cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.15139/s3/u6jnfk
title: The effect of HIV infection on CD4 T cell immunity to Mycobacterium tuberculosis

description: Infection with Mycobacterium tuberculosis (Mtb) results in 10 million cases of active tuberculosis (TB) disease each year and is the leading cause of death due to a single infectious agent. Although the correlates of protective immunity to Mtb are not clearly defined, co-infection with human immunodeficiency virus (HIV) is a significant risk factor for development of active TB disease. Moreover, the increased risk of TB disease is evident within the first year of HIV seroconversion, suggesting that impairment of immunity to Mtb occurs early after HIV infection. Although there is compelling evidence that HIV infection is associated with CD4 T cell dysfunction, the molecular mechanisms by which HIV infection impairs CD4 T cell responses to Mtb are unknown. The focus of this proposal is to determine the effect of HIV infection and treatment on the phenotype, function, epigenome and transcriptome of CD4 T cell responses to Mtb. We will leverage blood samples collected from a unique, well- characterized longitudinal cohort of women at high-risk for HIV infection in Mombasa, Kenya to test the hypotheses that (i) HIV infection modifies the epigenome and transcriptome of CD4 T cells to promote differentiation of dysfunctional CD4 T cells; and (ii) early initiation of antiretroviral therapy (ART), prior to HIV- induced CD4 T cell deficiency, preserves the molecular program and functional capacity of CD4 T cell responses that may contribute to enhanced immune control of Mtb. We will use longitudinal samples to conduct high- dimensional flow cytometry to define the phenotype and function of total and Mtb-specific CD4 T cells before and after HIV infection, and before and after ART. At each time point, we will also define the chromatin accessibility landscape, DNA methylome, and transcriptome of the total CD4 T cell population. Lastly, we will use cutting edge, single-cell RNA-sequencing to determine the effect of HIV infection and treatment on the transcriptional state of Mtb-specific CD4 T cells. These studies will generate unprecedented, novel insights into the phenotypic, functional, transcriptomic, and epigenetic profiles of CD4 T cells in HIV infection. Moreover, our genome-wide studies will define the molecular program of CD4 T cells in HIV infection and will potentially identify novel genes, pathways, and transcription factor-based regulatory modules that can be leveraged to enhance durable CD4 T cell-mediated control of Mtb.
DOI: 10.15139/s3/iw5zql
title: Mechanisms of antigen-specific CD4 T cell dysfunction in HIV/TB co-infection

description: Mycobacterium tuberculosis (Mtb) infects approximately 1.7 billion people worldwide, with over 10 million people developing active tuberculosis (TB) disease each year. The vast majority of infected individuals do not develop symptomatic disease and are considered to have latent Mtb infection (LTBI). The single greatest risk factor for development of active TB disease is co-infection with human immunodeficiency virus (HIV). Untreated HIV infection is associated with systemic immune activation, which is considered to be a significant driver of high levels of T cell activation, apoptosis of bystander T cells, and overall loss of CD4 T cells that is characteristic of chronic HIV infection. CD4 T cells are critical for successful immune control of Mtb infection, yet the precise mechanisms whereby HIV infection perturbs CD4 T cell immunity to Mtb and accelerates progression to TB disease have not been well defined. The focus of this proposal is to define potential mechanisms of HIV-associated dysregulation of Mtb-specific CD4 T cell responses in individuals with HIV/Mtb co-infection. We and others have shown that, compared with HIV-uninfected individuals, Mtb-specific CD4 T cells from HIV-infected individuals have diminished cytokine production, a heightened level of activation, profoundly impaired proliferative capacity, and an increased susceptibility to cell death following Mtb antigen stimulation, thus providing compelling evidence of Mtb-specific CD4 T cell dysfunction in the setting of HIV infection. We propose to test the hypotheses that (1) HIV-associated immune activation contributes to functional impairment of Mtb-specific CD4 T cell responses, and (2) HIV infection dysregulates immune signaling networks associated with cell death and T cell dysfunction in Mtb-specific CD4 T cells. Using samples collected from a well-characterized longitudinal cohort of HIV-infected individuals with LTBI in Kenya, sampled prior to and multiple times over the first year of antiretroviral therapy (ART), we will perform a detailed evaluation of the relationship between HIV viral load, immune activation, and the phenotypic and functional signatures of Mtb-specific CD4 T cells in individuals with HIV/Mtb co-infection. We will then utilize state-of-the- art technology to conduct single-cell RNA-sequencing of Mtb-specific CD4 T cells from HIV-infected and HIV- uninfected individuals with LTBI, to define novel immune signaling networks that are dysregulated in Ag- specific CD4 T cells from HIV-infected individuals. Identification of signaling pathways that are differentially expressed in Ag-specific CD4 T cells from HIV-infected individuals will open up new avenues of research in host-directed therapies to promote the generation and maintenance of protective Mtb-specific T cell responses that can mediate sustained control of Mtb infection and prevent progression to active TB disease.
DOI: 10.15139/s3/fgb7ny
title: The effect of HIV exposure and infection on immunity to TB in children

