👤 P W Teague

Understanding the time course of Alzheimer's disease biomarkers of amyloid and tau pathology and their temporal relation to clinical symptoms is key to identifying optimal windows for disease intervention and planning future drug trials. The goal of this work was to determine the extent to which Sampled Iterative Local Approximation (SILA), an algorithm extensively validated for amyloid PET, is capable of modeling longitudinal tau (T) PET trajectories and estimating person-level tau positivity onset ages in two commonly analyzed brain regions and two tracers from two different cohorts. 385 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; mean (SD) age = 73.4 (7.3) years) with longitudinal flortaucipir tau PET and 288 participants from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center (collectively referred to as WISC; mean (SD) age = 67.4 (6.7) years) with longitudinal MK-6240 tau PET were included in the study. Standard uptake value ratios (SUVRs) in the entorhinal cortex and a meta-temporal ROI were modeled with SILA separately, for each cohort and region. Forward and backward SUVR and T+/- prediction were characterized with ten-fold cross-validation and in-sample validation techniques. Accuracy of estimated T+ onset ages (ETOA) was characterized in T- to T+ converters. Differences in ETOA were tested between SILA was able to accurately estimate retrospective change in tau SUVR in the meta-temporal region regardless of age, sex, Our results suggest SILA can be used to accurately model longitudinal tau PET trajectories and retrospectively estimate individual T+ onset ages in the meta-temporal region. The accuracy of SILA time estimates in entorhinal cortex worsened amongst those with dementia in ADNI suggesting entorhinal cortex may only be suitable for studying the temporal progression of tau during the preclinical time frame. Show less

The role of FGF is the least understood of the morphogens driving mammalian gastrulation. Here, we have investigated FGF function in a 2D gastruloid model for human gastrulation. We observed a ring of FGF-dependent ERK activity that closely follows the emergence of primitive streak (PS)-like cells but expands further inward. This ERK activity pattern depends on localized activation of basolateral FGF receptor 1 (FGFR1) by endogenous FGF gradients and is required for PS-like differentiation, with loss of PS-like cells upon FGF receptor inhibition rescued by direct ERK activation. Single cell transcriptome analysis confirmed that, among the ligands, FGF2 is broadly expressed, FGF8 is transiently expressed during PS-like differentiation and FGF4/17 are specifically expressed in PS-like cells - similar to the human and monkey embryo but different from the mouse. FGF4 knockdown greatly reduced PS-like differentiation, while FGF17 knockdown primarily affected subsequent mesoderm differentiation. FGF8 expression was spatially and temporally displaced from PS markers and FGF4 expression, while knockdown expanded PS-like cells, suggesting FGF8 may limit PS-like differentiation. Thus, we have identified a previously unreported role for FGF-dependent ERK signaling in 2D gastruloids and possibly the human embryo, where FGF4 and FGF17 signal through basolateral FGFR1 to induce PS-like cells and derivatives, potentially restricted by FGF8. Show less

The role of FGF is the least understood of the morphogens driving mammalian gastrulation. Here we investigated the function of FGF in a stem cell model for human gastrulation known as a 2D gastruloid. We found a ring of FGF-dependent ERK activity that closely follows the emergence of primitive streak (PS)-like cells but expands further inward. We showed that this ERK activity pattern is required for PS-like differentiation and that loss of PS-like cells upon FGF receptor inhibition can be rescued by directly activating ERK. We further demonstrated that the ERK-ring depends on localized activation of basolaterally positioned FGF receptors (FGFR) by endogenous FGF gradients. We confirmed and extended previous studies in analyzing expression of FGF pathway components, showing FGFR1 is the main receptor, FGF2 is highly expressed across several cell types, and FGF4/17 are the main FGF ligands expressed in the PS-like cells, similar to the human and monkey embryo but different from the mouse. We found that knockdown of FGF4 greatly reduced PS-like differentiation while FGF17 knockdown primarily affected subsequent mesoderm differentiation. FGF8 expression was spatially displaced from PS-markers and FGF4 expression and peaked earlier, while knockdown led to an expansion in PS-like cells, suggesting FGF8 may counteract FGF4 to limit PS-like differentiation. Thus, we have identified a previously unknown role for FGF-dependent ERK signaling in 2D gastruloids and possibly the human embryo, driven by a mechanism where FGF4 and FGF17 signal through basally localized FGFR1 to induce PS-like cells and their derivatives, potentially restricted by FGF8. Show less

The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3 We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa. Show less

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, polydactyly, obesity, hypogenitalism, mental retardation, and renal anomalies. To detect linkage to BBS loci, 29 BBS families, of mixed but predominantly European ethnic origin, were typed with 37 microsatellite markers on chromosomes 2, 3, 11, 15, 16, and 17. The results show that an estimated 36-56% of the families are linked to the 11q13 chromosomal site (BBS1) previously described by M. Leppert et al. (1994, Nature Genet. 7, 108-112), with the gene order cen-D11S480-5 cM-BBS1-3 cM-D11S913/D11S987-qter. A further 32-35% of the families are linked to the BBS4 locus, reported by R. Carmi et al. (1995, Hum. Mol. Genet. 4, 9-13) in chromosomal region 15q22.3-q23, with the gene order cen-D15S125-5 cM-BBS4-2 cM-D15S131/D15S204-qter. Three consanguineous BBS families are homozygous for three adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis supports a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to the 16q21 (BBS2) region reported by A. E. Kwitek-Black et al. (1993, Nature Genet. 5, 392-396) was observed in 24-27% of families with the gene order cen-D16S408-2 cM-BBS2-5 cM-D16S400. A fourth group of families, estimated at 8%, are unlinked to all three of the above loci, showing that at least one other BBS locus remains to be found. No evidence of linkage was found to markers on chromosome 3, corresponding to the BBS3 locus, reported by V. C. Sheffield et al. (1994, Hum. Mol. Genet. 3, 1331-1335), or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with a t(2;17) translocation. Show less