bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-depth Clinical, Hemodynamic, and Volumetric Assessment of the Resection and Partial Liver Transplantation With Delayed Total Hepatectomy-Type Auxiliary Liver Transplantation in Noncirrhotic Setting
Authors: Coubeau Laurent , Fontaine Alix , Ciccarelli Olga , Bonaccorsi Eliano , Derudder Max , Dahqvist Géraldine , Marique Lancelot , Reding Raymond , Leclercq Isabelle A. , Dili Alexandra 
Published: August 2024

Background:
The Resection And Partial Liver Transplantation with Delayed total hepatectomy (RAPID) procedure involves left hepatectomy with orthotopic implantation of a left lobe and right portal vein ligation. This technique induces volumetric graft increase, allowing for a right completion hepatectomy within 15 days. Notably, there is a lack of data on the hemodynamics of small-for-size grafts exposed to portal overflow without triggering small-for-size syndrome.

Methods:
A prospective single-center protocol included 8 living donors and 8 RAPID noncirrhotic recipients. Comprehensive clinical and biological data were collected, accompanied by intraoperative arterial and portal flow and pressure measurements. Early kinetic growth rate (eKGR%) and graft function were assessed using computed tomography and 99Tc-mebrofenin scintigraphy on postoperative days 7 and 14. Findings were compared with retrospective data from 13 left living donor liver transplantation (LDLT) recipients.

Results:
The median Graft-body weight ratio was 0.41% (interquartile range: 0.34–0.49), markedly lower than in LDLT. However, there was no significant difference in eKGR between RAPID and LDLT grafts. Sequential analysis revealed variable eKGR per day: 10.6% (7.8–13.2) in the first week and 7.6% (6–9.1) in the second week posttransplantation. Indexed portal flow (indexed portal vein flow) was significantly higher in RAPID compared with left LDLT (P = 0.01). No hemodynamic parameters were found to correlate with regeneration speed. We modulated portal flow in 2 out of 8 cases.

Conclusions:
This study presents the first report of hemodynamic and volumetric data for the RAPID technique. Despite initial graft volumes falling below conventional LDLT recommendations, the study highlights acceptable clinical outcomes.
Barriers to Adherence to Overactive Bladder Treatment for Hispanic Women
Authors: Vurture Gregory , Jenkins Nicole , Jacobson Nina , Smilen Scott W. 
Published: August 2024

Importance
Adherence to overactive bladder (OAB) therapy is low among the general population. Prior studies suggest that OAB is more prevalent among Hispanic women compared with other ethnicities.

Objectives
The aims of this study were to analyze nonadherence to OAB therapy among Hispanic compared with non-Hispanic women and identify potential barriers to treatment to reduce disparities in care.

Study Design
All patients who received treatment for OAB between 2018 and 2022 were included in this retrospective study. Race and ethnicity were self-reported. Nonadherence was defined as failure to initiate therapy within 1 year. Non-Hispanic women were selected at random to form a control group. The study was powered to detect a 50% difference in treatment nonadherence. Comparisons were made using the Fisher exact test or χ2 test as appropriate for nominal variables, and the Mann-Whitney test for continuous variables.

Results
The analysis included 126 Hispanic and 126 non-Hispanic women. Both cohorts were similar in demographics. Nonadherence to OAB therapy was more frequent among Hispanic women (44.0 vs 20.9%, P < 0.0001). After adjusting for age, body mass index, primary language, parity, insurance type, and treatment offered, Hispanic women were at a 2.54-fold increased risk of nonadherence (P = 0.007). A subanalysis of only Hispanic women found that younger age (P = 0.033), higher parity (P = 0.035) underinsured status (P = 0.027), and fewer office visits (P = 0.0002) were associated with nonadherence.

Conclusions
Nonadherence to OAB therapy was greater among Hispanic women despite no difference in treatment patterns. Younger age, greater parity, lack of insurance, and fewer office visits may be barriers for Hispanic women.
The potential of regulatory variant prediction AI models to improve cattle traits
Authors: Zhao R , Owen R , Marr M , Siddharth J , Chue Hong N , Talenti A , Hassan MA , Prendergast JGD 
Published: August 2024