description: Over one million new cases of tuberculosis (TB) and 239,000 TB-related deaths occur in children each year. Despite evidence that HIV exposure in children is associated with a markedly increased risk of infection with Mycobacterium tuberculosis (Mtb) and development of TB disease, few studies have explored mechanisms for HIV-related susceptibility to TB in children. HIV-exposed uninfected children (HEU) are exposed in utero to both maternal HIV and anti-retroviral therapy (ART) and these exposures may influence subsequent immune responses to Mtb. In settings with high prevalence of HIV and TB, newborns typically receive BCG vaccination within the first few days of life, which confers some protection against severe forms of TB in young children. Interestingly, BCG vaccination has also been recognized to confer non-specific beneficial effects, including reduced neonatal and infant mortality. Moreover, vaccination with BCG is associated with enhanced innate immune responses to mycobacteria as well as heterologous pathogens, a phenomenon termed "trained immunity". Epigenetic reprogramming of innate immune cells, including monocytes and NK cells, is one mechanism identified that contributes to BCG-induced trained immunity. The effect of maternal HIV exposure and infant HIV infection on induction of trained immunity to Mtb in BCG-vaccinated infants has not been described. Our studies will characterize innate and adaptive immune responses to mycobacteria, cofactors such as ART that may influence immune responses, and the implications of these immune responses for susceptibility to pediatric Mtb infection. We will test the hypotheses that (1) maternal HIV exposure and infant HIV infection dampen induction of trained immunity to Mtb via epigenetic reprogramming of innate immune cells in BCG-vaccinated infants; and (2) ART enhances innate and adaptive anti-mycobacterial immune responses in HIV-infected children and that deficits in anti-mycobacterial immunity will predict acquisition of Mtb infection. Using clinically-well characterized longitudinal cohorts of infants and children in Kenya, we will perform a comprehensive analysis of the phenotype, function, epigenome and transcriptome of innate immune responses in HEU, HIV-infected, and HIV-unexposed uninfected infants. We will then determine the capacity of ART to restore innate and adaptive anti-mycobacterial immune responses in HIV-infected children and identify immune correlates that predict acquisition of Mtb infection. These studies will provide unprecedented insights into mechanisms of HIV-associated modulation of immunity to Mtb in infants and children and will inform novel TB preventive interventions in these at-risk populations.
DOI: 10.15139/s3/sglnft
title: Leveraging Telehealth to Overcome Research Implementation and Data Collection Challenges in the Era of COVID-19

description: In the era of the COVID-19 pandemic there has been an unprecedented scale of disruption in implementation of health research around the world. Health systems, health providers and patients alike have been negatively impacted by the lockdowns, restrictions to travel, the need for social distancing, the lack of personal protective equipment among others. Compliance to new requirements has resulted in protocol adjustments and unexpected expenses in the field research operations. The administrative supplemental funding request is motivated by our team's commitment to complete data collection to achieve a sample size with adequate power for statistical significance. The parent study protocol required close in-person interactions between research staff and patients during the baseline enrollment and follow up visits. The baseline enrollment visit involves face-to-face screening for study eligibility, obtaining written informed consent, clinical assessment, a baseline questionnaire and training patients in the VDOT intervention arm to use of a smartphone app as part of the trial. The follow-up involves 3 in-person visits follow up visits at the clinics. To-date, the parent study timeline expires April 30th 2021, yet only 30.6% of the study participants have completed the study. The goal of the supplement is to modify study implementation protocols to increase use of telehealth to enhance efficiency, safety and completion of follow up visits. The goal of this project will be accomplished through the following specific aims.
DOI: 10.15139/s3/hmxaac
title: Pulmonary impairment after tuberculosis in Georgia: Enhancing clinical research capacity to address the intersection of non-communicable diseases and tuberculosis

