bluuebunny/crossref_metadata_2025_split huggingface dataset:
A deep-learning workflow to predict upper tract urothelial cancer subtypes supporting the prioritization of patients for molecular testing
Authors: Angeloni Miriam , Doeveren Thomas van , Lindner Sebastian , Volland Patrick , Schmelmer Jorina , Foersch Sebastian , Matek Christian , Stoehr Robert , Geppert Carol I. , Heers Hendrik , Wach Sven , Taubert Helge , Sikic Danijel , Wullich Bernd , van Leenders Geert J. L. H. , Zaburdaev Vasily , Eckstein Markus , Hartmann Arndt , Boormans Joost L. , Ferrazzi Fulvia , Bahlinger Veronika 
Published: June 2023

AbstractBackgroundUrothelial carcinoma of the bladder (UBC) comprises several molecular subtypes, which are associated with different targetable therapeutic options. However, if and how these associations extend to the rare upper tract urothelial carcinoma (UTUC) remains unclear.ObjectiveIdentifying UTUC protein-based subtypes and developing a deep-learning (DL) workflow to predict these subtypes directly from histopathological H&E slides.Design, Setting, and ParticipantsSubtypes in a retrospective cohort of 163 invasive samples were assigned on the basis of the immunohistochemical expression of three luminal (FOXA1, GATA3, CK20) and three basal (CD44, CK5, CK14) markers. DL model building relied on a transfer-learning approach.Outcome Measurements and Statistical AnalysisClassification performance was measured via repeated cross-validation, including assessment of the area under the receiver operating characteristic (AUROC). The association of the predicted subtypes with histological features, PD-L1 status, andFGFR3mutation was investigated.Results and LimitationsDistinctive luminal and basal subtypes were identified and could be successfully predicted by the DL (AUROC 95thCI: 0.62-0.99). Predictions showed morphology as well as presence ofFGFR3-mutations and PD-L1 positivity that were consistent with the predicted subtype. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes.ConclusionsOur DL workflow is able to predict protein-based UTUC subtypes directly from H&E slides. Furthermore, the predicted subtypes associate with the presence of targetable genetic alterations.Patient SummaryUTUC is an aggressive, yet understudied, disease. Here, we present an artificial intelligence algorithm that can predict UTUC subtypes directly from routine histopathological slides and support the identification of patients that may benefit from targeted therapy.
“Non-Invasive Imaging Modalities in Coronary Artery Disease:A meta analysiscomparingCCTAandStandard of Care (SOC)”
Authors: Dani Avichal , Shah Pari , Desai Dev 
Published: June 2023

ABSTRACTIntroductionCoronary Artery Disease has become a global pandemic and a major cause of death especially among Older population. The risk factor calculation or the degree of Coronary artery damage is usually an invasive procedure. A paradigm change has occurred in the last ten years regarding the assessment of coronary artery disease (CAD) utilising coronary computed tomography angiography (CCTA).Aims and ObjectivesTo Comapre CCTA with Standard Care to calculate the need of revascularization, invasive coronary angiography as well as to compare both for MI and All cause mortalityResultsCCTA was found to be associated with a significant increase in revascularizations (RR =1.401, 95% CI =1.315-1.492, p<0.001) as well as invasive coronary angiography procedures (RR =1.304, 95% CI =1.208-1.409, p<0.001). However, it was associated with decreased incidences of MI (RR =0.752, 95% CI =0.578-1.409, p<0.033). There was no significant association with all-cause mortality.ConclusionCCTA is significantly correlated with a reduction in MI episodes and an increase in revascularizations and ICA procedures. However, it was found that it had no effect on all-cause mortality. On the contrary, standard care approaches were associated with greater rates of MI but lesser referrals for invasive coronary angiography and revascularization.
Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases
Authors: Wójcik Magdalena , Juhas Ulana , Mohammadi Elyas , Mattisson Jonas , Drężek-Chyła Kinga , Rychlicka-Buniowska Edyta , Bruhn-Olszewska Bożena , Davies Hanna , Chojnowska Katarzyna , Olszewski Paweł , Bieńkowski Michał , Jankowski Michał , Rostkowska Olga , Hellmann Andrzej , Pęksa Rafał , Kowalski Jacek , Zdrenka Marek , Kobiela Jarek , Zegarski Wojciech , Biernat Wojciech , Szylberg Łukasz , Remiszewski Piotr , Mieczkowski Jakub , Filipowicz Natalia , Dumanski Jan P. 
Published: June 2023

