bluuebunny/crossref_metadata_2025_split huggingface dataset:
Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas
Authors: Miller Tyler E. , Farran Chadi A. El , Couturier Charles P. , Chen Zeyu , D’Antonio Joshua P. , Verga Julia , Villanueva Martin A. , Castro L. Nicolas Gonzalez , Tong Yuzhou Evelyn , Saadi Tariq Al , Chiocca Andrew N. , Fischer David S. , Heiland Dieter Henrik , Guerriero Jennifer L. , Petrecca Kevin , Suva Mario L. , Shalek Alex K. , Bernstein Bradley E. 
Published: October 2023

ABSTRACTGliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.
Angular leaf spot inAcmella oleraceacaused by a foliar nematode
Authors: de Freitas Silva Marcela , Faccioli Felipe Castro , Honório Amanda Pereira , Fonseca Andressa Rodrigues , de Jesus Boari Alessandra , Buonicontro Dalila Sêni 
Published: October 2023

ABSTRACTJambu plants (Acmella oleracea) exhibiting necrotic angular leaf spots were collected in Belém - Pará, Brazil. After previous analysis, the presence of nematodes fromAphelenchoidesgenus was observed. These nematodes were cultured onFusariumsp. and subsequently morphologically and molecularly characterized for species-level identification.Aphelenchoidessp. associated with jambu exhibited morphological and morphometric characteristics very similar to those of species within theA. besseyicomplex (A. besseyi,A. oryzaeandA. pseudobesseyi), but these characteristics were not sufficient to separate them into a unique species. The Bayesian inference analysis, utilizing the expansion segment of the large subunit (D2-D3 LSU) of nuclear ribosomal DNA, yielded results with a high posterior probability, indicating that theAphelenchoidessp. associated with jambu belongs to theA. pseudobesseyispecies. Under controlled conditions, the reproduction of the nematode in the leaf tissues (FR > 1) was observed, resulting in disease symptoms. The highest reproduction rate ofA. pseudobesseyi(FR = 2.6) was observed from inoculation with 100 nematodes per leaf. It is concluded thatA. pseudobesseyiis the etiological agent of jambu angular leaf spot. For future research, like evaluating the resistance of jambu to this nematode, it is recommended to inoculate a maximum of 100 nematodes per leaf.
PhysiCell Studio: a graphical tool to make agent-based modeling more accessible
Authors: Heiland Randy , Bergman Daniel , Lyons Blair , Cass Julie , Rocha Heber L. , Ruscone Marco , Noël Vincent , Macklin Paul 
Published: October 2023

AbstractDefining a multicellular model can be challenging. There may be hundreds of parameters that specify the attributes and behaviors of objects. Hopefully the model will be defined using some format specification, e.g., a markup language, that will provide easy model sharing (and a minimal step toward reproducibility). PhysiCell is an open source, physics-based multicellular simulation framework with an active and growing user community. It uses XML to define a model and, traditionally, users needed to manually edit the XML to modify the model. PhysiCell Studio is a tool to make this task easier. It provides a graphical user interface that allows editing the XML model definition, including the creation and deletion of fundamental objects, e.g., cell types and substrates in the microenvironment. It also lets users build their model by defining initial conditions and biological rules, run simulations, and view results interactively. PhysiCell Studio has evolved over multiple workshops and academic courses in recent years which has led to many improvements. Its design and development has benefited from an active undergraduate and graduate research program. Like PhysiCell, the Studio is open source software and contributions from the community are encouraged.
Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKε-dependent activation of NF-κB
Authors: Chan Jonathan K. , Sun Yan , Bhushan Anand , Willard Belinda , Tam Connie 
Published: October 2023