description: The intersection of tuberculosis (TB) disease with non-communicable disease, including chronic pulmonary impairment, has emerged as a critical clinical and public health obstacle. Rapidly expanding non-communicable disease epidemics threaten TB control in low- and middle-income countries, including Georgia, where preventing and treating TB disease remains a great burden. However, to date, the notion that TB disease may increase the risk of chronic non-communicable disease has not been well explored. We will determine the extent to which multidrug-resistant (MDR) TB, smoking, and biomarkers of lung inflammation contribute to increased prevalence of pulmonary impairment post-TB in the country of Georgia. This research will advance understanding of dual burdens of communicable and non-communicable diseases and build individual and institutional research capacity in Georgia. The long-term objective of this research is to elucidate the relationship between TB patient and TB pathogen factors with post-TB chronic pulmonary impairment, and strengthen research capacity for future work to identify treatment and prevention strategies that reduce the risk of chronic non-communicable diseases after TB treatment completion. The specific aims of this proposal are to: (1) determine the burden, predictors, and trajectory of pulmonary impairment post-TB treatment; (2) explore the relationship between biomarkers of lung inflammation and lung destruction at time of TB treatment completion with severity of pulmonary impairment; and (3) build increased research infrastructure and capacity for Georgia that is focused on the intersection of TB and chronic pulmonary impairment. The aims of this project will be achieved by enrolling a cohort of patients (n=130) at the time of TB treatment completion and following them prospectively for one year. At both time points this study will measure spirometry, pulse oximetry, and quality of life among patients who were treated for drug susceptible TB (n=65) and among patients treated for MDR TB (n=65). The analysis will include multiple modeling strategies to assess the relationship between patient and host factors and the risk of chronic pulmonary impairment. The proposed study will help to characterize the extent to which TB contributes to chronic pulmonary impairment and will identify which existing clinical respiratory rehabilitation interventions may be used to improve quality of life throughout the lifespan among patients with TB. In addition, this R21 will leverage a cadre of current and former Fogarty-supported trainees and provide invaluable mentored training experiences in the areas of TB and chronic pulmonary diseases. A long term goal of the proposed work is to prepare for prospective studies that follow patient cohorts beginning at the time of TB diagnosis, during TB treatment, and several years after TB treatment.
DOI: 10.5281/zenodo.8284557
title: DATASET: Exploring the Residue-Level Interactions between the R2ab Protein and Polystyrene Nanoparticles

description: This file contains the raw hydrogen-deuterium exchange data used in the manuscript. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD044469. 202308
DOI: 10.5281/zenodo.8284556
title: DATASET: Exploring the Residue-Level Interactions between the R2ab Protein and Polystyrene Nanoparticles

description: This file contains the raw hydrogen-deuterium exchange data used in the manuscript. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD044469. 202308
DOI: 10.25919/jgz5-gx32
title: Parkes observations for project PX500 semester 2023APRS_25

description: This proposal relates to time purchased by the Chinese Academy of Sciences for Parkes follow-up confirmation and timing of FAST discoveries. As the observing time has been purchased this proposal (and the related PX501) does not require TAC grading. The primary reason for submitting a proposal is to ensure an outreach statement and that the proposal is entered into OPAL for the data archive to access. The Chinese team have two time requests. The time scheduled for the first, relating to this proposal, will be allocated in blocks of 24 hours and the data will become available in the data archive with an 18 month embargo period. The second type of time will be scheduled in shorter blocks and the data archived with a 10 year embargo.
DOI: 10.25919/vncm-wr59
title: Parkes observations for project P456 semester 2023APRS_12

description: The Parkes Pulsar Timing Array (PPTA) project has three primary goals: (a) detection of gravitational waves from astronomical sources, (b) establishment of a pulsar timescale, and (c) improvement of our understanding of Solar-system dynamics. We are now in an exciting regime where a signal detected in our (and other data sets) has the form expected for a gravitational wave background. We are therefore now attempting to confirm, or deny, this exciting result. With this proposal we aim to maintain our pre-eminent position in the field. Unlike most observing proposals, this is a continuing proposal for which the observations will continue to improve bounds on ultra-low-frequency gravitational waves until they are finally detected. Continued Parkes observations will remain valuable at least until the first stage of the SKA is able to improve on our sensitivity and observing cadence. Even after the gravitational wave background is detected we will want to continue observations in support of the nascent field of gravitational wave astronomy!
DOI: 10.22003/xfel.eu-data-900357-00
title: TST SASE2 storage tests with AGIPD
DOI: 10.22003/xfel.eu-data-003716-00
title: Disentangling the exciton dynamics and hole localization in colloidal CuInS2 quantum dots
DOI: 10.22003/xfel.eu-data-004137-00
title: Time-domain dynamics of the breathing-distortion in the photo-induced metal-insulator transition of NdNiO3 by laser pump - RIXS probe
DOI: 10.15139/s3/opmcid
title: Latent tuberculosis infection and risk of type 2 diabetes mellitus in US veterans