AbstractConsiderable progress has been made in developing machine learning models for predicting human functional variants, but progress in livestock species has been more limited. This is despite the disproportionate potential benefits such models could have to livestock research, from improving breeding values to prioritising functional variants at trait-associated loci. A key open question is what datasets and modelling approaches are most important to close this performance gap between species. In this work we have developed a new framework for predicting regulatory variants, that includes deriving key conservation metrics in cattle for the first time, variant annotation and model training. When trained on expression quantitative trait loci (eQTL) and massively parallel reporter assay (MPRA) data for human and cattle we show that this framework has a high performance at predicting regulatory variants, with a maximum area under the receiver operating characteristic curve (AUROC) score of 0.92 in human and 0.81 in cattle. We explore various approaches to further close this performance gap, including integrating advanced DNA sequence models and generating extra chromatin data, but illustrate that the best approach would be generating improved gold-standard sets of known cattle regulatory variants. Importantly we demonstrate both the human and cattle models substantially enrich for variants linked to important traits, with up to 25-fold enrichments for functional variants observed. Consequently, with our framework developed to be applicable across species these results not only demonstrate its potential utility for fine-mapping functional variants and improving breeding values in cattle, but also its potential for wider use across animal species.
Attenuation of Atherosclerosis with PAR4 Deficiency: Differential Platelet Outcomes in apoE-/-vs. Ldlr-/-Mice
Authors: Wadding-Lee Caris A. , Jay Megan , Jones Shannon M. , Thompson Joel , Howatt Deborah A. , Daugherty Alan , Mackman Nigel , Owens A. Phillip 
Published: August 2024

ABSTRACTObjectiveCardiovascular disease (CVD) is a significant burden globally and, despite current therapeutics, remains the leading cause of death. Platelet inhibitors are of interest in CVD treatment to reduce thrombus formation post-plaque rupture as well their contribution to inflammation throughout the progression of atherosclerosis. Protease activated receptor 4 (PAR4) is a receptor highly expressed by platelets, strongly activated by thrombin, and plays a vital role in platelet activation and aggregation. However, the role of PAR4Approach and ResultsMice on a low-density lipoprotein receptor-deficient (Ldlr-/-) background were bred withPar4deficient (Par4-/-) mice to createLdlr-/-/Par4+/+andLdlr-/-/Par4-/-cousin lines. Mice were fed high fat (42%) and cholesterol (0.2%) ‘Western’ diet for 12 weeks for all studies. Bone marrow transplant (BMT) studies were conducted by irradiatingLdlr-/-/Par4+/+andLdlr-/-/Par4-/-mice with 550 rads (2x, 4 hours apart) and then repopulated withPar4+/+orPar4-/-bone marrow. To determine if the effects of thrombin were mediated solely by PAR4, the thrombin inhibitor dabigatran was added to the ‘Western’ diet.Ldlr-/-/Par4-/-given dabigatran did not further decrease their atherosclerotic burden. Differences between apolipoprotein E deficient (apoE-/-) andLdlr-/-platelets were assessed for changes in reactivity. We observed higher PAR4 abundance in arteries with atherosclerosis in human and mice versus healthy controls. PAR4 deficiency attenuated atherosclerosis in the aortic sinus and root versus proficient controls. BMT studies demonstrated this effect was due to hematopoietic cells, most likely platelets. PAR4 appeared to be acting independent of PAR1, as there werer no changes with addition of dabigatran to PAR4 deficient mice.apoE-/-platelets are hyperreactive compared toLdlr-/-platelets.ConclusionsHematopoietic-derived PAR4, most likely platelets, plays a vital role in the development and progression of atherosclerosis. Specific targeting of PAR4 may be a potential therapeutic target for CVD.HighlightsDeficiency of protease-activated receptor 4 attenuates the development of diet-induced atherosclerosis in aLdlr-/-mouse model.PAR4 deficiency in hematopoietic cells is atheroprotective.PAR4 deficiency accounts for the majority of thrombin-induced atherosclerosis in aLdlr-/-mouse model.The examination of platelet-specific proteins and platelet activation should be carefully considered before using theapoE-/-orLdlr-/-mouse models of atherosclerosis.
PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells
Authors: Hor Jyh Liang , Schrom Edward C. , Wong-Rolle Abigail , Vistain Luke , Shang Wanjing , Dong Qiang , Zhao Chen , Jin Chengcheng , Germain Ronald N. 
Published: August 2024

AbstractStem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6histem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cellsin vivo. The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected relationship between TCR ligand affinity recognition, a key negative feedback regulatory loop, and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.
Pathophysiological response in experimental trauma-related acute kidney injury
Authors: Halbgebauer Rebecca , Schult Lorena , Borgel Onno , Maes Arne , Weißhaupt Florian , Rastner Christina , Ast Alitsia , Lupu Ludmila , Palmer Annette , Wachter Ulrich , Schmidt Stefan A. , Boor Peter , Rösler Reinhild , Wiese Sebastian , Kerckhofs Greet , Huber-Lang Markus S. 
Published: August 2024

AbstractBackgroundTrauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes.MethodsTo study the pathophysiology of TRAKI, we developed a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage that induces mild transient TRAKI.ResultsThe mice showed early and transient increased plasma creatinine, urea, NGAL, and urine albumin, resolving 5 days after TRAKI induction. Despite normal kidney morphology, significant damage to proximal tubular cells and a loss of the brush border was observed. This included kidney stress responses, e.g., with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes after trauma. 3D x-ray-based whole-organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood flow, especially during the first day post THS, which was partly resolved by day 5.ConclusionsOur novel model of murine TRAKI has revealed previously unknown aspects of the complex temporal pathophysiological response of the kidney along the nephron after trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.
Thrombo-inflammation analyzed in a validated seven-layer platelet decision model: cellular decisions are tough problems fast and heuristically solved
Authors: Prada Juan , Balkenhol Johannes , Osmanoglu Özge , Afshar Maral , Kaltdorf Martin , Hofmann Sarah , von Mammen Sebastian , Heinze Katrin G. , Schulze Harald , Dandekar Thomas 
Published: August 2024

AbstractDecisions in biology happen fast and are driven by evolution to optimize survival chances. In platelets, this is achieved by organizing signaling cascades into rapid decision-funnels with modulatory crosstalk. We show that network decision processes underlying cellular decisions are tough to solve (equivalent to classical satisfiability problems, SAT). Hence, heuristics, modular decision-making, and decision funnels are required for efficient decisions.We establish this using a seven-layer platelet decision network that agrees well with all available genetic and functional experimental data. Platelet decision cascades are robust to perturbations: For example, receptors such as TRPM7 modulate platelet activity. However, knockouts of the receptors still leave platelets reactive overall. Dynamic control resolves relaying functions from kinases to cytoskeleton alterations. This allows fast execution of platelet shape change or aggregation. Stress conditions can shift platelet decision funnels towards constant activation of aggregation or immune signaling, causing thrombosis or thrombo-inflammation. Based on the network dynamics, we conclude that platelets pragmatically resolve the complex (non-polynomial (NP)) cellular decision problems by using a similar relaxation to those proposed in mathematics – many different configurations end up in similar states. Metamathematical considerations (no mathematical proof) suggest that NP problems are more complex then P problems.One sentence abstractWe show that cellular decision problems like the platelet signaling cascade may need unexpectedly long to solve but in general, they are efficiently solved using heuristics (“decision funnels”), implying fast decisions but the risk of chronic stress and inflammation.
On the same side: The immune regulatory protein Vista and its ligands interact in cis
Authors: Smorodinsky-Atias Karina , Wiseglass Gil , Salem Mariana , Kashani Maya , Boni Nadir , Artyukhova Alina , Levy Rachel , Rubinstein Rotem 
Published: August 2024

AbstractVISTA, an essential immune checkpoint regulatory protein, regulates peripheral T-cell quiescence and tolerance. Despite its potential as a target for anti-tumor and autoimmune disease therapies, uncertainty regarding VISTA’s binding mode and membrane orientation has hindered these developments. Contrary to the prevailing paradigm, we found using cell aggregation assays that VISTA cannot interact with its ligands intrans(between cells). Using MST and flow cytometry, we showed that soluble VISTA binds to its ligands, suggesting that VISTA’s membrane orientation restrictstransinteractions. In contrast, split luciferase complementation assays showed that VISTA interacts with its ligands incis. We propose that a disulfide bond bends VISTA’s Ig domain towards the membrane in an orientation that preventstranswhile enablingcisinteractions. Co-expression data analysis from the cancer genome atlas showed a strong correlation between VISTA and its ligand, PSGL-1, consistent with our in-vitrocisinteraction data. Our findings reveal VISTA’s binding mechanism and suggest an intrinsic inhibition signaling pathway independent of additional cells. Importantly, our experimental framework provides a platform for identifying novel VISTA-targeted therapeutics.
Performance and Robustness of Parameter Estimation from Phylogenetic Trees Using Neural Networks
Authors: Qin Tianjian , van Benthem Koen J. , Valente Luis , Etienne Rampal S. 
Published: August 2024

