Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation

Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development

Symmetry Breaking in Crossed Magnetic and Electric Fields

We present the first observations of cylindrical symmetry breaking in highly excited diamagnetic hydrogen with a small crossed electric field, and we give a semiclassical interpretation of this effect. As the small perpendicular electric field is added, the recurrence strengths of closed orbits decrease smoothly to a minimum, and revive again. This phenomenon, caused by interference among the electron waves that return to the nucleus, can be computed from the azimuthal dependence of the classical closed orbits

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

INTRODUCTION Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets

Multivariate GWAS of Alzheimer\u27s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer\u27s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. RESULTS: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. CONCLUSIONS: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine

Vegetation history and climatic fluctuations on a transect along the Dead Sea west shore and impact on past societies over the last 3500 years.

This study represents the vegetation history of the last 3500 years and conducts an analysis of the climatic fluctuations on a 75 km long transect on the western Dead Sea shore. Palynological and sedimentological data are available from six cores near Mount Sedom, Ein Boqueq, and Ein Gedi and from outcrops near Ze'elim and Ein Feshkha. The comparison of the pollen data with the lake levels shows synchronous trends. During the Middle Bronze Age, Iron Age and Hellenistic to Byzantine Period the high lake level of the Dead Sea signals an increase in precipitation. Contemporaneously, values of cultivated plants indicate an increase in agriculture. Lake level is low during the Late Bronze Age, within the Iron Age and at the end of the Byzantine period, indicating dry periods when all pds show a decrease of cultivated plants. Forest regeneration led by drought-resistant pines is observed in all pollen diagrams (pds) following the agricultural decline in the Byzantine period and, in the pds near Ein Boqeq, Ze'elim and Ein Feshkha, during the late Iron Age. The modern vegetation gradient is reflected in the palaeo-records: a stronger expansion of Mediterranean vegetation and cultivated plants in the northern sites is recognisable

Investigating the impact of nicotine on executive functions using a novel virtual reality assessment

Aims Nicotine is known to enhance aspects of cognitive functioning in abstinent smokers but the effects on specific areas of executive functions, and in non-smokers are inconclusive. This may be due in part to the poor sensitivity of tests used to assess executive functions. This study used a new virtual reality assessment of executive functions known as JEF (the Jansari assessment of Executive Functions) to address this issue. Design 2x2 design manipulating group (smokers and never-smokers) and drug (nicotine [4mg for smokers; 2mg for never smokers] vs placebo gum). Setting School of Psychology; University of East LondonParticipants 72 participants (aged 18 to 54). 36 minimally-deprived (2 hr) smokers and 36 never-smokers.Measurements Components of executive function were measured using the virtual reality paradigm JEF, which assesses eight cognitive constructs simultaneously as well as providing an overall performance measure. Results Univariate ANOVAs revealed that nicotine improved overall JEF performance, time-based prospective memory and event-based prospective memory in smokers (p < 0.01) but not in never-smokers. Action-based prospective memory was enhanced in both groups (p < 0.01) and never-smokers out-performed smokers on selective thinking and adaptive thinking (p < 0.01). Conclusions. Overall executive functioning and prospective memory can be enhanced by nicotine gum in abstinent smokers. That smokers were only minimally deprived suggests that JEFis a sensitive measure of executive functioning and that prospective memory is particularly susceptible to disruption by abstinence

Deficits in trabecular bone microarchitecture in young women with Type 1 diabetes mellitus

Context: The pathophysiological mechanism of increased fractures in young adults with Type 1 Diabetes Mellitus (T1DM) is unclear. Objective: Case:control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Patients and Settings: 30 women with T1DM with a median (range) age of 22.0yrs (16.9, 36.1) attending one outpatient clinic with a median age at diagnosis of 9.7yrs (0.46, 14.8) were compared to 28 age-matched healthy women who acted as controls. Methods and Main Outcome Measures: Measurements included MRI-based assessment of proximal tibial bone volume/total volume (appBV/TV), trabecular separation (appTb.Sp), vertebral bone marrow adiposity (BMA) and abdominal adipose tissue and biochemical markers of GH/IGF-1 axis (IGF-1, IGFBP3, ALS) and bone turnover. Results: Median appBV/TV in cases and controls was 0.3 (0.22, 0.37) and 0.33 (0.26, 0.4), respectively (p = 0.018) and median appTb.Sp in T1DM was 2.59 (2.24, 3.38) and 2.32 (2.03, 2.97), respectively (p = 0.012). The median appBV/TV was 0.28 (0.22, 0.33) in those cases with retinopathy (n,15) compared to 0.33 (0.25, 0.37) in those without retinopathy (p = 0.02). Although median visceral adipose tissue in cases was higher than in controls at 5,733mm3 (2030, 11,144) and 3,460mm3 (1,808, 6,832), respectively (p = 0.012), there was no difference in median BMA which was 31.1% (9.9, 59.9) and 26.3% (8.5, 49.8) in cases and controls, respectively (p = 0.2). Serum IGF-1 and ALS were also lower in cases and the latter showed an inverse association to appTbSp (r = -0.30, p = 0.04). Conclusion: Detailed MRI studies in young women with childhood-onset T1DM have shown clear deficits in trabecular microarchitecture of the tibia. Underlying pathophysiological mechanisms may include a microvasculopathy

Biomechanical experimental data curation: an example for main lumbar spine ligaments characterization for a MBS spine model

Series : Mechanisms and machine science, ISSN 2211-0984, vol. 24This work overviews an extensive analysis in the context of mechanical characterization of human biomaterials, carried out over a broad set of published experimental data. Focused on main lumbar spine ligaments, several test procedures are exhaustively analyzed, in order to identify possible causes for divergences that have been found in some results. Moreover, guidelines are proposed for da-ta filtering and selection. The main objective of the task was to retrieve trustworthy inputs to a hybrid Finite Element Analysis / Multibody System dynamic simulation model of the human intervertebral disc, which can be used on the prediction of nucleus prosthetics working performance

Succinate dehydrogenase (SDH)-deficient renal carcinoma:a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis