bluuebunny/crossref_metadata_2025_split huggingface dataset:
EstablishedPseudomonas syringaepv.tomatoinfection disrupts immigration of leaf surface bacteria to the apoplast
Authors: Cowles Kimberly N. , Iyer Arjun S. , McConnell Iain , Guillemette Ellie G. , Nellore Dharshita , Zaacks Sonia C. , Barak Jeri D. 
Published: August 2024

ABSTRACTBacterial disease alters the infection court creating new niches. The apoplast is an oasis from the hardships of the leaf surface and is generally inaccessible to nonpathogenic members of the phyllosphere bacterial community. Previously, we demonstrated thatSalmonella entericaimmigrants to the leaf surface can both enter the apoplast and replicate due to conditions created by an establishedXanthomonas hortorumpv.gardneri(Xhg) infection. Here, we have expanded our investigation of how infection changes the host by examining the effects of another water-soaking pathogen,Pseudomonas syringaepvtomato(Pst), on immigrating bacteria. We discovered that, despite causing macroscopically similar symptoms as Xhg, Pst infection disruptsS. entericacolonization of the apoplast. To determine if these effects were broadly applicable to phyllosphere bacteria, we examined the fates of immigrant Xhg and Pst arriving on an infected leaf. We found that this effect is not specific toS. enterica, but that immigrating Xhg or Pst also struggled to fully join the infecting Pst population established in the apoplast. To identify the mechanisms underlying these results, we quantified macroscopic infection symptoms, examined stomata as a pinch point of bacterial entry, and characterized aspects of interbacterial competition. While it may be considered common knowledge that hosts are fundamentally altered following infection, the mechanisms that drive these changes remain poorly understood. Here, we investigated these pathogens to reach a deeper understanding of how infection alters a host from a rarely accessible, inhabitable environment to an obtainable, habitable niche.IMPORTANCEPathogens dramatically alter the host during infection. Changes in host physical and biochemical characteristics benefit the pathogen and can reshape the composition of the bacterial community. In fact, rare members of the plant microbiota, namely bacterial human pathogens, such asSalmonella enterica,thrive in some plant infection courts. The increased success of human pathogens results from the conversion of the rarely accessible, inhabitable apoplast to an obtainable, habitable niche following infection. Here, we compared two phytopathogens,Pseudomonas syringaepv.tomatoandXanthomonas hortorumpv.gardneriwithin a tomato host and uncovered relevant niche changes potentially overlooked by the similarity in macroscopic symptoms. We investigated mechanisms used to reshape the host environment to the pathogen’s benefit and either success or failure of newly arriving immigrant bacteria. This study reveals information about bacterial disease of leaves and key changes that remodel inhospitable niches to new, conducive environments in the diseased host.
Genetically-encoded phase separation sensors for intracellular probing of biomolecular condensates
Authors: Avecilla Alexa Regina Chua , Thomas Jeremy , Quiroz Felipe Garcia 
Published: August 2024

AbstractBiomolecular condensates are dynamic membraneless compartments with enigmatic roles across intracellular phenomena. Intrinsically-disordered proteins (IDPs) often function as condensate scaffolds, fueled by their liquid-liquid phase separation (LLPS) dynamics. Intracellular probing of these condensates relies on live-cell imaging of IDP-scaffolds tagged with fluorescent proteins. Conformational heterogeneity in IDPs, however, renders them uniquely sensitive to molecular-level fusions, risking distortion of the native biophysical properties of IDP-scaffolds and their assemblies. Probing epidermal condensates in mouse skin, we recently introduced genetically encoded LLPS-sensors that circumvent the need for molecular-level tagging of skin IDPs. The concept of LLPS-sensors involves a shift in focus from subcellular tracking of IDP-scaffolds to higher-level observations that report on the assembly and liquid-dynamics of their condensates. Towards advancing the repertoire of intracellular LLPS-sensors, here we demonstrate biomolecular approaches for the evolution and tunability of epidermal LLPS-sensors and assess their impact in early and late stages of intracellular LLPS dynamics. Benchmarking against scaffold-bound fluorescent reporters, we found that tunable ultraweak scaffold-sensor interactions are key to the sensitive and innocuous probing of nascent and established biomolecular condensates. Our LLPS-sensitive tools pave the way for the high-fidelity intracellular probing of IDP-governed biomolecular condensates across biological systems.
CoordinatedTbx3/Tbx5transcriptional control of the adult ventricular conduction system
Authors: Burnicka-Turek Ozanna , Trampel Katy A. , Laforest Brigitte , Broman Michael T. , Yang Xinan H. , Khan Zoheb , Rytkin Eric , Li Binjie , Schaffer Ella , Gadek Margaret , Shen Kaitlyn M. , Efimov Igor R. , Moskowitz Ivan P. 
Published: August 2024