AbstractSpecies diversification is characterized by speciation and extinction, the rates of which can, under some assumptions, be estimated from time-calibrated phylogenies. However, maximum likelihood estimation methods (MLE) for inferring rates are limited to simpler models and can show bias, particularly in small phylogenies. Likelihood-free methods to estimate parameters of diversification models using deep learning have started to emerge, but how robust neural network methods are at handling the intricate nature of phylogenetic data remains an open question. Here we present a new ensemble neural network approach to estimate diversification parameters from phylogenetic trees that leverages different classes of neural networks (dense neural network, graph neural network, and long short-term memory recurrent network) and simultaneously learns from graph representations of phylogenies, their branching times and their summary statistics. Our best-performing ensemble neural network (which corrects graph neural network result using a recurrent neural network) can compute estimates faster than MLE and is less affected by tree size. Our analysis suggests that the primary limitation to accurate parameter estimation is the amount of information contained within a phylogeny, as indicated by its size and the strength of effects shaping it. In cases where MLE is unavailable, our neural network method provides a promising alternative for estimating phylogenetic tree parameters. If there are detectable phylogenetic signals present, our approach delivers results that are comparable to MLE but without inherent biases.
Nutrient Challenges in a Changing Atmosphere: Investigating Biomass Growth and Mineral Concentration Changes in Soybean Plants under Elevated CO2
Authors: Kaur Ravneet , Durstock Mary , Prior Stephen A. , Runion G. Brett , Ainsworth Elizabeth A. , Baxter Ivan , Sanz-Sáez Alvaro , Leisner Courtney P. 
Published: August 2024

ABSTRACTRising atmospheric CO2levels, projected to reach ∼650 ppm by 2050, threaten the nutritional value of food crops. This rise is expected to increase biomass yield in C3plants through enhanced photosynthesis and water-use efficiency. However, elevated CO2(eCO2) reduces protein, nitrogen, and essential minerals like zinc (Zn) and iron (Fe) in plant leaves and seeds, posing a global nutrition risk. We conducted an experiment using Open Top Chambers to examine the response of three soybean cultivars (Clark, Flyer, and Loda) to ambient (∼410 ppm) and eCO2(∼610 ppm) conditions. These cultivars were selected due to their contrasting responses to eCO2. Measurements of physiological parameters (i.e., biomass, and nutrient concentration) were taken at different growth stages. Our results showed that eCO2increased carbon assimilation, leading to higher aboveground biomass and seed yield (through increased seed number) while root biomass remained unchanged. eCO2also reduced stomatal conductance and transpiration. There was a significant decrease in seed nutrient concentration at maturity, particularly iron (Fe), phosphorous (P), potassium (K), and magnesium (Mg), in plants grown in eCO2. These findings suggest that increased yield, reduced transpiration, and unchanged root biomass are key drivers of nutrient dilution in seeds under eCO2.
CHRONIC LUNG INFLAMMATION LEADS TO MYELOID SKEWING OF HEMATOPOIETIC STEM CELLS IN A CYSTIC FIBROSIS MOUSE MODEL
Authors: Braga Cassia Lisboa , Isler Mancuso Rubia , Thompson Evrett N. , Öz Hasan H. , Gudneppanavar Ravindra , Zhang Ping-Xia , Huang Pamela , Murray Thomas , Egan Marie , Krause Diane S. , Bruscia Emanuela M. 
Published: August 2024

ABSTRACTPersistent lung inflammation is a hallmark of Cystic fibrosis (CF) lung disease. Inflammation can lead to functional decline in hematopoietic stem cell (HSCs), tipping the balance towards myelopoiesis and contributing to chronic inflammation. However, it’s unknown whether the HSCs are dysfunctional in CF. We tested whether chronic lung inflammation impacts hematopoietic stem and progenitor cells (HSPCs) in a CF mouse model.Wild-type (WT) andCftr-/- mice were nebulized with lipopolysaccharide (LPS) from Pseudomonas aeruginosa for 5 weeks. The mice were euthanized before the exposure (T0), 24 hours after the last LPS nebulization (T1), or 6 weeks (T2) after the last LPS nebulization. The bone marrow (BM) and lung tissue were collected for flow cytometry analysis of the HSPC population and immune cells in the lungs, respectively. Peripheral blood was collected for complete blood count analysis.At baseline,Cftr-/- mice show a larger HSPC population with a myeloid bias, indicated by higher frequencies of LSK, LT-HSC, CD41+LT-HSC, GMPs, and MkPs. Following chronic LPS nebulization,Cftr-/- mice exhibit greater HSPC expansion and myeloid differentiation, alongside increased peripheral myeloid cell counts. Post-recovery, while most HSPC populations return to baseline,Cftr-/- mice retain elevated myeloid-biased LT-HSCs, suggesting a persistent myeloid bias. These findings underscore a prominent shift toward myeloid hematopoiesis in CF, which is accentuated by chronic inflammation and remains even after recovery.Further experiments are underway to assess maladaptive epigenetic changes in HSC as well as if chronic lung inflammation impacts HSC functionality.