Very high anisotropies of the magnetic susceptibility in ductile shear zones: first quantitative results from a metamorphic nappe in the Central Scandinavian Caledonides, Sweden

Shear zones in the Seve crystalline basement nappes of the central Scandinavian Caledonides contributed to exhumation and translation of these highgrade metamorphic rocks. The Seve unit is considered to represent the former distal passive margin of the continent Baltica, which was subducted beneath an island arc during Ordovician times and subsequently collided with the continent Laurentia during Silurian and early Devonian times. Strongly textured mylonitic garnet mica schists with well developed mica fish and S–C-fabrics from a shear zone within the Seve unit show unusual high anisotropies of the magnetic susceptibility (AMS). The corrected degrees of anisotropy of the magnetic susceptibility (P0) range from 1.78 to 4.24. Bulk susceptibilities range from 2.8 × 10−3 to 96.9 × 10−3. The shape factors range from 0.32 to 0.62, documenting an oblate shape. Magnetic foliation is subparallel with metamorphic foliation. Magnetic lineation scatters due to permutations of the maximum and intermediate principal susceptibility axes...conferenc

Criteria and geological setting for the generic geothermal underground research laboratory, GEOLAB

High flow rate injection and related hydromechanical interaction are the most important factors in reservoir development of Enhanced Geothermal Systems (EGS). GeoLaB, a new generic geothermal underground research laboratory (URL), is proposed for controlled high flow rate experiments (CHFE) to address limited comprehension of coupled processes connected to EGS reservoir flow conditions. As analogue for typical EGS development, CHFE require specific hydromechanical conditions including a connected fracture network in crystalline basement rock, sufficient hydraulic fracture transmissivities, a strike-slip to normal faulting tectonic regime, controllable hydraulic boundary conditions, and hydrothermal alteration fracture fillings that improve conditions for hydromechanical interaction. With the aim to identify most appropriate areas for future site selection, four criteria have been established based on the EGS reference site of Soultz. Two URLs in crystalline basement worldwide approximate the requirements of a new generic GeoLaB and may be used for accompanying experimentation. Besides favourable geological, hydraulic, and stress conditions, the vicinity to long-term EGS production favours the southern Black Forest as potential region for GeoLaB. Therefore, an exemplary site assessment has been carried out at “Wilhelminenstollen” in the southern Black Forest (Germany). New remote sensing, hydrochemical, and geophysical analyses as well as reactivation potential, and stress modelling were added to complement existing geological and hydrogeological information. At this site, reactivation potential analysis reveals two local maxima prone for shear reactivation as strike-slip faults. The highest lineament density is observed for the N110°E strike direction that is associated with both slip and dilation tendency maxima. Clay minerals occur in fractures and the matrix. Local, partly water-bearing fractures, when partly filled with ore minerals, were connected to veins in the tunnel using shallow geophysical methods. Hydrochemical data reveal infiltration of the tunnel water from at least 500 m above the tunnel. The results suggest a crystalline basement with a fracture network that is regionally connected and water-conducting. Hydraulic conductivity in the southern Black Forest granite is estimated to amount to about 4.5·10−8 m s−1 at 500 m depth. The hydraulic boundary conditions exclude unknown drainage. Analyses of the influence of topography on orientation and magnitude of the maximum stress indicate a minimum overburden of about 500 m for regional reactivation to be valid. In conclusion, the southern Black Forest and in particular “Wilhelminenstollen” offers favourable condition for CHFE. Final decision on the GeoLaB site is to be drawn from forthcoming exploration wells

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Background Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results CSF NfL levels were significantly higher in patients with SD (median: 2326\u2009pg/mL, IQR: 1628\u20133593) than in controls (577 (446\u2013766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs = 120.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs = 120.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers

Altres ajuts: European Alzheimer DNA BioBank, EADB; EU Joint Programme, Neurodegenerative Disease Research (JPND); Neurodegeneration research program of Amsterdam Neuroscience; Stichting Alzheimer Nederland; Stichting VUmc fonds; Stichting Dioraphte; JPco-fuND FP-829-029 (ZonMW projectnumber 733051061); Dutch Federation of University Medical Centers; Dutch Government (from 2007-2011); JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A); German Research Foundation (DFG RA 1971/6-1, RA1971/7-1, RA 1971/8-1); Grifols SA; Fundación bancaria 'La Caixa'; Fundació ACE; CIBERNED; Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'); NIH (P30AG066444, P01AG003991); Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund; Siemens Healthineers; Valdecilla Biobank (PT17/0015/0019); Academy of Finland (338182); German Center for Neurodegenerative Diseases (DZNE); German Federal Ministry of Education and Research (BMBF 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711); ZonMW (#73305095007); Health~Holland, Topsector Life Sciences & Health (PPP-allowance #LSHM20106); Hersenstichting; Edwin Bouw Fonds; Gieskes-Strijbisfonds; NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012); Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361); Dementia Foundation (2020-04-13, 2021-04-17); Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALF 716681); Swedish Research Council (11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096); Swedish Research Council for Health, Working Life and Welfare (2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 2005-0762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 2013-2496); Swedish Brain Power, Hjärnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163); Alzheimer's Association Zenith Award (ZEN-01-3151); Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimer's Association (IIRG-03-6168, IIRG-09-131338); Bank of Sweden Tercentenary Foundation; Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALFGBG-771071); Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825); Swedish Research Council (2019-02075); Swedish Research Council (2016-01590); BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012); Swedish Research Council (2018-02532); Swedish State Support for Clinical Research (ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (201809-2016862); UK Dementia Research Institute at UCL; Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); National Institute of Health (NIH), USA, (#1R01AG068398-01); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614); Chuck Zuckerberg Initiative (CZI).Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Magnetic structures and quadratic magnetoelectric effect in LiNiPO4 beyond 30 T

Neutron diffraction with static and pulsed magnetic fields is used to directly probe the magnetic structures in LiNiPO4 up to 25 T and 42 T, respectively. By combining these results with magnetometry and electric polarization measurements under pulsed fields, the magnetic and magnetoelectric phases are investigated up to 56 T applied along the easy c axis. In addition to the already known transitions at lower fields, three new ones are reported at 37.6, 39.4, and 54 T. Ordering vectors are identified with Q(VI) = (0, 1/3, 0) in the interval 37.6 - 39.4 T and Q(VII) = (0, 0, 0) in the interval 39.4 - 54 T. A quadratic magnetoelectric effect is discovered in the Q(VII) = (0, 0, 0) phase and the field dependence of the induced electric polarization is described using a simple mean-field model. The observed magnetic structure and magnetoelectric tensor elements point to a change in the lattice symmetry in this phase. We speculate on the possible physical mechanism responsible for the magnetoelectric effect in LiNiPO4