Multiplexed gene expression analysis of HLA class II-associated podoconiosis implicates chronic immune activation in its pathogenesis

Background Podoconiosis is a tropical lymphoedema of the leg resulting from barefoot exposure to irritant volcanic soils. Approximately 4 million people are affected, mainly in African highland regions. The pathogenesis of this neglected tropical disease is still largely unknown, although HLA class II (HLAII) polymorphisms are associated with the disease. Methods NanoString technology was used to assess expression of 579 immune-related genes in formalin-fixed and paraffin-embedded lymph node archival samples from podoconiosis patients and unaffected controls. Results Forty-eight genes were upregulated and 21 downregulated in podoconiosis samples compared with controls. Gene ontology analysis showed differentially expressed genes to be closely related to major histocompatibility complex protein, cytokine and TNF receptor binding genes. Pathway enrichment analysis revealed involvement of lymphocyte activation, adaptive immunity, cytokine signalling, antigen processing and the IL-12 pathways. Conclusions This exploratory study reports a multiplex gene expression analysis in podoconiosis and shows upregulation of pro-inflammatory transcripts compatible with the notion of local, chronic immune activation in this HLAII-associated disease. Implicated pathways will inform future research into podoconiosis immunopathogenesis

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Cortical cell loss is a core feature of Huntington Disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate this using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild type Huntingtin is known to play a role in neurodevelopment, we explored the association between wild type Huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders was also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell-types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types

Brane Tilings and Exceptional Collections

Both brane tilings and exceptional collections are useful tools for describing the low energy gauge theory on a stack of D3-branes probing a Calabi-Yau singularity. We provide a dictionary that translates between these two heretofore unconnected languages. Given a brane tiling, we compute an exceptional collection of line bundles associated to the base of the non-compact Calabi-Yau threefold. Given an exceptional collection, we derive the periodic quiver of the gauge theory which is the graph theoretic dual of the brane tiling. Our results give new insight to the construction of quiver theories and their relation to geometry.Comment: 46 pages, 37 figures, JHEP3; v2: reference added, figure 13 correcte

Observation of High-Energy Astrophysical Neutrinos in Three Years of IceCube Data

A search for high-energy neutrinos interacting within the IceCube detector between 2010 and 2012 provided the first evidence for a high-energy neutrino flux of extraterrestrial origin. Results from an analysis using the same methods with a third year (2012-2013) of data from the complete IceCube detector are consistent with the previously reported astrophysical flux in the 100 TeV - PeV range at the level of $10^{-8}\, \mathrm{GeV}\, \mathrm{cm}^{-2}\, \mathrm{s}^{-1}\, \mathrm{sr}^{-1}$ per flavor and reject a purely atmospheric explanation for the combined 3-year data at $5.7 \sigma$. The data are consistent with expectations for equal fluxes of all three neutrino flavors and with isotropic arrival directions, suggesting either numerous or spatially extended sources. The three-year dataset, with a livetime of 988 days, contains a total of 37 neutrino candidate events with deposited energies ranging from 30 to 2000 TeV. The 2000 TeV event is the highest-energy neutrino interaction ever observed.Comment: 8 pages, 5 figures. Accepted by PRL. The event catalog, event displays, and other data tables are included after the final page of the article. Changed from the initial submission to reflect referee comments, expanding the section on atmospheric backgrounds, and fixes offsets of up to 0.9 seconds in reported event times. Address correspondence to: J. Feintzeig, C. Kopper, N. Whitehor

Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data

We report a quasi-differential upper limit on the extremely-high-energy (EHE) neutrino flux above $5\times 10^{6}$ GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above $10^{6}$ GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between $5 \times 10^{6}$ and $5 \times 10^{10}$ GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\ {\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}$at$10^9\ {\rm GeV}$. A significant part of the parameter-space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

The Evolution of Ly-alpha Emitting Galaxies Between z = 2.1 and z = 3.1

We describe the results of a new, wide-field survey for z=3.1 Ly-alpha emission-line galaxies (LAEs) in the Extended Chandra Deep Field South (ECDF-S). By using a nearly top-hat 5010 Angstrom filter and complementary broadband photometry from the MUSYC survey, we identify a complete sample of 141 objects with monochromatic fluxes brighter than 2.4E-17 ergs/cm^2/s and observers-frame equivalent widths greater than ~ 80 Angstroms (i.e., 20 Angstroms in the rest-frame of Ly-alpha). The bright-end of this dataset is dominated by x-ray sources and foreground objects with GALEX detections, but when these interlopers are removed, we are still left with a sample of 130 LAE candidates, 39 of which have spectroscopic confirmations. This sample overlaps the set of objects found in an earlier ECDF-S survey, but due to our filter's redder bandpass, it also includes 68 previously uncataloged sources. We confirm earlier measurements of the z=3.1 LAE emission-line luminosity function, and show that an apparent anti-correlation between equivalent width and continuum brightness is likely due to the effect of correlated errors in our heteroskedastic dataset. Finally, we compare the properties of z=3.1 LAEs to LAEs found at z=2.1. We show that in the ~1 Gyr after z~3, the LAE luminosity function evolved significantly, with L* fading by ~0.4 mag, the number density of sources with L > 1.5E42 ergs/s declining by ~50%, and the equivalent width scale-length contracting from 70^{+7}_{-5} Angstroms to 50^{+9}_{-6} Angstroms. When combined with literature results, our observations demonstrate that over the redshift range z~0 to z~4, LAEs contain less than ~10% of the star-formation rate density of the universe.Comment: 39 pages, 12 figures, Accepted to Ap

The Yeast La Related Protein Slf1p Is a Key Activator of Translation during the Oxidative Stress Response

The mechanisms by which RNA-binding proteins control the translation of subsets of mRNAs are not yet clear. Slf1p and Sro9p are atypical-La motif containing proteins which are members of a superfamily of RNA-binding proteins conserved in eukaryotes. RIP-Seq analysis of these two yeast proteins identified overlapping and distinct sets of mRNA targets, including highly translated mRNAs such as those encoding ribosomal proteins. In paralell, transcriptome analysis of slf1Δ and sro9Δ mutant strains indicated altered gene expression in similar functional classes of mRNAs following loss of each factor. The loss of SLF1 had a greater impact on the transcriptome, and in particular, revealed changes in genes involved in the oxidative stress response. slf1Δ cells are more sensitive to oxidants and RIP-Seq analysis of oxidatively stressed cells enriched Slf1p targets encoding antioxidants and other proteins required for oxidant tolerance. To quantify these effects at the protein level, we used label-free mass spectrometry to compare the proteomes of wild-type and slf1Δ strains following oxidative stress. This analysis identified several proteins which are normally induced in response to hydrogen peroxide, but where this increase is attenuated in the slf1Δ mutant. Importantly, a significant number of the mRNAs encoding these targets were also identified as Slf1p-mRNA targets. We show that Slf1p remains associated with the few translating ribosomes following hydrogen peroxide stress and that Slf1p co-immunoprecipitates ribosomes and members of the eIF4E/eIF4G/Pab1p ‘closed loop’ complex suggesting that Slf1p interacts with actively translated mRNAs following stress. Finally, mutational analysis of SLF1 revealed a novel ribosome interacting domain in Slf1p, independent of its RNA binding La-motif. Together, our results indicate that Slf1p mediates a translational response to oxidative stress via mRNA-specific translational control

It takes two: Evidence for reduced sexual conflict over parental care in a biparental canid

In biparental systems, sexual conflict over parental investment predicts that the parent providing care experiences greater reproductive costs. This inequality in parental contribution is reduced when offspring survival is dependent on biparental care. However, this idea has received little empirical attention. Here, we determined whether mothers and fathers differed in their contribution to care in a captive population of coyotes (Canis latrans). We performed parental care assays on 8 (n = 8 males, 8 females) mated pairs repeatedly over a 10-week period (i.e., 5–15 weeks of litter age) when pairs were first-time breeders (2011), and again as experienced breeders (2013). We quantified consistent individual variation (i.e., repeatability) in 8 care behaviors and examined within- and among-individual correlations to determine if behavioral plasticity within or parental personality across seasons varied by sex. Finally, we extracted hormone metabolites (i.e., cortisol and testosterone) from fecal samples collected during gestation to describe potential links between hormonal mechanisms and individual consistency in parental behaviors. Parents differed in which behaviors were repeatable: mothers demonstrated consistency in provisioning and pup-directed aggression, whereas fathers were consistent in pup checks. However, positive within-individual correlations for identical behaviors (e.g., maternal versus paternal play) suggested that the rate of change in all behaviors except provisioning was highly correlated between the sexes. Moreover, positive among-individual correlations among 50% of identical behaviors suggested that personality differences across parents were highly correlated. Lastly, negative among-individual correlations among pup-directed aggression, provisioning, and gestational testosterone in both sexes demonstrated potential links between preparental hormones and labile parental traits. We provide novel evidence that paternal contribution in a biparental species reaches near equivalent rates of their partners