description: Low- and middle-income countries are projected to have substantial increases in incidence of type 2 diabetes mellitus, the same regions where tuberculosis (TB) is endemic and a public health priority. Diabetes increases the risk of TB disease by three times and an estimated 15% of incident TB cases are due to diabetes, similar to the proportion of TB cases attributable to HIV. In the context of increasing rates of co-occurring TB and diabetes, prevention efforts to reduce the burden of dual disease are severely limited by critical gaps in knowledge of the relationship between latent TB infection and risk of diabetes mellitus. The specific aims of this proposal are to: (1) determine the extent to which latent TB infection (measured by interferon-gamma release assay [IGRA]) increases the risk of incident type 2 diabetes mellitus; (2) determine if latent TB increases the risk of progression from normal blood glucose to pre-diabetes; and (3) determine the extent to which latent TB treatment decreases the risk of incident type 2 diabetes among patients with latent TB infection. The aims of this project will be achieved by building a large database of patients with known latent TB infection status who are at risk of developing diabetes. The study will use longitudinal data from the Veterans Affairs Corporate Data Warehouse from 2000-2015 to build a retrospective cohort of more than 100,000 patients. The analysis will include multiple modeling strategies and propensity scores to assess the relationship between latent TB infection and rate of incident diabetes. This research has the potential to have far-reaching implications for biomedical approaches to diabetes prevention and TB control. The proposed study includes an unprecedented hypothesis that challenges current assumptions and the paradigm that the observed association between active TB and diabetes is singularly due to increased susceptibility to TB among patients with diabetes. Existing epidemiologic data demonstrate a higher prevalence of diabetes in patients with active TB compared to the background population prevalence of diabetes. However, it is unknown if the increased prevalence of diabetes among patients with active TB is due to diabetes impacting 1) risk of latent infection, 2) risk of reactivation from latent TB to active disease, 3) risk for primary progression from Mycobacterium tuberculosis exposure to active TB disease, 4) or alternatively, if TB infection or disease impacts the risk of diabetes incidence. The proposed study will help to clarify TB-diabetes pathways and will generate preliminary data useful to deconstruct the pathways which lead to increased diabetes prevalence among patients with active TB. The long term goal of the proposed work is to prepare for a prospective study to examine the relationship between TB infection and risk of diabetes and ultimately better characterize the effect of immune activity related to TB infection on metabolic function.
DOI: 10.15139/s3/py4ade
title: Immunometabolic impact of stress hyperglycemia on tuberculosis treatment outcomes and risk of diabetes mellitus

description: The intersection of tuberculosis (TB) with non-communicable diseases, including diabetes mellitus, has emerged as a critical clinical and public health obstacle. Rapidly expanding diabetes epidemics threaten TB control in low- and middle-income countries, including the country of Georgia, where preventing and treating TB disease remains a great burden. However, to date, the notion that TB disease may increase the risk of metabolic diseases like diabetes has not been well explored. This study will determine the extent to which TB-induced stress hyperglycemia impacts the risk of poor TB treatment outcomes. We will also assess whether stress hyperglycemia or adipose tissue inflammation during TB increase the risk of diabetes post-TB. This research will advance understanding of dual burdens of TB-diabetes and inform treatment guidelines for management of stress hyperglycemia during TB. The long-term objective of this research is to develop an evidence base to help identify which patients with TB are likely to benefit most from adjunctive anti-inflammatory glucose-lowering agents. The specific aims of this proposal are to: (1) determine the relationship between stress hyperglycemia and TB outcomes, including TB cure rate and time to sputum culture conversion; (2) determine the extent that stress hyperglycemia during TB increases the risk of diabetes 1-year after TB treatment; and (3) explore the relationship between plasma and subcutaneous tissue biomarkers of adipose tissue inflammation with stress hyperglycemia and diabetes risk. The aims of this project will be achieved by enrolling a cohort of patients at the time of TB diagnosis and following them prospectively during treatment and for 1-year post-TB treatment. At multiple time points during this study we will measure glucose, insulin resistance, lipids, adipokines, and anthropometry among participants with diabetes, stress hyperglycemia, and euglycemia. In a subset of the cohort we will perform adipose tissue biopsies and measure adipose tissue inflammation. The analyses will include multiple modeling strategies to assess the relationship between patient and host factors and the risk of post-TB metabolic disease. This proposal will directly address clinical uncertainties related to the growing global concern of intersecting TB and diabetes epidemics. The study will help to characterize the extent to which TB contributes to diabetes incidence and will identify which patients with hyperglycemia are at greatest risk of poor TB outcomes. In addition, this R01 will explore novel biomarkers of adipose tissue inflammation to determine whether TB alters immune activity or metabolic function within human adipose tissue. A long-term goal of the proposed work is to prepare for prospective interventional studies that will evaluate glucose-lowering agents during active TB as adjunctive therapy to improve TB outcomes and reduce risk of diabetes after TB.