The Case for a Muon Collider Higgs Factory

We propose the construction of a compact Muon Collider Higgs Factory. Such a machine can produce up to \sim 14,000 at 8\times 10^{31} cm^-2 sec^-1 clean Higgs events per year, enabling the most precise possible measurement of the mass, width and Higgs-Yukawa coupling constants.Comment: Supporting letter for the document: "Muon Collider Higgs Factory for Smowmass 2013", A White Paper submitted to the 2013 U.S. Community Summer Study of the Division of Particles and Fields of the American Physical Society, Y. Alexahin, et. al, FERMILAB-CONF-13-245-T (July, 2013

Sleep characteristics in type 1 diabetes and associations with glycemic control: systematic review and meta-analysis

AbstractObjectivesThe association between inadequate sleep and type 2 diabetes has garnered much attention, but little is known about sleep and type 1 diabetes (T1D). Our objectives were to conduct a systematic review and meta-analysis comparing sleep in persons with and without T1D, and to explore relationships between sleep and glycemic control in T1D.MethodsStudies were identified from Medline and Scopus. Studies reporting measures of sleep in T1D patients and controls, and/or associations between sleep and glycemic control, were selected.ResultsA total of 22 studies were eligible for the meta-analysis. Children with T1D had shorter sleep duration (mean difference [MD] = −26.4 minutes; 95% confidence interval [CI] = −35.4, −17.7) than controls. Adults with T1D reported poorer sleep quality (MD in standardized sleep quality score = 0.51; 95% CI = 0.33, 0.70), with higher scores reflecting worse sleep quality) than controls, but there was no difference in self-reported sleep duration. Adults with TID who reported sleeping >6 hours had lower hemoglobin A1c (HbA1c) levels than those sleeping ≤6 hours (MD = −0.24%; 95% CI = −0.47, −0.02), and participants reporting good sleep quality had lower HbA1c than those with poor sleep quality (MD = −0.19%; 95% CI = −0.30, −0.08). The estimated prevalence of obstructive sleep apnea (OSA) in adults with TID was 51.9% (95% CI = 31.2, 72.6). Patients with moderate-to-severe OSA had a trend toward higher HbA1c (MD = 0.39%, 95% CI = −0.08, 0.87).ConclusionT1D was associated with poorer sleep and high prevalence of OSA. Poor sleep quality, shorter sleep duration, and OSA were associated with suboptimal glycemic control in T1D patients

Adult attention deficit hyperactivity disorder is associated with migraine headaches

Attention deficit hyperactivity disorder (ADHD) is now recognized as a common disorder both in child and adult psychiatry. Adult patients with a diagnosis of ADHD (n = 572) and community controls (n = 675) responded to auto-questionnaires rating past and present symptoms of ADHD, co-morbid conditions, including migraine, treatment history and work status. The prevalence of migraine was significantly higher in the patient group compared to the controls (28.3% vs. 19.2%, P < 0.001, OR = 1.67, CI 1.28–2.17). The difference from controls was particularly marked for men (22.5% vs. 10.7%, P < 0.001, OR = 2.43, CI 1.51–3.90) but was also significant for women (34.4% vs. 24.9%, P = 0.008, OR = 1.58, CI 1.13–2.21). In both patients and controls, migraine was associated with symptoms of mood and anxiety disorders. These findings point to a co-morbidity of migraine with ADHD, and it is possible that these patients represent a clinical and biological subgroup of adult patients with ADHD

Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis

Extent: 9p.Background: Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods: Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results: MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions: MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.Zainab Samaan, Daria Gaysina, Sarah Cohen-Woods, Nick Craddock, Lisa Jones, Ania Korszun, Mike Owen, Andrew Mente, Peter McGuffin and Anne Farme

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic

The genetics and neuropathology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (MAPT), the growth factor precursor gene granulin (GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors