DR37 DataRelease
Release Date: 12/15/2020
| SDY1599: Synovial fibroblast positional identity controlled by inductive Notch signaling underlies pathologic damage in inflammatory arthritis | |||||||
| Status: | New | ||||||
| Description: | The synovium is a mesenchymal tissue composed mainly of fibroblasts with a lining and sublining that surrounds the joints. In rheumatoid arthritis (RA), the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive and destroys the joint1,2. Recently, we and others found that a subset of fibroblasts located in the sublining undergoes major expansion in RA and is linked to disease activity 35. However, the molecular mechanism by which these fibroblasts expand in RA remains unknown. Here, we identified a critical role for NOTCH3 signaling in the differentiation of perivascular and sublining CD90(THY1)+ fibroblasts. Using single cell RNA-sequencing and mixed cell micromass organoids, we found that NOTCH3 signaling drives both transcriptional and spatial gradients in fibroblasts emanating from vascular endothelial cells outward. In active RA, NOTCH3 and NOTCH target genes are markedly upregulated in synovial fibroblasts. Importantly, genetic deletion of Notch3 or monoclonal antibody-blockade of NOTCH3 signaling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit positional identity regulated by endothelium-derived Notch signaling and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3R2HHAQ4Q | ||||||
| Subjects: | 32 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1619: Study of Safety and Effectiveness of Intravenous Immunization With PfSPZ Vaccine in Healthy African Adults - Vaccine Safety Cohort | ||||||||||
| Status: | New | |||||||||
| Description: | Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo controlled trial based in Doneguebougou and surrounding villages in Mali. We recruited 18-35 year old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2.7x10^5 PfSPZ or normal saline at days 1, 29, 57, 85, and 141 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. | |||||||||
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| DOI: | 10.21430/M3UCU1AZLC | |||||||||
| Subjects: | 12 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1631: The roles of CD103 and CD49a in adherence and motility of CD8 T cells | |||||||
| Status: | New | ||||||
| Description: | Tissue resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon re-exposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/_7 and CD49a/CD29(_1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by two-weeks post-infection and that each integrin contributes a distinct function regulating CD8 T cell motility both in vitro and in vivo, with CD49a facilitating migration and CD103 limiting motility through tethering. These results demonstrate for the first time how CD103 and CD49a differentially impact adherence and migration in the tissue, likely affecting overall retention, maintenance of TRM, and host protection. | ||||||
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| DOI: | 10.21430/M3IV53ZSX3 | ||||||
| Subjects: | 12 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1646: 43rd Multicenter Airway Research Collaboration (MARC-43) | |||||||
| Status: | New | ||||||
| Description: | We enrolled healthy infants from a primary care group practice from November 2013 through May 2014. Fecal samples were collected via a standardized protocol at home before the clinic visit. First, diapers containing feces were refrigerated or stored in a cooler by parents immediately after collection. The fecal samples were then placed in sterile Sarstedt feces collection containers and immediately stored at _80C. Frozen samples were shipped on dry ice to Baylor College | ||||||
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| DOI: | 10.21430/M3UNSL0593 | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1671: Study of Safety and Effectiveness of Intravenous Immunization With PfSPZ Vaccine in Healthy African Adults - Vaccine Efficacy and Placebo Cohorts | ||||||||||
| Status: | New | |||||||||
| Description: | Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo controlled trial based in Doneguebougou and surrounding villages in Mali. We recruited 18-35 year old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2.7x10^5 PfSPZ or normal saline at days 1, 29, 57, 85, and 141 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. | |||||||||
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| DOI: | 10.21430/M3XAASI63D | |||||||||
| Subjects: | 93 | |||||||||
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| Assays: | None | |||||||||
| Clinical Assessments: | None | |||||||||
| SDY1679: Relaxed constraint and functional divergence of PGR | |||||||
| Status: | New | ||||||
| Description: | To resolve existing conflicting data on progesterone receptor gene (PGR) evolution, the study assembled a dataset of 119 Eutherian PGRs and used a suite of maximum likelihood-based methods to characterize the strength and direction of selection acting on PGR. The result shows that PGR evolved rapidly in the human lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology | ||||||
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| DOI: | 10.21430/M3SB6G69P1 | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1680: Flow Cytometry of T cells from HAARVI COVID-19 Cohort | |||||
| Status: | New | ||||
| Description: | Intracellular Cytokine Staining data and Surface Marker Phenotyping data from convalescent COVID-19 infected individuals who were previously either hospitalized or not hospitalized. Both the magnitude and functional breadth of antigen-specific CD4 T cell responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. CD4 T cell responses to all antigens were driven by IFN-?-independent poyfunctional profiles that are not typically the focus of vaccine studies. | ||||
