bluuebunny/crossref_metadata_2025_split huggingface dataset:
The single-cell transcriptional landscape of lung carcinoid tumors
Authors: Bischoff Philip , Trinks Alexandra , Wiederspahn Jennifer , Obermayer Benedikt , Pett Jan Patrick , Jurmeister Philipp , Elsner Aron , Dziodzio Tomasz , Rückert Jens-Carsten , Neudecker Jens , Falk Christine , Beule Dieter , Sers Christine , Morkel Markus , Horst David , Klauschen Frederick , Blüthgen Nils 
Published: December 2021

AbstractLung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread while no consensus treatment exists for metastasized carcinoids. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown.To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFβ and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data.Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the non-inflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.
Mycobacterium tuberculosisinfection, immune activation, and risk of HIV acquisition
Authors: Bender Ignacio Rachel A. , Long Jessica , Saha Aparajita , Nguyen Felicia K. , Joudeh Lara , Valinetz Ethan , Mendelsohn Simon C. , Scriba Thomas J. , Hatherill Mark , Janes Holly , Churchyard Gavin , Buchbinder Susan , Duerr Ann , Shah Javeed A. , Hawn Thomas R. 
Published: December 2021

AbstractBackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses toM. tuberculosis(Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study within the Step MRKAd5 HIV-1 vaccine study. PBMCs from the last HIV-negative sample from incident HIV cases and controls who did not acquire HIV were stimulated withMtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining.Combinatorialpolyfunctionality analysis ofantigen-specific T-cellsubsets (COMPASS) determined overallMtb-antigen-specific T cell activation. We measured inflammatory profiles with five Correlates of TB Risk (CoR) peripheral blood transcriptomic signatures. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether either cellular markers of TB-associated immune activation or transcriptomic predictors of TB disease states were associated with HIV acquisition.ResultsAmong 465 participants, latentMtbinfection (LTBI) prevalence (21.5% controls vs 19.1% cases, p=0.51) andMtbantigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.76 (0.60, 0.95)), were associated with HIV acquisition in multivariable analysis. The Sweeney3 signature best predicted odds of acquiring HIV in unadjusted and adjusted analyses, including when restricted to LTBI-negative participants.ConclusionsLTBI andMtbpolyfunctional antigen-specific CD4+ T cell immune activation were not identified as risk factors for HIV acquisition, but transcriptomic analyses demonstrated that two CoR signatures predicted HIV risk after adjustment for known behavioral and clinical risk factors. CoR signatures can demonstrate host gene expression associated with HIV acquisition, but the observed effects are likely not mediated throughMtbinfection.
The unequal impact of the COVID-19 pandemic on life expectancy across Chile
Authors: Mena Gonzalo E. , Aburto José Manuel 
Published: December 2021

AbstractObjectivesTo quantify the effect of the COVID-19 pandemic on life expectancy in Chile categorized by rural and urban, and to correlate life expectancy changes with socioeconomic factors at the municipal level.DesignRetrospective cross-sectional demographic analysis using aggregated data.SettingVital and demographic statistics from the national institute of statistics and department of vital statistics of ministry of health.ParticipantsAggregated national all-cause death data stratified by year (2000-2020), sex, and municipality.Main Outcome measuresStratified mortality rates using a Bayesian methodology. With this, we assessed the unequal impact of the pandemic in 2020 on life expectancy across Chilean municipalities for men and women and analyzed previous mortality trends since 2010.ResultsLife expectancy declined for both men and women in 2020. Urban areas were the most affected, with males losing 1.89 and females 1.33 in 2020. The strength of the decline in life expectancy correlated with indicators of social deprivation and poverty. Also, inequality in life expectancy between municipalities increased, largely due to excess mortality among the working-age population in socially disadvantaged municipalities.ConclusionsNot only do people in poorer areas live shorter lives, they also have been substantially more affected by the COVID-19 pandemic, leading to increased population health inequalities. Quantifying the impact of the COVID-19 pandemic on life expectancy provides a more comprehensive picture of the toll.Strengths and limitationsFirst study to analyze changes in life expectancy in Chile with small-area resolution.We applied a hierarchical Bayesian methodology to estimate life expectancies in the past 20 years.We show that COVID-19 led to declines in life expectancy in Chile greater than a year in magnitude. These declines correlated with poverty levels, indicating that socially deprived populations were hit the hardest.We also show that inequality in life expectancy between municipalities increased due to excess mortality among the working-age population in socially disadvantaged municipalities.The main limitation is that our estimates depend on accurate small-area stratified population estimates. We implemented several estimates and showed that our findings are robust to the choice of them.
Host immune responses to enzootic and invasive pathogen lineages vary in magnitude, timing, and efficacy
Authors: McDonald Coby A. , Guilherme Becker C. , Lambertini Carolina , Felipe Toledo L. , Haddad Célio F.B. , Zamudio Kelly R. 
Published: December 2021