AbstractMale sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematological cancer, as well as higher LOY in CD4+ T-lymphocytes in men with prostate cancer vs. controls. However, nothing is known about LOY in leukocytes infiltrating TME and we address this aspect here. We studied frequency and functional effects of LOY in blood, TME and non-tumorous tissue. Regulatory T-lymphocytes (Tregs) in TME had the highest frequency of LOY-cells (22%) in comparison to CD4+ T-lymphocytes and cytotoxic CD8+ T-lymphocytes. Using scRNA-seq LOY was also linked to higher expression ofPDCD1, TIGITandIKZF2in Tregs.PDCD1andTIGITencode immune checkpoint receptors involved in the regulation of Tregs function. Our study sets the direction for further functional research regarding a probable role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and consequently a possible influence on immunotherapy response in CRC patients.
Light-exercise-induced dopaminergic and noradrenergic stimulation in the dorsal hippocampus: using a rat physiological exercise model
Authors: Hiraga Taichi , Hata Toshiaki , Soya Shingo , Shimoda Ryo , Takahashi Kanako , Soya Mariko , Inoue Koshiro , Johansen Joshua P. , Okamoto Masahiro , Soya Hideaki 
Published: June 2023

AbstractExercise activates the dorsal hippocampus, which triggers the synaptic and cellar plasticity and ultimately promotes memory formation. For decades, these benefits have been explored using demanding and stress-response-inducing exercise at moderate-to-vigorous intensities. In contrast, our translational research with animals and humans has focused on light exercise below the lactate threshold (LT), which almost anyone can safely perform with minimal stress, and found that even light exercise can stimulate hippocampal activity and enhance memory performance. Although the circuit mechanism of this boost remains unclear, arousal promotion even with light exercise implies the involvement of the ascending monoaminergic system, which is essential to modulate hippocampal activity and impact memory. To examine this hypothesis, we employed our physiological exercise model based on the LT of rats that can be applied to human and immunohistochemically assessed the neuronal activation of the dorsal hippocampal sub-regions and brainstem monoaminergic neurons. Also, we monitored the dynamics of monoamine release at the dorsal hippocampus usingin vivomicrodialysis. We found that even light exercise increased neuronal activity in the dorsal hippocampal sub-regions and induced noradrenaline and dopamine release. Furthermore, we found that tyrosine hydroxylase-positive neurons in the locus coeruleus (LC) and the ventral tegmental area (VTA) were activated even by light exercise and were both positively correlated with the dorsal hippocampal activation. In conclusion, our findings demonstrate that light exercise stimulates hippocampal neurons, possibly through the LC-noradrenergic and/or VTA-dopaminergic neurons. This sheds light on the circuit mechanisms responsible for hippocampal neural activation during exercise, consequently enhancing memory function.Graphical abstractOur previous research with animals and humans has demonstrated that even light exercise can boost neuronal activity in the dorsal hippocampus and improve memory. While the mechanism underlying this remains undetermined, recent studies suggest the involvement of the ascending monoaminergic system. Here, we examined this hypothesis and found a possible contribution of noradrenergic neurons in the locus coeruleus and dopaminergic neurons in the ventral tegmental area to dorsal hippocampal activation during light exercise, implying a circuit mechanism for light-exercise-enhanced memory.
Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes
Authors: Milenkovic Dusanka , Misic Jelena , Hevler Johannes F , Molinié Thibaut , Chung Injae , Atanassov Ilian , Li Xinping , Filograna Roberta , Mesaros Andrea , Mourier Arnaud , Heck Albert J R , Hirst Judy , Larsson Nils-Göran 
Published: June 2023

SUMMARYThe mammalian respiratory chain complexes I, III2and IV (CI, CIII2and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI- CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate thein vivorole of the respirasome, we generated homozygous knock-in mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in the mouse, but raises questions about their alternate functions, such as relating to regulation of protein stability and prevention of age-associated protein aggregation.
Robust axis elongation by Nodal-dependent restriction of BMP signaling
Authors: Schauer Alexandra , Pranjic-Ferscha Kornelija , Hauschild Robert , Heisenberg Carl-Philipp 
Published: June 2023

AbstractEmbryogenesis is brought about by the coordinated activities of different signaling pathways controlling cell fate specification and morphogenesis. In vertebrate gastrulation, both Nodal and BMP signaling play key roles in germ layer specification and morphogenesis, yet their interplay to coordinate embryo patterning with morphogenesis is still insufficiently understood. Here, we took a reductionist approach using zebrafish embryonic explants to study the coordination of Nodal and BMP signaling for embryo patterning and morphogenesis. We show that Nodal signaling not only triggers explant elongation by inducing mesendodermal progenitors but also by suppressing BMP signaling activity at the site of mesendoderm induction. Ectopic BMP signaling in the mesendoderm blocks cell alignment and oriented mesendoderm intercalations, key processes to drive explant elongation. Translating theseex vivoobservations to the intact zebrafish embryo showed that, similar to explants, Nodal signaling renders the dorsal domain less sensitive towards BMP signaling to allow effective cell intercalations and thus robust embryonic axis elongation. These findings suggest a dual function of Nodal signaling in embryonic axis elongation by both inducing mesendoderm and maintaining low levels of BMP signaling activity in the dorsal portion of the mesendoderm.
Androgen exposure impairs neutrophil maturation and function within the infected kidney
Authors: Hreha Teri N. , Collins Christina A. , Hunstad David A. 
Published: June 2023

AbstractUrinary tract infections (UTIs) in men are uncommon but carry increased risk for severe pyelonephritis and other complications. In models ofEscherichia coliUTI, male C3H/HeN mice uniformly develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by an additional reduction of neutrophil function specifically within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenicE. coli(UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101–). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced functionsin vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Further, aged immature neutrophils exhibited little phagocytic activity within intratubular UPEC communitiesin vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens reflects urinary tract-specific impairment of neutrophil maturation (largely via cell-intrinsic AR signaling) and kidney-specific reduction in neutrophil antimicrobial capacity, resulting in failure to control renal bacterial infection.
Unraveling the Genomic Diversity and Admixture History of Captive Tigers in the United States
Authors: Armstrong Ellie E. , Mooney Jazlyn A. , Solari Katherine A. , Kim Bernard Y. , Barsh Gregory S. , Grant Victoria B. , Greenbaum Gili , Kaelin Christopher B. , Panchenko Katya , Pickrell Joseph K. , Rosenberg Noah , Ryder Oliver A. , Yokoyama Tsuya , Ramakrishnan Uma , Petrov Dmitri A. , Hadly Elizabeth A. 
Published: June 2023