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| DOI: | 10.21430/M3OCS4VQWY | ||||
| Subjects: | 68 | ||||
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| Clinical Assessments: | None | ||||
| SDY1681: Endometrial Gland Organoids | |||||||
| Status: | New | ||||||
| Description: | The study established endometrial gland organoids from decidua isolated from term placental membranes. These organoids express typical markers of glandular epithelia such as E-cadherin, Laminin and Cytokeratin 7, and can be propagated in cell culture through multiple passages. Potential survival factors for the co-culture of organoids and endometrial stromal fibroblasts were identified. These modifications facilitate the generation of patient-specific endometrial gland organoids with known pregnancy outcomes | ||||||
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| DOI: | 10.21430/M3H8HWJ1IC | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1683: PLA2G6 in attenuating ferroptosis | |||||||
| Status: | New | ||||||
| Description: | The study found that spontaneous preterm birth (SPTB) is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, the role for the phospholipase PLA2G6, known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, was uncovered in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, ferroptosis signaling and the role for PLA2G6 in attenuating trophoblastic ferroptosis in the human and mouse placenta was identified, which provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies | ||||||
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| DOI: | 10.21430/M3KAQ17AWD | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1684: Clinical Immunology of Infant Macaques | |||||||
| Status: | New | ||||||
| Description: | We collected and analyzed blood samples from 151 healthy rhesus | ||||||
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| DOI: | 10.21430/M3W5PX1Q02 | ||||||
| Subjects: | 143 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1686: Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes | |||||||
| Status: | New | ||||||
| Description: | Based on 10,734 mother?infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, the study constructed haplotype genetic scores using SNPs known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). And tested associations between these haplotype genetic scores and birth outcomes (gestational duration, birth weight). In addition, constructed the infant-specific birth weight genetic scores to examine the effects of fetal growth on gestational duration and maternal phenotypes during pregnancy. The conclusions of the study are that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes | ||||||
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| DOI: | 10.21430/M3PC6GT19O | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1688: Computational discovery of therapeutic candidates for preventing preterm birth | ||||||||
| Status: | New | |||||||
| Description: | Few therapeutic methods exist for preventing preterm birth (PTB). In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness (only 1/3 of cases). To identify repositioning drug candidates, the study used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, were identified. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B ? indicating no known risk in human pregnancy. The drug lansoprazole (a proton-pump inhibitor) with a strong reversal score and a good safety profile was selected for validation in LPS-induced inflammation mouse model. The result showed a significant increase in fetal viability by lansoprazole compared with controls | |||||||
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| DOI: | 10.21430/M3NWW7IS3O | |||||||
| Subjects: | 0 | |||||||
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| Assays: | None | |||||||
| Clinical Assessments: | None | |||||||
| SDY1692: High-throughput quantitation of serological ceramides/dihydroceramides by LC/MS/MS | |||||||
| Status: | New | ||||||
| Description: | The study developed the LC/MS/MS assay to quantify 16 ceramides and 10 dihydroceramides in human serum within 5 minutes. Validated the assay results against a set of quality criteria in FDA guidelines: Lower Limit of Quantitation (1 nM), linearity (R2>0.99), precision (imprecision<15 %), accuracy (inaccuracy<15 %), extraction recovery (>90 %), stability (>85 %), and carryover (<0.01 %). With enhanced sensitivity and specificity, the study established gestation baselines of ceramides and dihydroceramides in pregnancy | ||||||
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| DOI: | 10.21430/M3WBUTVTO4 | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1693: The association between vaginal bacterial composition and miscarriage | |||||||
| Status: | New | ||||||
| Description: | To characterise vaginal bacterial composition in early pregnancy and investigate its relationship with first and second trimester miscarriages, the study conducted prospective profiling on 161 pregnancies by using 16S rRNA gene?based metataxonomics from 5 weeks? gestation in pregnancies ending in miscarriage (78) or uncomplicated term deliveries (83) matched for age, gestation and body mass index. Relative vaginal bacteria abundance, diversity and richness were measured and compared among cohorts. RESULTs: Vaginal bacterial composition in first trimester miscarriage is associated with reduced Lactobacillus spp. abundance and is independent of vaginal bleeding. Incomplete/complete miscarriage associated with higher proportions of Lactobacillus spp.?depleted communities compared with missed miscarriage. Early pregnancy vaginal bacterial stability was similar between miscarriage and term pregnancies. | ||||||