AbstractThe corneal epithelium at the ocular surface is constantly exposed to the environment and represents the first line of defense against infection, mechanical injury or chemical irritation. Through TLR-mediated recognition of pathogen- and damage-associated molecular patterns, it engages in direct antimicrobial responses and alerts the immune system on intruder and tissue damage by secreting pro-inflammatory and chemotactic cytokines that promote immune cell infiltration. How the corneal epithelium downregulates TLR signaling is unclear, yet it highly expresses keratin 6a (K6a), a cytoskeletal protein that has emerged to play essential regulatory roles in corneal innate immune response. Here we report that mice harboring genetic deletion of K6a are more susceptible to developing bacterial keratitis with unresolved corneal opacification and higher bacterial load. Such disease phenotype is caused by the increased pro-inflammatory cytokine and chemokine secretions from the K6a-null corneal epithelium, which further promotes the infiltration of immune cells and their associated pro-inflammatory response. Using human corneal epithelial cells immortalized by telomerase reverse transcriptase (hTCEpi cells), we demonstrated that knocking down K6a enhances NF-κB/ RelA-dependent cytokine and chemokine expression. Moreover, proteomic screen reveals that K6a interacts with ELKS, a critical NEMO-binding scaffold that links between canonical IKKα/β and the principal cytoplasmic inhibitor of RelA, i.e. IκBα., to promote its phosphorylation and degradation. Surprisingly, K6a does not antagonize any of these canonical NF-κB signaling events. Instead, we found that ELKS in addition to canonical IKKs interacts with the atypical IKK member IKKε. Furthermore, knockdown of K6a in hTCEpi cells promotes ELKS-dependent phosphoactivation of IKKε, which in turn phosphorylates and activates RelA. Our study thus demonstrated an unexpected role of cytosolic K6a as a novel negative regulator of TLR/NF-κB signaling in preventing excess proinflammatory cytokine and chemokine expressions. It further highlighted the functional importance of ELKS as a common signaling scaffold for both canonical and atypical IKK-dependent activation of NF-κB in corneal epithelial cells. Using both IKK classes other than only canonical IKKs for TLR/NF-κB induction as in other cell types including myeloid immune cells suggest that the cornea epithelium is more flexible in modulating its inflammatory response, which could greatly minimize corneal damage while preserving its essential functions for barrier protection and light refraction.
Reduced Monocyte Proportions and Responsiveness in Convalescent COVID-19 Patients
Authors: Ravkov Eugene V. , Williams Elizabeth S.C.P. , Elgort Mark , Barker Adam P. , Planelles Vicente , Spivak Adam M. , Delgado Julio C. , Lin Leo , Hanley Timothy M. 
Published: October 2023

ABSTRACTThe clinical manifestations of acute severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and COVID-19 suggest a dysregulation of the host immune response that leads to inflammation, thrombosis, and organ dysfunction. It is less clear whether these dysregulated processes persist during the convalescent phase of disease or during long COVID. We investigated the effects of SARS-CoV-2 infection on the proportions of classical, intermediate, and non-classical monocytes, their activation status, and their functional properties in convalescent COVID-19 patients and uninfected control subjects. We found that the percentage of total monocytes was decreased in convalescent COVID-19 patients compared to uninfected controls. This was due to decreased intermediate and non-classical monocytes. Classical monocytes from convalescent COVID-19 patients demonstrated a decrease in activation markers, such as CD56, in response to stimulation with bacterial lipopolysaccharide (LPS). In addition, classical monocytes from convalescent COVID-19 patients showed decreased expression of CD142 (tissue factor), which can initiate the extrinsic coagulation cascade, in response to LPS stimulation. Finally, we found that monocytes from convalescent COVID-19 patients produced less TNF-α and IL-6 in response to LPS stimulation, than those from uninfected controls. In conclusion, SARS-CoV-2 infection exhibits a clear effect on the relative proportions of monocyte subsets, the activation status of classical monocytes, and proinflammatory cytokine production that persists during the convalescent phase of disease.
Vagus nerve stimulation limits the germinal center B cell response via CD4+ T cell-derived acetylcholine
Authors: Kurata-Sato Izumi , Mughrabi Ibrahim T , Rana Minakshi , Gerber Michael , Al-Abed Yousef , Sherry Barbara , Zanos Stavros , Diamond Betty 
Published: October 2023

AbstractNeural signals are known to contribute to immune regulation and modulation of the innate immune response downstream of the vagus nerve has been well studied. The effects of vagus nerve activity on antibody production, however, have been largely unexplored. Here we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of vagal activation on T-dependent B cell responses. We observed lower titers of high-affinity serum IgG and fewer antigen-specific germinal center (GC) B cells in the spleen. GC B cells from chronic VNS mice expressed more active caspase-3 and exhibited an altered gene expression profile suggesting increased susceptibility to apoptosis and impaired maturation. Follicular dendritic cell (FDC) cluster dispersal and altered FDC gene expression suggested poor FDC function. These alterations were diminished in the absence of a subset of acetylcholine-producing CD4+ T cells. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. Engagement of the α4 nAChR subunit on B cells impaired Akt phosphorylation, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed, at least in part, to the effect of acetylcholine on B cell intrinsic pathways, resulting in hindered B cell survival and maturation and leading to an alteration in FDC function. Our findings identify a potential therapeutic target to prevent immunosuppression in conditions associated with increased vagal activity.
Multi-omics Quality Assessment in Personalized Medicine through EATRIS
Authors:   EATRIS Plus Multi-omics working group and stakeholders (in alphabetical order by last name), Alonso-Andrés Patricia , Baldazzi Davide , Chen Qiaochu , Conde Moreno Elisa , Crespo-Toro Lorena , Donner Kati , Džubák Petr , Ekberg Sara , Garcia-Bermejo Maria Laura , Gasparotto Daniela , Ghimire Bishwa , Gloerich Jolein , Habier Janine , Hajdúch Marián , Halder Rashi , Hannula Sari , Lindgren Hanna , Liu Yaqing , Maestro Roberta , Martin Tom , Mattila Pirkko , Najdekr Lukáš , Nazir Kenneth , Niehues Anna , Nieminen Anni I , Nordlund Jessica , Oldoni Emanuela , Övernäs Elin , Palva Aino , Puhka Maija , Quintero Ileana , Ramos-Muñoz Miren Edurne , Rodríguez-Serrano Esperanza Macarena , Saracino Sabrina , Scherer Andreas , Shi Leming , Stanková Jarmila , ’t Hoen Peter-Bram , Tunstall Tanushree , Valenti Beatrice , van Gool Alain , Weiss Marjan , Yadav Bhagwan , Zheng Yuanting , Žižkovičová Patricia 
Published: October 2023

ABSTRACTMolecular characterization of a biological sample, e.g., with omics approaches, is fundamental for the development and implementation of personalized and precision medicine approaches. In this context, quality assessment is one of the most critical aspects. Accurate performance and interpretation of omics techniques is based on consensus, harmonization, and standardization of protocols, procedures, data analysis and reference values and materials. EATRIS, the European Infrastructure for Translational Medicine (www.EATRIS.eu), brings together resources and services to support researchers in developing their biomedical discoveries into novel translational tools and interventions for better health outcomes. Here we describe activities of member facilities of EATRIS towards quality assessment of pre-clinical sample processing, clinical omics data generation, multi-omics data integration, and dissemination of the resources in a Multi-Omics Toolbox, the principal deliverable of the EATRIS Plus project for the consolidation of EATRIS towards translational Medicine.
MatK impacts Differential Chloroplast Translation of Ribosomal and Photosynthetic genes by limiting spliced tRNA-K(UUU) abundance
Authors: Muino Jose M. , Qu Yujiao , Ruwe Hannes , Maschmann Sascha , Chen Wei , Zoschke Reimo , Ohler Uwe , Kaufmann Kerstin , Schmitz-Linneweber Christian 
Published: October 2023

