Tackling the dimensions in imaging genetics with CLUB-PLS

A major challenge in imaging genetics and similar fields is to link high-dimensional data in one domain, e.g., genetic data, to high dimensional data in a second domain, e.g., brain imaging data. The standard approach in the area are mass univariate analyses across genetic factors and imaging phenotypes. That entails executing one genome-wide association study (GWAS) for each pre-defined imaging measure. Although this approach has been tremendously successful, one shortcoming is that phenotypes must be pre-defined. Consequently, effects that are not confined to pre-selected regions of interest or that reflect larger brain-wide patterns can easily be missed. In this work we introduce a Partial Least Squares (PLS)-based framework, which we term Cluster-Bootstrap PLS (CLUB-PLS), that can work with large input dimensions in both domains as well as with large sample sizes. One key factor of the framework is to use cluster bootstrap to provide robust statistics for single input features in both domains. We applied CLUB-PLS to investigating the genetic basis of surface area and cortical thickness in a sample of 33,000 subjects from the UK Biobank. We found 107 genome-wide significant locus-phenotype pairs that are linked to 386 different genes. We found that a vast majority of these loci could be technically validated at a high rate: using classic GWAS or Genome-Wide Inferred Statistics (GWIS) we found that 85 locus-phenotype pairs exceeded the genome-wide suggestive (P<1e-05) threshold.Comment: 12 pages, 4 Figures, 2 Table

Assessing spatial and temporal changes in diversity of copepod crustaceans. A key step for biodiversity conservation in groundwater-fed springs

Despite the close attention springs have received from a hydrologic perspective and as biodiversity hotspots, the multiple dimensions of spring meiofaunal assemblage diversity are still poorly investigated. Knowledge of beta diversity patterns and drivers can inform and improve management decisions on biodiversity conservation. Here, we analyzed beta diversity of copepod assemblages in karst springs in Central Italy by focusing on: 1) relative contributions of turnover and nestedness components to taxonomic and phylogenetic beta diversity; 2) temporal variation of species richness and beta diversity within and between the target springs in conjunction with models of the influence of physical-chemical parameters on within-spring diversity changes; 3) expected risk of habitat loss due to variation in groundwater recharge under climate change. To this end, we gathered data from 168 samples collected in four karst springs from 2004 to 2016. Overall, we found 48 copepod species, 22 of which are obligate groundwater dwellers while the remaining 26 usually occur in surface freshwaters. All springs showed significant changes in taxonomic and phylogenetic beta diversity over time. Total beta diversity was high for both the taxonomic and phylogenetic dimensions, and turnover was the main component. Inter-site variability in dissolved oxygen explained a noticeable part of temporal variation in beta diversity, likely reflecting the role of microhabitat heterogeneity in shaping site-specific assemblages. However, most of the temporal variation in species richness and beta diversity remained unexplained, suggesting a major role of other factors, such as seasonal discharge variations. Modelling of recharge rates for all the four springs over 2001–2020 suggested a potential &gt;40% recharge deficit under dry conditions. Moreover, Cellular Automata-based modelling of rainfall over the Gran Sasso-Sirente hydrogeologic unit (feeding three of the four springs) predicted an overall precipitation decrease in the 2081–2095 period. Such changes could produce severe effects on springs’ microhabitats and related communities. Our results indicate that partitioning beta diversity, monitoring its temporal changes and assessing its environmental drivers are critical to evidence-based conservation of springs. Particularly, the high species turnover we have observed suggests that conservation strategies should seek to preserve as many microhabitats as possible within and among karst springs

Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption.