AbstractGenomic studies of rare and endangered species have focused broadly on describing diversity patterns and resolving phylogenetic relationships, with the overarching goal of informing conservation efforts. However, few studies have investigated the genomic diversity potentially housed in captive populations. For tigers (Panthera tigris) in particular, captive individuals vastly outnumber those in the wild, yet the diversity of the captive population remains largely unexplored. Here, we present the first large-scale genetic study of the private (non-zoo) captive tiger population in the United States (U.S.), also known as ‘Generic’ tigers. We find that the U.S. Generic tiger population has an admixture fingerprint comprising all six extant wild tiger subspecies (P. t. altaica, Amur;P. t. tigris, Bengal;P. t. corbetti, Indochinese;P. t. jacksoni, Malayan;P. t. amoyensis, South China;P. t. sumatrae, Sumatran). We show that the Generic tiger population has a comparable amount of genetic diversity to most wild subspecies, relatively few private variants, and fewer deleterious mutations. We also observe inbreeding coefficients that are similar to wild populations, suggesting that inbreeding in captive populations is not pervasive, although there are some individuals within the Generic population that are substantially inbred. Our results elucidate the admixture history of the Generic tiger population in the U.S. Additionally, we develop a reference panel for tigers and show that it can be used with imputation to accurately distinguish individuals and assign ancestry even with ultra-low coverage (0.25×) data. The study and reference panel will provide a resource to assist in tiger conservation efforts.
Astrocyte Ca2+signalling mediates long-distance metaplasticity in the hippocampal CA1
Authors: Jones Owen D. , Singh Anurag , Logan Barbara J. , Abraham Wickliffe C. 
Published: June 2023

AbstractAstrocytes play an increasingly recognised role in regulating synaptic plasticity, but their contribution to metaplasticity is poorly understood. We have previously described a long-distance form of metaplasticity whereby priming stimulation in stratum oriens inhibits subsequent LTP in the neighbouring stratum radiatum of the hippocampal CA1 region of both rats and mice. Using genetic and pharmacological strategies to manipulate astrocytic Ca2+signalling, we now show this form of metaplasticity requires inositol triphosphate receptor-dependent Ca2+release in these cells. Blocking Ca2+signalling or inositol triphosphate receptors in single radiatum astrocytes abolishes the metaplasticity at nearby synapses. We also show the relevant Ca2+release in astrocytes is driven by adenosine A2Breceptors, and stimulation of these receptors elicits the metaplasticity effect bothin vitroandin vivo. Further, the metaplasticity requires signalling via tumor necrosis factor, but this cytokine is required to act on astrocytes, not neurons. Instead, glutamate, acting on GluN2B-containing NMDA receptors, is the likely gliotransmitter that signals to neurons to inhibit LTP. Together these data reveal a novel role for astrocytes in hippocampal LTP regulation across broader spatiotemporal scales than previously recognised.Main pointsIn hippocampal CA1, “priming” activity inhibits subsequent LTP at synapses hundreds of microns away.This effect requires astrocytic Ca2+signaling, and a molecular cascade involving adenosine A2Breceptors, tumor necrosis factor and GluN2B-containing NMDA receptors.The metaplasticity effect is evidentin vitroandin vivo.Long-distance astrocyte signaling is a mechanism for regulating neural activity over broad spatiotemporal scales.
Uncovering the association mechanism between two intrinsically flexible proteins
Authors: Dávalos Angy L. , Rivera José D. , Favaro Denize C. , Oliveira Ronaldo J. , Carretero Gustavo PB. , Lacerda Caroline D. , Cuccovia Iolanda M. , Cardoso Marcus V. C. , Farah Chuck S. , Salinas Roberto K. 
Published: June 2023