AbstractThe protein levels of chloroplast photosynthetic genes and genes related to the chloroplast genetic apparatus vary to adapt to different conditions. However, the underlying mechanisms governing these variations remain unclear. The chloroplast intron Maturase K is encoded within thetrnKintron and has been suggested to be required for splicing several group IIA introns, including thetrnKintron. In this study, we employed RNA immunoprecipitation followed by high-throughput sequencing (RIP-Seq) to identify MatK’s preference for binding to group IIA intron domains I and VI within target transcripts. Importantly, these domains are crucial for branch point selection, and we discovered alternative branch points in three MatK target introns, the first observed instances of alternative splicing in chloroplasts. The alternativetrnKlariat structure showed increased accumulation during heat acclimation. The cognate codon of tRNA-K(UUU) is highly enriched in mRNAs encoding ribosomal proteins and ribosome profiling in atrnK-matKover-expressor exhibited elevated levels of the spliced tRNA-K(UUU). Our analysis revealed a significant up-shift in the translation of ribosomal proteins compared to photosynthetic genes. Our findings suggest the existence of a novel regulatory mechanism linked to the abundance of tRNA-K(UUU), enabling the differential expression of functional chloroplast gene groups.
Medical tourism’s vulnerability to COVID-19 and its path to recovery: a 10-year data analysis of international patient visits
Authors: Myung Gihyun , Lim Juwon 
Published: October 2023

AbstractBackgroundThis study seeks to assess the trends in international patient intake over the past decade, with a specific focus on the impact of the COVID-19 pandemic.MethodsThis is a retrospective study on the data obtained from SUPREME (CDW Research Search System) of Information Center from a single university hospital. Patient demographics on the gender, age, nationality, and diagnosis visiting International Healthcare Center from January 2013 to June 2023 were collected, and the impact and recovery rates from COVID-19 were calculated in terms of the number of foreign patients. The patient number was further analyzed based on gender, age, nationality, and diagnosis.ResultsThe impact and recovery rates of COVID-19 on the number of foreign patients was 57% and 71%, respectively. The patients from USA, the old adult group (age 40-64), and patients with cancer were least affected by COVID-19, whereas the patients from the UAE, the young adult group (age 19-39), and patients for medical screening were most affected by COVID-19.ConclusionsThe number of international patients steadily was steadily rising since 2013 with a drop in number more than half with the advent of COVID-19 in 2019. However, recent data suggests a revival of this trend, signaling a gradual return to pre-pandemic levels. Despite the overall recovery, future trends are not entirely predictable due to potential factors. Future pandemics, international conflicts, or economic instability could potentially affect the influx of foreign patients. To revive medical tourism, a joint effort from the government and hospital is necessary.
Adapting a Data to Care Approach for HIV to Promote HCV Cure for Persons with HIV/HCV Co-infection
Authors: Wegener Maximilian , Gosselin Deborah , Brooks Ralph , Speers Suzanne , Villanueva Merceditas 
Published: October 2023

ABSTRACTWith Direct Acting Antivirals for Hepatitis C virus (HCV), cure is possible in >95% including those with HIV/HCV co-infection. Achieving strategic targets for cure requires addressing barriers including suboptimal care engagement. We adapted Data to Care (D2C), a public health strategy designed to identify and link persons out of care (OOC) for HIV, for persons with HIV/HCV co-infection untreated for HCV. In partnership with Connecticut Department of Public Health (DPH), persons OOC for HIV (defined as no HIV surveillance laboratory tests from 10/1/2018-10/1/2019) were matched to a list of persons co-infected with HIV/HCV (through 12/31/2019). We used a three-phase follow-up approach (pre-work, case conferencing, and Disease Intervention Specialist (DIS) follow-up) to track outreach outcomes and re-engagement/HCV cure success. There were 90 HIV/HCV co-infected persons who were OOC for HIV. The pre-work and case conferencing phases determined that 33 (36.7%) had previous HCV cure or were in treatment. There were 41 eligible for DIS-follow-up of which 21 (51%) were successfully contacted and 7 (33%) successfully re-engaged (kept appointment with HCV provider). No new HCV treatment initiations were recorded. Using a D2C approach, we identified and conducted outreach to persons who were OOC for HIV to promote HCV treatment. This approach resulted in intensive data clean-up and outreach efforts which produced modest re-engagement and no HCV treatment initiations. Future studies should develop alternative and complementary interventions to promote effective re-engagement and HCV treatment.
Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders
Authors: Arbabi Keon , Newton Dwight F. , Oh Hyunjung , Davie Melanie C. , Lewis David A. , Wainberg Michael , Tripathy Shreejoy J. , Sibille Etienne 
Published: October 2023