AbstractThe cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factorsTBX3andTBX5are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role ofTbx3andTbx5in the murine ventricular conduction system (VCS). We engineered a compoundTbx3:Tbx5conditional knockout allele for both genes located incison mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specificMinK:Cre,caused loss of VCS function and molecular identity. CombinedTbx3andTbx5deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiological defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect.Tbx3:Tbx5double knockout VCS cardiomyocytes revealed a transcriptional shift towards non-CCS-specialized working myocardium, indicating a change to their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate thatTbx3andTbx5coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.
Analogues of the anti-malaria drug mefloquine have broad spectrum antifungal activity and are efficacious in a model of disseminatedCandida aurisinfection
Authors: Guin Soumitra , Montoya Marhiah C. , Wang Xiaoyu , Zarnowski Robert , Andes David R. , Meyers Marvin J. , Williams Noelle S. , Krysan Damian J. 
Published: August 2024

AbstractOnly three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad spectrum antifungal activity including difficult to treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate it penetrates the central nervous system and is active againstCandida aurisin vivo. These data strongly support the further development of mefloquine analogs as a potentially new class of antifungal molecules.
Functional characterisation of neuropeptides that act as ligands for both calcitonin-type and pigment-dispersing factor-type receptors in a deuterostome
Authors: Cong Xiao , Liu Huachen , Liu Lihua , Elphick Maurice R. , Chen Muyan 
Published: August 2024

AbstractThe calcitonin (CT) family of related peptides exert their diverse physiological effects in mammals via two G-protein coupled receptors, CTR and the CTR-like receptor CLR. Analysis of the phylogenetic distribution of CT-type signaling has revealed the occurrence of CT-type peptides and CTR/CLR-type proteins in deuterostome and protostome invertebrates. Furthermore, experimental studies have revealed that in the protostomeDrosophila melanogasterthe CT-like peptide DH31can act as a ligand for a CTR/CLR-type receptor and a pigment-dispersing factor (PDF) receptor. Here we investigated the signaling mechanisms and functions of CT-type neuropeptides in a deuterostome invertebrate, the sea cucumberApostichopus japonicus(phylum Echinodermata). InA. japonicus,a single gene encodes two CT-type peptides (AjCT1 and AjCT2), both of which act as ligands for a CTR/CLR-type receptor (AjCTR) and two PDF-type receptors (AjPDFR1, AjPDFR2), but with differential activation of downstream cAMP/PKA, Gαq/Ca2+/PKC and ERK1/2 signaling pathways. Analysis of the expression of the gene encoding AjCT1 and AjCT2 revealed transcripts in a variety of organ systems, but with highest expression in the circumoral nervous system.In vitropharmacological experiments revealed that AjCT1 and/or AjCT2 cause dose-dependent relaxation of longitudinal body wall muscle and intestine preparations. Furthermore,in vivopharmacological experiments and loss-of-function tests revealed a potential physiological role for AjCT2 signaling in promoting feeding and growth inA. japonicus. This is the first study to obtain evidence that CT-type peptides can act as ligands for both CTR/CLR-type and PDF-type receptors in a deuterostome. Furthermore, because of the economic importance ofA. japonicusas a foodstuff, discovery of the potential role for CT-type peptides as regulators of feeding and growth in this species may provide a basis for practical applications in aquaculture.Graphical abstractA schematic showing proposed molecular mechanisms by which CT-type neuropeptides regulate feeding and growth inA. japonicus. AjCT1 and AjCT2 are represented by purple and yellow circles, respectively. For cell signaling, black arrows indicate that this process is activated, whilst the pink arrow indicates that the ERK1/2 is activated in the AjCT1/AjPDFR1, AjCT2/AjPDFR1 and AjCT2/AjPDFR2 signaling pathways.
Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers
Authors: Owens Katherine , Rahman Aminur , Bozic Ivana 
Published: August 2024

AbstractThe success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.
Effect of high-intensity anaerobic exercise on electrocortical activity in athletes and non-athletes
Authors: Costa Élida , Gongora Mariana , Bittencourt Juliana , Marinho Victor , Cagy Mauricio , Teixeira Silmar , Nicoliche Eduardo , Fernandes Isabelle , Fagundes Danilo , Machado Caroline , Dias Juliana , Vicente Renan , Ribeiro Pedro , Gupta Daya S. , Velasques Bruna , Budde Henning 
Published: August 2024