ABSTRACTInfectious diseases of wildlife continue to pose a threat to biodiversity worldwide, yet pathogens are far from monolithic in virulence. Within the same pathogen species, virulence can vary considerably depending on strain or lineage, in turn eliciting variable host responses. One pathogen that has caused extensive biodiversity loss is the amphibian-killing fungus, Batrachochytrium dendrobatidis (Bd), which is comprised of a globally widespread hypervirulent lineage (Bd-GPL), and multiple geographically restricted lineages. Whereas host immunogenomic responses to Bd-GPL have been characterized in a number of amphibian species, immunogenomic responses to geographically-restricted, enzootic Bd lineages are unknown. To examine lineage- specific host immune responses to Bd, we exposed a species of pumpkin toadlet, Brachycephalus pitanga, which is endemic to Brazil’s Southern Atlantic Forest, to either the Bd-GPL or the enzootic Bd-Asia-2/Brazil (hereafter Bd-Brazil) lineage. We quantified functional immunogenomic responses over the course of infection using differential gene expression tests and coexpression network analyses. Host immune responses varied significantly with Bd lineage. Toadlet responses to Bd-Brazil were weak at early infection (26 genes differentially expressed), peaked by mid-stage infection (435 genes) and were nearly fully resolved by late-stage disease (9 genes). In contrast, responses to Bd-GPL were magnified and delayed; toadlets differentially expressed 97 genes early, 86 genes at mid-stage infection, and 728 genes by late-stage infection. Given that infection intensity did not vary between mid- and late-stage disease, this suggests that pumpkin toadlets may be at least partially tolerant to the geographically-restricted Bd- Brazil lineage. In contrast, mortality was higher in Bd-GPL-infected toadlets, suggesting that late-stage immune activation against Bd-GPL was not protective and was consistent with immune dysregulation previously observed in other species. Our results demonstrate that both the timing of immune response and the particular immune pathways activated are specific to Bd lineage. Within regions where multiple Bd lineages co-occur, and given continued global Bd movement, these differential host responses may influence not only individual disease outcome, but transmission dynamics at the population and community levels.
Identification and Validation of Novel Microtubule Suppressors with an Imidazopyridine Scaffold through Structure-Based Virtual Screening and Docking
Authors: Elseginy Samia A. , Oliveira A. Sofia F. , Shoemark Deborah K. , Sessions Richard B. 
Published: December 2021

AbstractTargeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-Hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b] pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC50 = 6.1 ±0.1 μM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity.
Co-radiation of Leptospira and Tenrecidae (Afrotheria) on Madagascar
Authors: Gomard Yann , Goodman Steven M. , Soarimalala Voahangy , Turpin Magali , Lenclume Guenaëlle , Ah-Vane Marion , Golden Christopher D. , Tortosa Pablo 
Published: December 2021

AbstractLeptospirosis is a bacterial zoonosis caused by pathogenic Leptospira that are maintained in the kidney lumen of infected animals acting as reservoirs and contaminating the environment via infected urine. The investigation of leptospirosis through a One Health framework has been stimulated by notable genetic diversity of pathogenic Leptospira together with a high infection prevalence in certain animal reservoirs. Studies of Madagascar’s native mammal fauna have revealed a diversity of Leptospira with high levels of host-specificity. Native rodents, tenrecids, and bats shelter several distinct lineages and species of Leptospira, some of which have also been detected in acute human cases. Specifically, Leptospira mayottensis, first discovered in humans on Mayotte, an island neighboring Madagascar, was subsequently identified in a few species of Malagasy tenrecids, an endemic family of small mammals. Distinct L. mayottensis lineages were identified in shrew tenrecs (Microgale cowani and Nesogale dobsoni) on Madagascar, and later in spiny tenrecs (Tenrec ecaudatus) on Mayotte. These findings suggest that L. mayottensis (i) has co-radiated with tenrecids on Madagascar, and (ii) has recently emerged in human populations on Mayotte following the introduction of T. ecaudatus from Madagascar. Hitherto, L. mayottensis has not been detected in spiny tenrecs on Madagascar. In the present study, we broaden the investigation of Malagasy tenrecids and describe the presence of L. mayottensis in Malagasy T. ecaudatus and M. thomasi. These results confirm the hypothesis that L. mayottensis was introduced to Mayotte, presumably via T. ecaudatus, and provide additional data on the co-radiation of Leptospira and Tenrecidae.
CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis
Authors: Dunbar Andrew , Kim Dongjoo , Lu Min , Farina Mirko , Yang Julie L. , Park Young , Gobbo Francesca , Verachi Paola , Martelli Fabrizio , Karzai Abdul , Xiao Wenbin , Xia Lijuan , Elmansy Nada , Kleppe Maria , Chen Zhuo , Xiao Yang , McGovern Erin , Snyder Jenna , Krishnan Aishwarya , Hill Corrine , Cordner Keith , Zouak Anouar , Salama Mohamed E. , Yohai Jayden , Tucker Eric , Chen Jonathan , Zhou Jing , McConnell Tim , Koche Richard , Rampal Raajit , Migliaccio Anna Rita , Fan Rong , Levine Ross L. , Hoffman Ronald 
Published: December 2021

SUMMARYPro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.
Cylindromatosis Drives Synapse Pruning and Weakening by Promoting Macroautophagy through Akt-mTOR Signaling
Authors: Zajicek Alexis S. , Ruan Hongyu , Dai Huihui , Skolfield Mary C. , Phillips Hannah L. , Burnette Wendi J. , Javidfar Behnam , Sun Shao-Cong , Akbarian Schahram , Yao Wei-Dong 
Published: December 2021

ABSTRACTThe lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux and, conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.
Drosophila gustatory projections are segregated by taste modality and connectivity
Authors: Engert Stefanie , Sterne Gabriella R. , Bock Davi D. , Scott Kristin 
Published: December 2021

AbstractGustatory sensory neurons detect caloric and harmful compounds in potential food and convey this information to the brain to inform feeding decisions. To examine the signals that gustatory neurons transmit and receive, we reconstructed gustatory axons and their synaptic sites in the adult Drosophila melanogaster brain, utilizing a whole-brain electron microscopy volume. We reconstructed 87 gustatory projections from the proboscis labellum in the right hemisphere and 57 from the left, representing the majority of labellar gustatory axons. Gustatory neurons contain a nearly equal number of interspersed pre-and post-synaptic sites, with extensive synaptic connectivity among gustatory axons. Morphology- and connectivity-based clustering revealed six distinct groups, likely representing neurons recognizing different taste modalities. The vast majority of synaptic connections are between neurons of the same group. This study resolves the anatomy of labellar gustatory projections, reveals that gustatory projections are segregated based on taste modality, and uncovers synaptic connections that may alter the transmission of gustatory signals.
The Gulf Coast tick, Amblyomma maculatum (Ixodida: Ixodidae) and spotted fever group Rickettsia in the highly urbanized northeastern US
Authors: Bajwa Waheed I. , Tsynman Leonid , Egizi Andrea M. , Tokarz Rafal , Maestas Lauren P. , Fonseca Dina M. 
Published: December 2021

AbstractWe report the multi-year collection of the Gulf Coast tick, Amblyomma maculatum Koch (Acaridae: Ixodida: Ixodidae) in Staten Island, New York City (NYC) as well as their detection in Brooklyn, NYC, and in Atlantic and Cumberland counties in southern NJ, USA. The first detections on all sites were of adults but in Freshkills Park on Staten Island larvae were collected in a following year. Based on known observations on birds of this tick species, it is likely A. maculatum are expanding north on migratory birds, which are now often seen in Freshkills Park. The presence of larvae indicates that adults are being successful at finding hosts in Staten Island. We describe the landscape features of the area in Staten Island where populations were highest and larvae were detected, which could have facilitated the establishment of A. maculatum. Notably, we also report the presence of human pathogens Rickettsia parkeri in 5/10 (50%) of adults tested and R. felis in 1/24 (4.17%) of larvae tested. In addition to established populations in Staten Island we found evidence of A. maculatum in NJ and other NYC boroughs, suggesting current or future establishment is possible. The failure thus far to detect established populations in these areas may be due to inherent difficulties in detecting low density, spatially heterogeneous incipient populations, which could require targeted surveillance efforts for this species. We discuss the consequences to public health of the establishment of A. maculatum and detection of two additional rickettsial pathogens in the densely populated Northeastern US.
Development and validation of inducible protein degradation and quantitative phosphoproteomics to identify kinase-substrate relationships
Authors: Hards Rufus , Howarth Charles L. , Wiredu Kwame , LaCroix Ian , Valle Juan Mercado del , Adamo Mark , Kettenbach Arminja N. , Holland Andrew J. , Gerber Scott A. 
Published: December 2021

AbstractPhosphorylation signaling is an essential post-translational regulatory mechanism that governs almost all eukaryotic biological processes and is controlled by an interplay between protein kinases and phosphatases. Knowledge of direct substrates of kinases provides evidence of mechanisms that relate activity to biological function. Linking kinases to their protein substrates can be achieved by inhibiting or reducing kinase activity and quantitative comparisons of phosphoproteomes in the presence and absence of kinase activity. Unfortunately, most of the human kinases lack chemical inhibitors with selectivity required to unambiguously assign protein substrates to their respective kinases. Here, we develop and validate a chemical proteomics strategy for linking kinase activities to protein substrates via targeted protein degradation and quantitative phosphoproteomics and apply it to the well-studied, essential mitotic regulator polo-like kinase 1 (Plk1). We leveraged the Tir1/auxin system to engineer HeLa cells with endogenously homozygous auxin-inducible degron (AID)-Plk1). We used HeLa cells and determined the impact of AID-tagging on Plk1 activity, localization, protein interactors, and substrate motifs. Using quantitative proteomics, we show that of over 8,000 proteins quantified, auxin addition is highly selective for degrading AID-Plk1 in mitotic cells. Comparison of phosphoproteome changes in response to chemical Plk1 inhibition to auxin-induced degradation revealed a striking degree of correlation. Finally, we explored basal protein turnover as a potential basis for clonal differences in auxin-induced degradation rates for AID-Plk1 cells. Taken together, our work provides a roadmap for the application of AID technology as a general strategy for the kinome-wide discovery of kinase-substrate relationships.