Multiple Gene Variants Linked to Alzheimer\u27s-Type Clinical Dementia via GWAS are Also Associated with Non-Alzheimer\u27s Neuropathologic Entities

The classic pathologic hallmarks of Alzheimer’s disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer’s disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as ADrelated were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P \u3c 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies

A Study of the Residual 39Ar Content in Argon from Underground Sources

The discovery of argon from underground sources with significantly less 39Ar than atmospheric argon was an important step in the development of direct-detection dark matter experiments using argon as the active target. We report on the design and operation of a low background detector with a single phase liquid argon target that was built to study the 39Ar content of the underground argon. Underground argon from the Kinder Morgan CO2 plant in Cortez, Colorado was determined to have less than 0.65% of the 39Ar activity in atmospheric argon.Comment: 21 pages, 10 figure

Impact of Motivational Interviewing by Social Workers on Service Users - a systematic review

Purpose: This systematic review was undertaken to determine the effectiveness of motivational interviewing (MI), by social workers, on service user outcomes. Methods: A literature search was undertaken between 2007 and 2018. All eligible studies were analyzed using the Critical Appraisal Skills Programme tool. As heterogeneity was high, a narrative synthesis approach was employed, using thematic analysis for categorizing data. Results: Eleven studies met the inclusion criteria and were included in this review. MI had a positive effect on service user experience, but this was not consistent. Training was variable, but the evidence suggests that practitioner’s need ongoing training, supervision, or coaching while providing MI. Discussion: There is a paucity of research examining the impact of MI on children, which was a limitation of this review. There is a need for more qualitative research to surface views and experience of service users to determine why MI is effective

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.

BACKGROUND: There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. METHODS AND FINDINGS: We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. CONCLUSIONS: In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD

Discovery of underground argon with low level of radioactive 39Ar and possible applications to WIMP dark matter detectors

We report on the first measurement of 39Ar in argon from underground natural gas reservoirs. The gas stored in the US National Helium Reserve was found to contain a low level of 39Ar. The ratio of 39Ar to stable argon was found to be <=4x10-17 (84% C.L.), less than 5% the value in atmospheric argon (39Ar/Ar=8x10-16). The total quantity of argon currently stored in the National Helium Reserve is estimated at 1000 tons. 39Ar represents one of the most important backgrounds in argon detectors for WIMP dark matter searches. The findings reported demonstrate the possibility of constructing large multi-ton argon detectors with low radioactivity suitable for WIMP dark matter searches.Comment: 6 pages, 2 figures, 2 table

Analysis of Genes (\u3ci\u3eTMEM106B\u3c/i\u3e, \u3ci\u3eGRN\u3c/i\u3e, \u3ci\u3eABCC9\u3c/i\u3e, \u3ci\u3eKCNMB2\u3c/i\u3e, and \u3ci\u3eAPOE\u3c/i\u3e) Implicated in Risk for LATE-NC and Hippocampal Sclerosis Provides Pathogenetic Insights: A Retrospective Genetic Association Study

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer’s Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer’s pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer’s-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS

GRB 050505: A high redshift burst discovered by Swift

We report the discovery and subsequent multi-wavelength afterglow behaviour of the high redshift (z = 4.27) Gamma Ray Burst GRB 050505. This burst is the third most distant burst, measured by spectroscopic redshift, discovered after GRB 000131 (z = 4.50) and GRB 050904 (z = 6.29). GRB 050505 is a long GRB with a multipeaked gamma-ray light curve, with a duration of T_90 = 63+/-2 s and an inferred isotropic release in gamma-rays of ~4.44 x 10^53 ergs in the 1-10^4 keV rest frame energy range. The Swift X-Ray Telescope followed the afterglow for 14 days, detecting two breaks in the light curve at 7.4(+/-1.5) ks and 58.0 (+9.9/-15.4) ks after the burst trigger. The power law decay slopes before, between and after these breaks were 0.25 (+0.16/-0.17), 1.17 (+0.08/-0.09) and 1.97 (+0.27/-0.28) respectively. The light curve can also be fit with a `smoothly broken' power law model with a break observed at ~ T+18.5 ks, with decay slopes of ~0.4 and ~1.8 before and after the break respectively. The X-ray afterglow shows no spectral variation over the course of the Swift observations, being well fit with a single power law of photon index ~1.90. This behaviour is expected for the cessation of continued energisation of the ISM shock followed by a break caused by a jet, either uniform or structured. Neither break is consistent with a cooling break. The spectral energy distribution indeed shows the cooling frequency to be below the X-ray but above optical frequencies. The optical -- X-ray spectrum also shows that there is significant X-ray absorption in excess of that due to our Galaxy but very little optical/UV extinction, with E(B-V) ~0.10 for a SMC-like extinction curve.Comment: 9 pages, 6 figures. Accepted by MNRA

Veterinary Considerations for the Theoretical Resurrection of Extinct Species

The de-extinction of the dinosaur is a dubious possibility but its consideration brings forth some issues that are at least worthy of scientific discussion. In this review, we discuss two distinct issues that have implications for a de-extinct species such as a dinosaur: the ability, or lack thereof, to safely sedate a rare and potentially fractious animal capable of harming the veterinary staff tasked with its care; and, disease risks associated with a species that has been extinct for millions of years. To identify potential sedatives, comparative pharmacology will be needed to uncover the links between receptor pharmacology and the desired clinical outcomes of activating established alpha-2 adrenergic, opioid, and benzodiazepine receptors. Specific to disease control, it will be necessary to understand the unique susceptibility of the new species to current diseases as well as predicting their reservoir capacity for potential human and veterinary pandemic diseases. While the topics presented herein are not exhaustive, this review highlights some of the foremost research that should be conducted in order to serve the unique veterinary needs of a de-extinct species using the dinosaur as a paradigm. Addressing these issues should be considered if an intact dinosaur genome becomes available, regardless of the feasibility of dinosaur resurrection