AbstractThe understanding of protein-protein interaction mechanisms is key to the atomistic description of cell signalling pathways and for the development of new drugs. In this context, the mechanism of intrinsically disordered proteins folding upon binding has attracted attention. The VirB9 C-terminal domain (VirB9Ct) and the VirB7 N-terminal motif (VirB7Nt) associate with VirB10 to form the outer membrane core complex of the Type IV Secretion System injectisome. Despite forming a stable and rigid complex, VirB7Ntbehaves as a random coil while VirB9Ctis intrinsically dynamic in the free state. Here we combined NMR, stopped-flow fluorescence and computer simulations using structure-based models to characterize the VirB9Ct-VirB7Ntcoupled folding and binding mechanism. Our data indicated that VirB9Ctbinds to VirB7Ntby way of a conformational selection mechanism. However, at higher temperatures energy barriers between different VirB9Ctconformations are more easily surpassed. Under these conditions the formation of non-native initial encounter complexes may not be neglected, providing alternative pathways towards the native complex conformation. These observations highlight the intimate relationship between folding and binding, calling attention to the fact that the two molecular partners must search for the most favored intramolecular and intermolecular interactions on a rugged and funnelled conformational energy landscape, along which multiple intermediates may lead to the final native state.
Pharmacokinetic profile of the synthetic mu-opioid receptor agonist [Lys7]Dermorphin-IRDye®800CW and its feasibility as a biomarker for opioid use disorder
Authors: Samkoe Kimberley S. , Strawbridge Rendall R. , Spaller Mark R. , Pletnev Alexandre A. , Wirth Dennis J. , Byrd Brook K. , Meng Boyu , Sottosanti J. Scott , Davis Scott C. , Elliott Jonathan T. 
Published: June 2023

AbstractBackgroundOpioid use disorder (OUD) affects more than 14 million Americans and poses a high risk of relapse, overdose, and death. Current treatments are not tailored to individual needs and do not monitor the effectiveness of the medication. We propose a novel method to measure the occupancy of mu opioid receptors (MOR), which are key targets for opioid pharmacotherapy, in peripheral tissues with high MOR density. We developed a fluorescent peptide agonist that binds to MOR and can be detected by non-invasive point-of-care techniques. We presentin vitroandin vivoresults that demonstrate the feasibility and potential of this method to assess MOR availability and treatment efficacy in OUD patients.MethodsA new fluorescent-labeled synthetic peptide agonist [Lys7]Dermorphin-IRDye800CW, called DRM-800, was synthesized and characterizedin vitroto evaluate binding and internalization. Wildtype and MOR knock-out mice were used to quantify plasma kinetics and, using a cyromacrotome, fluorescence images were acquired post-mortem on whole-body sections 150 um apart. These volumes were used to comparein vivoenhancement of MOR-rich structures.ResultsIn vitro assays and microscope visualization of DRM-800 showed high MOR-affinity and rapid, robust internalization. Plasma half-life following intravenous injection in mice was 8-12 minutes. Specific binding by tissue structures of interest, measured by the ratio of relative fluorescent units in wild-type vs. MOR knockout mice showed high binding in dorsal root ganglia, spiral ganglia and trigeminal ganglion, as well as in the small and large intestine.ConclusionsThe pharmacokinetics and distribution, binding kinetics and rapid internalization suggests that MOR-specific fluorescence enhancement corresponding to opioid rich structures could serve as a potential biomarker in opioid use disorder.
Can higher-order interactions resolve the species coexistence paradox?
Authors: Gibbs Theo , Gellner Gabriel , Levin Simon A. , McCann Kevin S. , Hastings Alan , Levine Jonathan M. 
Published: June 2023

AbstractMost ecological models are based on the assumption that species interact in pairs. Emerging in diverse communities, however, are higher-order interactions, in which two or more species jointly impact the growth of a third species. A pitfall of the pairwise approach is that it misses the higher-order interactions potentially responsible for maintaining diversity in nature. Here, we explore how well higher-order interactions enable coexistence when pairwise interactions are insufficient to do so. Specifically, we explore the stability properties of systems where higher-order interactions guarantee that a specified set of abundances are a feasible equilibrium of the dynamics. Even these higher-order interactions do not necessarily produce robust coexistence. We find that facilitative higher-order interactions that counter pairwise competitive interactions are less likely to generate stable equilibria than competitive interactions countering pairwise facilitation. In both cases the system is more likely to be stable when the pairwise interactions are weak, and when the equilibrium abundances are near those produced by the pairwise interactions. Last, we show that correlations between the pairwise and higher-order interactions permit robust coexistence in diverse systems. Our work reveals the challenges in generating stable coexistence through higher-order interactions, but also uncovers higher-order interaction patterns that can enable diversity.