Constraining fundamental constants of physics with quasar absorption line systems

We summarize the attempts by our group and others to derive constraints on variations of fundamental constants over cosmic time using quasar absorption lines. Most upper limits reside in the range 0.5-1.5x10-5 at the 3sigma level over a redshift range of approximately 0.5-2.5 for the fine-structure constant, alpha, the proton-to-electron mass ratio, mu, and a combination of the proton gyromagnetic factor and the two previous constants, gp(alpha^2/mu)^nu, for only one claimed variation of alpha. It is therefore very important to perform new measurements to improve the sensitivity of the numerous methods to at least <0.1x10-5 which should be possible in the next few years. Future instrumentations on ELTs in the optical and/or ALMA, EVLA and SKA pathfinders in the radio will undoutedly boost this field by allowing to reach much better signal-to-noise ratios at higher spectral resolution and to perform measurements on molecules in the ISM of high redshift galaxies.Comment: 11 pages, 3 figure

Lowest-Landau-level theory of the quantum Hall effect: the Fermi-liquid-like state

A theory for a Fermi-liquid-like state in a system of charged bosons at filling factor one is developed, working in the lowest Landau level. The approach is based on a representation of the problem as fermions with a system of constraints, introduced by Pasquier and Haldane (unpublished). This makes the system a gauge theory with gauge algebra W_infty. The low-energy theory is analyzed based on Hartree-Fock and a corresponding conserving approximation. This is shown to be equivalent to introducing a gauge field, which at long wavelengths gives an infinite-coupling U(1) gauge theory, without a Chern-Simons term. The system is compressible, and the Fermi-liquid properties are similar, but not identical, to those in the previous U(1) Chern-Simons fermion theory. The fermions in the theory are effectively neutral but carry a dipole moment. The density-density response, longitudinal conductivity, and the current density are considered explicitly.Comment: 32 pages, revtex multicol

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

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues