their progenitors. We demonstrate a partial cell intrinsic differentiation defect, along with a dysregulated neutrophil inflammatory response in BTHS, including elevated formation of neutrophil extracellular traps (NETs) in response to calcium flux. Developmental and functional alterations in BTHS neutrophils are underpinned by perturbations in the unfolded protein response (UPR) signaling pathway, suggesting potential therapeutic avenues for targeting BTHS neutropenia.