The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination

Genetic study of multimodal imaging Alzheimer’s disease progression score implicates novel loci

International audienc

Sustained Oscillations of NF-κB Produce Distinct Genome Scanning and Gene Expression Profiles

NF-κB is a prototypic stress-responsive transcription factor that acts within a complex regulatory network. The signaling dynamics of endogenous NF-κB in single cells remain poorly understood. To examine real time dynamics in living cells, we monitored NF-κB activities at multiple timescales using GFP-p65 knock-in mouse embryonic fibroblasts. Oscillations in NF-κB were sustained in most cells, with several cycles of transient nuclear translocation after TNF-α stimulation. Mathematical modeling suggests that NF-κB oscillations are selected over other non-oscillatory dynamics by fine-tuning the relative strengths of feedback loops like IκBα. The ability of NF-κB to scan and interact with the genome in vivo remained remarkably constant from early to late cycles, as observed by fluorescence recovery after photobleaching (FRAP). Perturbation of long-term NF-κB oscillations interfered with its short-term interaction with chromatin and balanced transcriptional output, as predicted by the mathematical model. We propose that negative feedback loops do not simply terminate signaling, but rather promote oscillations of NF-κB in the nucleus, and these oscillations are functionally advantageous

Template Shape Estimation: Correcting an Asymptotic Bias

International audienceWe use tools from geometric statistics to analyze the usual estimation procedure of a template shape. This applies to shapes from landmarks, curves, surfaces, images etc. We demonstrate the asymptotic bias of the template shape estimation using the stratified geometry of the shape space. We give a Taylor expansion of the bias with respect to a parameter σ describing the measurement error on the data. We propose two bootstrap procedures that quantify the bias and correct it, if needed. They are applicable for any type of shape data. We give a rule of thumb to provide intuition on whether the bias has to be corrected. This exhibits the parameters that control the bias' magnitude. We illustrate our results on simulated and real shape data

Design, construction, and test of the Gas Pixel Detectors for the IXPE mission

Due to be launched in late 2021, the Imaging X-Ray Polarimetry Explorer (IXPE) is a NASA Small Explorer mission designed to perform polarization measurements in the 2-8 keV band, complemented with imaging, spectroscopy and timing capabilities. At the heart of the focal plane is a set of three polarization-sensitive Gas Pixel Detectors (GPD), each based on a custom ASIC acting as a charge-collecting anode. In this paper we shall review the design, manufacturing, and test of the IXPE focal-plane detectors, with particular emphasis on the connection between the science drivers, the performance metrics and the operational aspects. We shall present a thorough characterization of the GPDs in terms of effective noise, trigger efficiency, dead time, uniformity of response, and spectral and polarimetric performance. In addition, we shall discuss in detail a number of instrumental effects that are relevant for high-level science analysis -- particularly as far as the response to unpolarized radiation and the stability in time are concerned.Comment: To be published in Astroparticle Physic

Precise Masses in the WASP-47 System

We present precise radial velocity observations of WASP-47, a star known to host a hot Jupiter, a distant Jovian companion, and, uniquely, two additional transiting planets in short-period orbits: a super-Earth in a ~19 hour orbit, and a Neptune in a ~9 day orbit. We analyze our observations from the HARPS-N spectrograph along with previously published data to measure the most precise planet masses yet for this system. When combined with new stellar parameters and reanalyzed transit photometry, our mass measurements place strong constraints on the compositions of the two small planets. We find unlike most other ultra-short-period planets, the inner planet, WASP-47 e, has a mass (6.83 +/- 0.66 Me) and radius (1.810 +/- 0.027 Re) inconsistent with an Earth-like composition. Instead, WASP-47 e likely has a volatile-rich envelope surrounding an Earth-like core and mantle. We also perform a dynamical analysis to constrain the orbital inclination of WASP-47 c, the outer Jovian planet. This planet likely orbits close to the plane of the inner three planets, suggesting a quiet dynamical history for the system. Our dynamical constraints also imply that WASP-47 c is much more likely to transit than a geometric calculation would suggest. We calculate a transit probability for WASP-47 c of about 10%, more than an order of magnitude larger than the geometric transit probability of 0.6%.Comment: 15 pages, 3 figures, 3 tables. Accepted in A