AbstractAimThe present study aims to verify the information processing in athletes through electroencephalography, analyze cortical areas responsible for cognitive functions related to attentional processing of visual stimuli, and investigate motor activity’s influence on cognitive aspects.Material and MethodsThe sample consisted of 29 subjects, divided into an experimental group (n = 13 modern pentathlon athletes) and a control group (n = 16 non-athletes). We collected the electrocortical activity before and after the Wingate Anaerobic Test. During the electrophysiological measures, the volunteers performed a saccadic eye movement paradigm. They also performed cognitive tasks, resting heart rate, and anthropometric measurements.ResultsA mixed ANOVA was applied to analyze the statistical differences between groups (athletes and control) and moments (before and after exercise) for F3, F4, P3, and P4 electrodes during rest one and task (pre-stimulus GO). There was an interaction for the group vs. moment factors in F3 [F = 17,129; p = 0,000; η² = 0.512], F4 [F = 22,774; p = 0,000; η² = 0.510], P3 [F = 11,429; p = 0,001; η² = 0.405], and P4 electrodes [F = 18,651; p = 0,000; η² = 0.379]. We found the main effect for group factors in the frontal and parietal electrodes of the right hemisphere (F4 and P4) and a main effect of the moment factor on the frontal (F3 and F4) and parietal (P3 and P4) electrodes. There was an interaction between the group vs. moment factors for the reaction time. The groups were different in Peak Power (Watts/kg), Average Power (Watts/kg), Fatigue Index (%), and Maximum Power (ms).ConclusionsWe identified chronic effects of exercise training on the cortical activity of modern pentathlon athletes, read-through differences in absolute alpha power, and acute effects of a high-intensity exercise session for athletes and non-athletes for electrocortical and behavioral responses.
Computational design of serine hydrolases
Authors: Lauko Anna , Pellock Samuel J. , Anischanka Ivan , Sumida Kiera H. , Juergens David , Ahern Woody , Shida Alex , Hunt Andrew , Kalvet Indrek , Norn Christoffer , Humphreys Ian R. , Jamieson Cooper , Kang Alex , Brackenbrough Evans , Bera Asim K. , Sankaran Banumathi , Houk K. N. , Baker David 
Published: August 2024

AbstractEnzymes that proceed through multistep reaction mechanisms often utilize complex, polar active sites positioned with sub-angstrom precision to mediate distinct chemical steps, which makes their de novo construction extremely challenging. We sought to overcome this challenge using the classic catalytic triad and oxyanion hole of serine hydrolases as a model system. We used RFdiffusion1to generate proteins housing catalytic sites of increasing complexity and varying geometry, and a newly developed ensemble generation method called ChemNet to assess active site geometry and preorganization at each step of the reaction. Experimental characterization revealed novel serine hydrolases that catalyze ester hydrolysis with catalytic efficiencies (kcat/Km) up to 3.8 × 103M-1s-1, closely match the design models (Cα RMSDs < 1 Å), and have folds distinct from natural serine hydrolases. In silico selection of designs based on active site preorganization across the reaction coordinate considerably increased success rates, enabling identification of new catalysts in screens of as few as 20 designs. Our de novo buildup approach provides insight into the geometric determinants of catalysis that complements what can be obtained from structural and mutational studies of native enzymes (in which catalytic group geometry and active site makeup cannot be so systematically varied), and provides a roadmap for the design of industrially relevant serine hydrolases and, more generally, for designing complex enzymes that catalyze multi-step transformations.
Comprehensive profiling of migratory primordial germ cells reveals niche-specific differences in non-canonical Wnt and Nodal-Lefty signaling in anterior vs posterior migrants
Authors: Jaszczak Rebecca G. , Zussman Jay W. , Wagner Daniel E. , Laird Diana J. 
Published: August 2024