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| DOI: | 10.21430/M3JL1IWXGZ | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1697: Influenza / S. aureus Superinfection | |||||||
| Status: | New | ||||||
| Description: | Infection of mice with Influenza virus, S. aureus, or both | ||||||
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| DOI: | 10.21430/M3AVN5HGTN | ||||||
| Subjects: | 14 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1699: Vaginal dysbiosis increases risk of PPROM, neonatal sepsis and is exacerbated by erythromycin | |||||||
| Status: | New | ||||||
| Description: | To understand the dynamics of vaginal microbiota compositions associated with PPROM and the impact by antibiotics, the study prospectively assessed vaginal microbiota prior to and following PPROM using MiSeq-based sequencing of 16S rRNA gene amplicons and examined the impact of erythromycin prophylaxis on bacterial load and community structures. RESULTS: vaginal dysbiosis characterised by Lactobacillus spp. depletion was present prior to the rupture of fetal membranes in approximately a third of cases and persisted following membrane rupture. Vaginal dysbiosis was exacerbated by erythromycin treatment particularly in women initially colonised by Lactobacillus spp. Lactobacillus depletion and increased relative abundance of Sneathia spp. were associated with subsequent funisitis and early onset neonatal sepsis. This highlights vaginal microbiota as a potentially modifiable antenatal risk factor for PPROM and suggests that routine use of erythromycin for PPROM be re-examined. | ||||||
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| DOI: | 10.21430/M31ZXG1MZW | ||||||
| Subjects: | 119 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1701: Unique transcriptomic landscapes identified in isPTB and infectiion-PTB/AHC | |||||||
| Status: | New | ||||||
| Description: | The study compared placental villous transcriptomes from carefully phenotyped cohorts of PTB due to infection or isPTB (idiopathic spontaneous preterm birth) between 28?36 weeks gestation and healthy term placentas. Transcriptomic analyses revealed a unique expression signature for isPTB, which included three upregulated IGF binding proteins (IGFBP1, IGFBP2, and IGFBP6), supporting a role for aberrant IGF signaling in isPTB, and secondary signatures of inflammatory markers including TNC, C3, CFH, and C1R, which have been associated with placental maturity. In contrast, the expression signature of the PTB-infection cohort included upregulation of proliferative genes along with cell cycling and mitosis pathways. Together, these data suggest an isPTB molecular signature of placental hypermaturity, likely contributing to the premature activation of inflammatory pathways associated with birth and providing a molecular basis for idiopathic spontaneous birth | ||||||
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| DOI: | 10.21430/M3CWCOQDNW | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1466: Monozygotic and Dizygotic Twin Pair T-Cell Responses to Influenza Vaccination SLVP018 2013 | |||||||
| Status: | Updated | ||||||
| Description: | Evaluate the variation in immune response between individuals and assess whether it changes as a function of age and similarity in genetic and environmental background (by comparing differences between monozygotic and dizygotic twin pairs of different ages). | ||||||
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| DOI: | 10.21430/M33B64BQUE | ||||||
| Subjects: | 21 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1471: B-cell Immunity to Influenza (SLVP017) 2013 | |||||||
| Status: | Updated | ||||||
| Description: | Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people. | ||||||
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| DOI: | 10.21430/M3WEPI1HA3 | ||||||
| Subjects: | 9 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1514: An Observational Study of Childhood Food Allergy (CoFAR2) | |||||||
| Status: | Updated | ||||||
| Description: | This observational study will investigate the developmental immunology of peanut, egg, and milk allergy in a cohort of milk- or egg-allergic children who are at risk for peanut allergy. This strategy will help to delineate, compare, and contrast biological markers and immunologic changes associated with the development of peanut allergy and loss of egg and milk allergy, while simultaneously evaluating important clinical and environmental influences likely to account for the recent rise in the prevalence of these allergies. The hallmark of food-allergic disease is the production of food-specific Immunoglobulin E (IgE) antibodies that represent an end result of a T helper 2 (Th2) influenced immune response. Currently, there is only a limited understanding of the mechanisms involved in the developmental course of food allergies. To effectively prevent or reverse the progression of food allergy, immune interventions will be needed. Furthermore, it is likely that successful strategies will need to be directed to those persons at identifiable risk (e.g., who have biomarkers associated with development of peanut allergy). | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3CCG5XNFF | ||||||
| Subjects: | 515 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1626: Transcriptome and Regulatory Maps of Decidua-derived Stromal Cells Inform Gene Discovery in Preterm Birth | |||||||||
| Status: | Updated | ||||||||
| Description: | While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. | ||||||||
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| DOI: | 10.21430/M3FQ76H3IG | ||||||||
| Subjects: | 4 | ||||||||
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| Clinical Assessments: | None | ||||||||