•Large Atlantic bluefin tuna tagged off the coast of Ireland utilize the warm North Atlantic Current to access foraging areas in the North Atlantic Ocean.•Five hotspots of Atlantic bluefin tuna occur ...in the central and eastern North Atlantic Ocean. Each are in regions with long-lived, quasi-stationary anticyclonic features (i.e., eddies or recirculation).•Daily maximum depth and time at mesopelagic depths (i.e., greater than 200 m) are positively correlated with absolute dynamic topography in the open ocean.•In the Winter, a majority of Atlantic bluefin tuna tagged in Irish waters travel to the Newfoundland Basin, a region with intense mesoscale eddy activity and high mesopelagic fish biomass.•Some Atlantic bluefin tuna migrated in the Spring to the Mediterranean Sea, an important spawning ground for this species.
Electronic tagging of Atlantic bluefin tuna (ABT; Thunnus thynnus) has shaped our understanding of their movements and migrations throughout the Atlantic basin. In this study, we used pop-up satellite archival tagging data to examine the movements of 51 large (CFL µ ± σ: 215 ± 15 cm) ABT tagged off the coast of Ireland. When combined with satellite oceanographic data, we found that ABT take advantage of the warm North Atlantic Current to access foraging areas in the North Atlantic Ocean. We identified four potential foraging regions: (1) off the coast of Ireland, (2) the Bay of Biscay, (3) the Newfoundland Basin, and (4) the West European Basin. In addition, 14 ABT migrated to their spawning grounds in the Mediterranean Sea, entering by May 16 and exiting by July 7, on average. In all five regions, anticyclonic ocean features (i.e., eddies or recirculation) were present. In the open ocean, these features often co-occurred with areas where the daily maximum depth of tuna exceeded 400 m and tuna spent extended time at mesopelagic depths (i.e., greater than 200 m). We hypothesize that ABT exploit anticyclonic structures to forage on the abundant mesopelagic fish communities. Additionally, our results suggest that ABT are travelling across the North Atlantic Ocean in a directed migration to the Newfoundland Basin to reach what may be one of the best mesopelagic feeding grounds in the world.
We investigated extreme changes in diet patterns on the gut microbiota of elite race walkers undertaking intensified training and its possible links with athlete performance. Numerous studies with ...sedentary subjects have shown that diet and/or exercise can exert strong selective pressures on the gut microbiota. Similar studies with elite athletes are relatively scant, despite the recognition that diet is an important contributor to sports performance. In this study, stool samples were collected from the cohort at the beginning (baseline; BL) and end (post-treatment; PT) of a three-week intensified training program during which athletes were assigned to a High Carbohydrate (HCHO), Periodised Carbohydrate (PCHO) or ketogenic Low Carbohydrate High Fat (LCHF) diet (post treatment). Microbial community profiles were determined by 16S rRNA gene amplicon sequencing. The microbiota profiles at BL could be separated into distinct "enterotypes," with either a
or
dominated enterotype. While enterotypes were relatively stable and remained evident post treatment, the LCHF diet resulted in a greater relative abundance of
and
and a reduction of
Significant negative correlations were observed between
and fat oxidation and between
and economy test following LCHF intervention.
Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree ...of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.
Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative ...stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects).
We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).
These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.
Abstract The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological ...characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 ...repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE ...locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these "actionable" variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5 × 10⁻⁰⁵; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
Abstract
Background
Using an objective mathematical algorithm to assess corticolimbic involvement of neurofibrillary tangle pathology, we identified three AD subtypes: hippocampal sparing (HpSp) AD, ...typical AD, and limbic predominant AD. Typical AD brains were representative of the expected patterns of hippocampal and cortical involvement as outlined by Braak tangle stage. In contrast, we discovered an extreme phenotype that exists outside of the Braakian‐concept of neurofibrillary tangle patterns. Hippocampal sparing AD cases demonstrate unexpected sparing of the hippocampus relative to severely involved association cortices and limbic predominant AD cases demonstrate inundation of the hippocampus relative to mildly involved association cortices. Using these AD subtypes, our objective was to leverage our understanding of disease spectrum to uncover transcriptomic changes that underlie selective vulnerability of the hippocampus in AD.