ABSTRACTMammalian primordial germ cells (PGCs) migrate asynchronously through the embryonic hindgut and dorsal mesentery to reach the gonads. We previously found that interaction with different somatic niches regulates PGC proliferation along the migration route. To characterize transcriptional heterogeneity of migrating PGCs and their niches, we performed single-cell RNA sequencing of 13,262 mouse PGCs and 7,868 surrounding somatic cells during migration (E9.5, E10.5, E11.5) and in anterior versus posterior locations to enrich for leading and lagging migrants. Analysis of PGCs by position revealed dynamic gene expression changes between faster or earlier migrants in the anterior and slower or later migrants in the posterior at E9.5; these differences include migration-associated actin polymerization machinery and epigenetic reprogramming-associated genes. We furthermore identified changes in signaling with various somatic niches, notably strengthened interactions with hindgut epithelium via non-canonical WNT (ncWNT) in posterior PGCs compared to anterior. Reanalysis of a previously published dataset suggests that ncWNT signaling from the hindgut epithelium to early migratory PGCs is conserved in humans. Trajectory inference methods identified putative differentiation trajectories linking cell states across timepoints and from posterior to anterior in our mouse dataset. At E9.5, we mainly observed differences in cell adhesion and actin cytoskeletal dynamics between E9.5 posterior and anterior migrants. At E10.5, we observed divergent gene expression patterns between putative differentiation trajectories from posterior to anterior including Nodal signaling response genesLefty1, Lefty2,andPycr2and reprogramming factorsDnmt1, Prc1,andTet1.At E10.5, we experimentally validated anterior migrant-specificLefty1/2upregulation via whole-mount immunofluorescence staining for LEFTY1/2 proteins, suggesting that elevated autocrine Nodal signaling accompanies the late stages of PGC migration. Together, this positional and temporal atlas of mouse PGCs supports the idea that niche interactions along the migratory route elicit changes in proliferation, actin dynamics, pluripotency, and epigenetic reprogramming.
Consensus guideline for the management of patients with appendiceal tumors: Part 2: Appendiceal tumors with peritoneal involvement
Authors:   PSM Appendiceal Tumor Writing Group,   PSM Consortium Group, Turaga Kiran K. 
Published: August 2024

ABSTRACTBackgroundAppendiceal tumors comprise a heterogeneous group of tumors which frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high quality data, given its rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit. Many practices are controversial and vary widely between institutions. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care. Herein we present recommendations for management of appendiceal tumors with peritoneal involvement.MethodsAs previously described, modified Delphi consensus was performed to update the previous 2018 Chicago consensus guideline. Recommendations were supported using rapid systematic reviews of key issues in surgical and systemic therapy. Key pathology concepts and recommendations were synthesized in collaboration with content experts.ResultsA consensus-based pathway was generated for any type of non-neuroendocrine appendiceal tumor with peritoneal involvement. The first round of Delphi consensus included 138 participants and 133 (96%) participated in the second round, with over 90% consensus achieved for all pathway blocks. Key items include recommending evaluation for cytoreduction to most patients with low-grade peritoneal disease who are surgical candidates, and to many patients with high-grade disease, as well as timing of systemic chemotherapy and surveillance protocols. Common pitfalls in pathologic classification and their clinical implications are also presented.ConclusionThese consensus recommendations provide guidance regarding the management of appendiceal tumors with peritoneal involvement, including a review of current evidence in management of recurrent and unresectable disease.
Thoracic Aortic Shape: A Data-Driven Scale Space Approach
Authors: Pugar Joseph A. , Kim Junsung , Khabaz Kameel , Yuan Karen , Pocivavsek Luka 
Published: August 2024

AbstractThe scale and resolution of anatomical features extracted from medical CT images are crucial for advancing clinical decision-making tools. While traditional metrics, such as maximum aortic diameter, have long been the standard for classifying aortic diseases, these one-dimensional measures often fall short in capturing the rich geometrical nuances available in progressively advancing imaging modalities. Recent advancements in computational methods and imaging have introduced more sophisticated geometric signatures, in particular scale-invariant measures of aortic shape. Among these, the normalized fluctuation in total integrated Gaussian curvatureover a surface mesh model of the aorta has emerged as a particularly promising metric. However, there exists a critical tradeoff between noise reduction and shape signal preservation within the scale space parameters – namely, smoothing intensity, meshing density, and partitioning size. Through a comprehensive analysis of over 1200 unique scale space constructions derived from a cohort of 185 aortic dissection patients, this work pinpoints optimal resolution scales at which shape variations are most strongly correlated with surgical outcomes. Importantly, these findings emphasize the pivotal role of a secondary discretization step, which consistently yield the most robust signal when scaled to approximately 1 cm. This approach enables the development of models that are not only clinically effective but also inherently resilient to biases introduced by patient population heterogeneity. By focusing on the appropriate intermediate scales for analysis, this study paves the way for more precise and reliable tools in medical imaging, ultimately contributing to improved patient outcomes in cardiovascular surgery.