The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD.

Using transgenic mice harboring a targeted LacZ insertion, we studied the expression pattern of the C9ORF72 mouse ortholog (3110043O21Rik). Unlike most genes that are mutated in amyotrophic lateral sclerosis (ALS), which are ubiquitously expressed, the C9ORF72 ortholog was most highly transcribed in the neuronal populations that are sensitive to degeneration in ALS and frontotemporal dementia. Thus, our results provide a potential explanation for the cell type specificity of neuronal degeneration caused by C9ORF72 mutations

A genome-wide association study of myasthenia gravis

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10(−8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the over all case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10(−8); odds ratio, 1.37; 95% CI, 1.25–1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10(−8); odds ratio, 2.31; 95% CI, 2.02 – 2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10(−9); odds ratio, 1.41; 95% CI, 1.29–1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10(−12); odds ratio, 1.56; 95% CI, 1.44–1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10(−18); odds ratio, 4.27; 95% CI, 3.92–4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10(−11); odds ratio, 4.0; 95% CI, 3.57–4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes1, with epidemiological association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration

Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling

Molecular dynamics simulation of aqueous solutions of 26-unit segments of p(NIPAAm) and of p(NIPAAm) "doped" with amino acid based comonomers

We have performed 75-ns molecular dynamics (MD) simulations of aqueous solutions of a 26-unit NIPAAm oligomer at two temperatures, 302 and 315 K, below and above the experimentally determined lower critical solution temperature (LCST) of p(NIPAAm). We have been able to show that at 315 K the oligomer assumes a compact form, while it keeps a more extended form at 302 K. A similar behavior has been demonstrated for a similar NIPAAm oligomer, where two units had been substituted by methacryloyl-l-valine (MAVA) comonomers, one of them being charged and one neutral. For another analogous oligomer, where the same units had been substituted by methacryloyl-l-leucine (MALEU) comonomers, no transition from the extended to the more compact conformation has been found within the same simulation time. Statistical analysis of the trajectories indicates that this transition is related to the dynamics of the oligomer backbone, and to the formation of intramolecular hydrogen bonds and water-bridges between distant units of the solute. In the MAVA case, we have also evidenced an important role of the neutral MAVA comonomer in stabilizing the compact coiled structure. In the MALEU case, the corresponding comonomer is not equally efficacious and, possibly, is even hindering the readjustment of the oligomer backbone. Finally the self-diffusion coefficient of water molecules surrounding the oligomers at the two temperatures for selected relevant times is observed to characteristically depend on the distance from the solute molecules

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

'I Wanna See Some History': Recent Writing on British Punk

© 2016 Cambridge University Press. Tucked away on the b-side of the Sex Pistols' third single, 'Pretty Vacant' (1977), is a cover version of The Stooges' 'No Fun'. The song had long been a staple of the Pistols' live set; on record, however, Johnny Rotten chose to open the track with a diatribe against those attempting to imbue the punk culture he helped instigate with broader socio-economic, cultural or political implications. 'Here we go now', he snarled, 'a sociology lecture, with a bit of psychology, a bit of neurology, a bit of fuckology'

Literary studies and the academy

In 1885 the University of Oxford invited applications for the newly created Merton Professorship of English Language and Literature. The holder of the chair was, according to the statutes, to ‘lecture and give instruction on the broad history and criticism of English Language and Literature, and on the works of approved English authors’. This was not in itself a particularly innovatory move, as the study of English vernacular literature had played some part in higher education in Britain for over a century. Oxford University had put English as a subject into its pass degree in 1873, had been participating since 1878 in extension teaching, of which literary study formed a significant part, and had since 1881 been setting special examinations in the subject for its non-graduating women students. What was new was the fact that this ancient university appeared to be on the verge of granting the solid academic legitimacy of an established chair to an institutionally marginal and often contentious intellectual pursuit, acknowledging the study of literary texts in English to be a fit subject not just for women and the educationally disadvantaged but also for university men