125 research outputs found
Velocity and attenuation analysis of Gulf Coast sediments using vertical seismic profiling
Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Earth and Planetary Sciences, 1981.Microfiche copy available in Archives and Science.Bibliography: leaves 40-43.by James Raymond Wingo.M.S
Fluid Phase Separation (FPS) experiment for flight on a space shuttle Get Away Special (GAS) canister
The separation of fluid phases in microgravity environments is of importance to environmental control and life support systems (ECLSS) and materials processing in space. A successful fluid phase separation experiment will demonstrate a proof of concept for the separation technique and add to the knowledge base of material behavior. The phase separation experiment will contain a premixed fluid which will be exposed to a microgravity environment. After the phase separation of the compound has occurred, small samples of each of the species will be taken for analysis on the Earth. By correlating the time of separation and the temperature history of the fluid, it will be possible to characterize the process. The experiment has been integrated into space available on a manifested Get Away Special (GAS) experiment, CONCAP 2, part of the Consortium for Materials Complex Autonomous Payload (CAP) Program, scheduled for STS-42. The design and the production of a fluid phase separation experiment for rapid implementation at low cost is presented
Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age
In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery (n = 104) and replication cohort (n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.Accelerating Medicine Partnership for AD [U01AG046161, U01 AG061357]; Emory Alzheimer's Disease Research Center [P50 AG025688]; NINDS Emory Neuroscience Core [P30 NS055077]; intramural program of the National Institute on Aging (NIA); Alzheimer's Association; Alzheimer's Research UK; Michael J. Fox Foundation for Parkinson's Research; Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant [11060]; National Institute of Neurological Disorders and Stroke [U24 NS072026]; National Institute on Aging [P30 AG19610]; Arizona Department of Health Services [211002]; Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]; [R01 AG056533]; [R01 AG053960]; [U01 MH115484]; [I01 BX003853]; [IK2 BX001820]; [R01 AG061800]; [R01 AG057911]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer's Disease
Polymorphic alleles in the apolipoprotein E (APOE) gene are the main genetic determinants of late-onset Alzheimer's disease (AD) risk. Individuals carrying the APOE E4 allele are at increased risk to develop AD compared to those carrying the more common E3 allele, whereas those carrying the E2 allele are at decreased risk for developing AD. How ApoE isoforms influence risk for AD remains unclear. To help fill this gap in knowledge, we performed a comparative unbiased mass spectrometry-based proteomic analysis of post-mortem brain cortical tissues from pathologically-defined AD or control cases of different APOE genotypes. Control cases (n = 10) were homozygous for the common E3 allele, whereas AD cases (n = 24) were equally distributed among E2/3, E3/3, and E4/4 genotypes. We used differential protein expression and co-expression analytical approaches to assess how changes in the brain proteome are related to APOE genotype. We observed similar levels of amyloid-β, but reduced levels of neurofibrillary tau, in E2/3 brains compared to E3/3 and E4/4 AD brains. Weighted co-expression network analysis revealed 33 modules of co-expressed proteins, 12 of which were significantly different by APOE genotype in AD. The modules that were significantly different by APOE genotype were associated with synaptic transmission and inflammation, among other biological processes. Deconvolution and analysis of brain cell type changes revealed that the E2 allele suppressed homeostatic and disease-associated cell type changes in astrocytes, microglia, oligodendroglia, and endothelia. The E2 allele-specific effect on brain cell type changes was validated in a separate cohort of 130 brains. Our systems-level proteomic analyses of AD brain reveal alterations in the brain proteome and brain cell types associated with allelic variants in APOE, and suggest further areas for investigation into the upstream mechanisms that drive ApoE-associated risk for AD
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid- (A ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A and tau
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer's disease
Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-& beta;(A & beta;) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A & beta;plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A & beta;plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A & beta;and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A & beta;and tau. Proteomic analysis of cerebrospinal fluid from individuals with autosomal dominant Alzheimer's disease reveals how this complex and chronic disease evolves over many decades
Gender identity and future thinking about parenthood: a qualitative analysis of focus group data with transgender and non-binary people in the UK
The idea that people who are transgender or non-binary are not interested in becoming parents has been refuted by several studies. However, both medical unknowns and cisnormativity surround the process of becoming a parent for transgender or non-binary people, with little known about the psychosocial impact on the family formation dilemmas of transgender and non-binary adults. Employing Life Course Theory as our theoretical framework, three focus group interviews were conducted with eleven transgender or non-binary adults. Qualitative data analysis of focus group interview transcripts was conducted through Thematic Analysis. Four overarching interlinked themes were identified concerning the dilemmas perceived by the nine participants who contemplated future parenthood: (i) Balancing a desire for parenthood and desires for other life goals; (ii) Feeling that who I am doesn’t fit into the cisgender system of accessing fostering, adoption or fertility services; (iii) Experiencing the conjoined challenges of gender and fertility embodiment as I see them; (iv) Searching for a non-binary or gender appropriate self and the need for flexible future planning centered on reproductive capacity. Overall, thoughts about gender transition were often interwoven with parenthood plans and in a dialectical fashion the desire and intention to have, or not have, children was implicated in satisfaction with gender transition. The significance of these themes is discussed in relation to how hopes for parenthood could be realized without jeopardizing gender identity and the need for a future focused, flexible, and open-minded approach on the part of fertility and adoption services
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development
Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer’s disease
Sporadic early onset Alzheimer’s disease (sEOAD) exhibits the symptoms of late onset Alzheimer’s disease (LOAD) but lacks the familial aspect of the early onset familial form. The genetics of Alzheimer’s disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRS) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases were genotyped on the NeuroX array and PRS were generated using PRSice. The target dataset consisted of 408 sEOAD cases and 436 controls. The base dataset was collated by the IGAP consortium, with association data from 17,008 LOAD cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRS were generated using all common SNPs between the base and target dataset, PRS were also generated using only SNPs within a 500kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap amongst the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy
Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array
We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration
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