Method
We performed RNA‐sequencing in 40 neuropathologically diagnosed AD cases (10 HpSp, 20 Typical and 10 Limbic) and 15 controls to uncover gene expression changes associated with phenotype differences allowing us to prioritize 44 genes for further exploration. Validation with NanoString and quantification with digital pathology were performed in an expanded cohort of 158 AD cases (36 HpSp, 79 Typical and 35 Limbic) and 32 controls. We quantified digital pathology measures of early tangle pathology (CP13), mature tangle pathology (Ab39), amyloid‐β (33.1.1). In addition, we measured cellular markers for microglia (CD68), endothelia (CD34), and astroglia (GFAP). Deep learning based prediction models were employed, which nominated the
SLC38A2
gene as a predictor of AD.
Result
The
SLC38A2
gene was originally prioritized in our RNA‐sequencing data based upon differential expression between controls and typical AD. We observed upregulation of
SLC38A2
in all AD subtypes. RNA‐seq gene expression measures validated well with NanoString for
SLC38A2
(R=0.97, p<0.001). Regression analysis identified early tangle (p=0.011) and late tangle measures (p=0.026) as significant predictors of gene expression, but not amyloid measures (p=0.74). Microgliosis approached significance (p=0.052), but with no contribution from endothelial cell burden (p=0.17) or astrogliosis (p=0.58). Age approached significance (p=0.06), but not sex (p=0.88) or
APOE
‐ε4 status (p=0.10).
Conclusion
Our data supports consideration of intra‐disease divergence with regard to case stratification and may reveal genes previously masked by heterogeneity of cohorts.
Background
Using an objective mathematical algorithm to assess corticolimbic involvement of neurofibrillary tangle pathology, we identified three AD subtypes: hippocampal sparing (HpSp) AD, typical ...AD, and limbic predominant AD. Typical AD brains were representative of the expected patterns of hippocampal and cortical involvement as outlined by Braak tangle stage. In contrast, we discovered an extreme phenotype that exists outside of the Braakian‐concept of neurofibrillary tangle patterns. Hippocampal sparing AD cases demonstrate unexpected sparing of the hippocampus relative to severely involved association cortices and limbic predominant AD cases demonstrate inundation of the hippocampus relative to mildly involved association cortices. Using these AD subtypes, our objective was to leverage our understanding of disease spectrum to uncover transcriptomic changes that underlie selective vulnerability of the hippocampus in AD.
Method
We performed RNA‐sequencing in 40 neuropathologically diagnosed AD cases (10 HpSp, 20 Typical and 10 Limbic) and 15 controls to uncover gene expression changes associated with phenotype differences allowing us to prioritize 44 genes for further exploration. Validation with NanoString and quantification with digital pathology were performed in an expanded cohort of 158 AD cases (36 HpSp, 79 Typical and 35 Limbic) and 32 controls. We quantified digital pathology measures of early tangle pathology (CP13), mature tangle pathology (Ab39), amyloid‐β (33.1.1). In addition, we measured cellular markers for microglia (CD68), endothelia (CD34), and astroglia (GFAP). Deep learning based prediction models were employed, which nominated the SLC38A2 gene as a predictor of AD.
Result
The SLC38A2 gene was originally prioritized in our RNA‐sequencing data based upon differential expression between controls and typical AD. We observed upregulation of SLC38A2 in all AD subtypes. RNA‐seq gene expression measures validated well with NanoString for SLC38A2 (R=0.97, p<0.001). Regression analysis identified early tangle (p=0.011) and late tangle measures (p=0.026) as significant predictors of gene expression, but not amyloid measures (p=0.74). Microgliosis approached significance (p=0.052), but with no contribution from endothelial cell burden (p=0.17) or astrogliosis (p=0.58). Age approached significance (p=0.06), but not sex (p=0.88) or APOE‐ε4 status (p=0.10).
Conclusion
Our data supports consideration of intra‐disease divergence with regard to case stratification and may reveal genes previously masked by heterogeneity of cohorts.
α-Synuclein (α-syn) protein and a fragment of it, called NAC, have been found in association with the pathological lesions of a number of neurodegenerative diseases. Recently, mutations in the α-syn ...gene have been reported in families susceptible to an inherited form of Parkinson's disease. We have shown that human wild-type α-syn, mutant α-syn(Ala30Pro) and mutant α-syn(Ala53Thr) proteins can self-aggregate and form amyloid-like filaments. Here we report that aggregates of NAC and α-syn proteins induced apoptotic cell death in human neuroblastoma SH-SY5Y cells. These findings indicate that accumulation of α-syn and its degradation products may play a major role in the development of the pathogenesis of these neurodegenerative diseases.