AbstractBackgroundPsychiatric disorders like major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are characterized by altered cognition and mood, brain functions that depend on information processing by cortical microcircuits. We hypothesized that psychiatric disorders would display cell type-specific transcriptional alterations in neuronal subpopulations that make up cortical microcircuits: excitatory pyramidal (PYR) neurons and vasoactive intestinal peptide- (VIP), somatostatin- (SST), and parvalbumin- (PVALB) expressing inhibitory interneurons.MethodsWe performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control, using laser capture microdissection followed by RNA sequencing (LCM-seq). We sequenced libraries from 130 whole cells pooled per neuronal subtype (VIP, SST, PVALB, superficial and deep PYR) in 76 subjects from the University of Pittsburgh Brain Tissue Donation Program, evenly split between MDD, BD, and SCZ subjects and healthy controls.ResultsWe identified hundreds of differentially expressed (DE) genes and biological pathways across disorders and neuronal subtypes, with the vast majority in inhibitory neuron types, primarily PVALB. DE genes were distinct across cell types, but partially shared across disorders, with nearly all shared genes involved in the formation and maintenance of neuronal circuits. Coordinated alterations in biological pathways were observed between select pairs of microcircuit cell types and partially shared across disorders. Finally, DE genes coincided with known risk variants from psychiatric genome-wide association studies, indicating cell type-specific convergence between genetic and transcriptomic risk for psychiatric disorders.ConclusionsWe present the first cell type-specific dataset of cortical microcircuit gene expression across multiple psychiatric disorders. Each neuronal subtype displayed unique dysregulation signatures, some shared across cell types and disorders. Inhibitory interneurons showed more dysregulation than excitatory pyramidal neurons. Our study suggests transdiagnostic cortical microcircuit pathology in SCZ, BD, and MDD and sets the stage for larger-scale studies investigating how cell circuit-based changes contribute to shared psychiatric risk.
Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS-CARES Study
Authors: Blake Jason A. , Long D. Leann , Knight Amy J. , Goodin Burel R. , Crowe Michael , Judd Suzanne E. , Rhodes J. David , Roth David L. , Clay Olivio J. 
Published: October 2023

ABSTRACTObjectiveCognitive impairment after stroke is common, present up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of two stroke severity ratings and a caregiver-report of post-stroke functioning with longitudinal cognitive outcomes.MethodsThe analysis was conducted on 157 caregivers and stroke survivor dyads who participated in the Caring for Adults Recovering from the Effects of Stroke (CARES) project, an ancillary study of the REasons for Geographic and Racial Differences in Stroke (REGARDS) national cohort study. Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) collected at hospitalization discharge were included as two primary predictors of cognitive impairment. The number of caregiver-reported problems and impairments at nine months following stroke were included as a third predictor. Cognition was assessed using a biennial telephone battery, incorporating multiple cognitive assessments to assess learning, memory, and executive functioning. Longitudinal cognitive scores were analyzed up to five years post-stroke, controlling for baseline (pre-stroke) cognitive scores and demographic variables of each stroke survivor collected at CARES baseline.ResultsSeparate mixed models showed significant main effects of GOS (b=0.3280, p=0.0009), mRS (b=-0.2119, p=0.0002), and caregiver-reported impairments (b=-0.0671, p<0.0001) on longitudinal cognitive scores. In a combined model including all three predictors, only caregiver-reported problems significantly predicted cognitive outcomes (b=-0.0480, p<0.0001).ImpactThese findings underscore the importance of incorporating caregivers feedback in understanding cognitive consequences of stroke.