Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A.

Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease.

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in aging processes. We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homolog, myostatin (MSTN), based on unique amino acid sequence features. Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging.

Population and Evolutionary Genomics of Amblyomma americanum, an Expanding Arthropod Disease Vector.

The lone star tick, Amblyomma americanum, is an important disease vector and the most frequent tick found attached to humans in the eastern United States. The lone star tick has recently experienced a rapid range expansion into the Northeast and Midwest, but despite this emerging infectious threat to wildlife, livestock, and human health, little is known about the genetic causes and consequences of the geographic expansion. In the first population genomic analysis of any tick species, we characterize the genetic diversity and population structure of A.

Neonatal seizures induced by pentylenetetrazol or kainic acid disrupt primary cilia growth on developing mouse cortical neurons.

Neonatal or early-life seizures (ELS) are often associated with life-long neurophysiological, cognitive and behavioral deficits, but the underlying mechanisms contributing to these deficits remain poorly understood. Newborn, post-migratory cortical neurons sprout ciliary buds (procilia) that mature into primary cilia. Disruption of the growth or signaling capabilities of these cilia has been linked to atypical neurite outgrowth from neurons and abnormalities in neuronal circuitry.

Sex-Specific Genetic Variants are Associated With Coronary Endothelial Dysfunction.

Background: Endothelial dysfunction is an early stage of atherosclerosis. Single-nucleotide polymorphisms (SNPs) have been associated with vascular dysfunction, cardiac events, and coronary artery remodeling. We aimed to detect SNPs associated with endothelial dysfunction and determine whether these associations are sex specific.

Low incidence of primary biliary cirrhosis (PBC) in the first-degree relatives of PBC probands after 8 years of follow-up.

Background & Aims: Primary biliary cirrhosis (PBC) is characterized by chronic cholestasis and disease-specific antimitochondrial antibodies (AMA). A high prevalence of AMAs in first-degree relatives (FDRs) of PBC probands has been reported, although the natural history of such patients has not been described. We aimed to assess the risk of developing PBC in AMA+ FDRs of patients with PBC.

Duration of Inflammatory Bowel Disease Is Associated With Increased Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis and IBD.

Objectives: Primary sclerosing cholangitis (PSC) often coexists with inflammatory bowel disease (IBD) and can be complicated by cholangiocarcinoma (CCA), a lethal malignancy for which reliable predictors remain unknown. We aimed to characterize the influence of colectomy and IBD duration on risk of CCA in patients with PSC-IBD.

Methods: A retrospective review of patients with PSC-IBD seen at the Mayo Clinic, Rochester, between January 2005 and May 2013 was performed.

Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice.

Objective: To investigate whether osteocytic connexin 43 (Cx43) is required for the bone response to intermittent PTH administration, and whether the connexin is involved in maintaining the bone matrix.

Methods: Human PTH(1-34) was injected to adult male mice expressing (Cx43(fl/fl)) or not osteocytic Cx43 (Cx43(fl/fl);DMP1-8kb-Cre) daily (100 µg/kg/d) for 14 days.

Results: Cx43(fl/fl);DMP1-8kb-Cre mice have no difference in body weight and BMD from 1 to 4 months of age.

Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience.

Objective: To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC).

Patients And Methods: The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories.

Interventions to prevent or reduce the level of frailty in community-dwelling older adults: a protocol for a scoping review of the literature and international policies.

Introduction: With ageing comes increased vulnerability such that older adults' ability to recover from acute illnesses, fall-related injuries and other stresses related to the physical ageing processes declines. This increased vulnerability, also known as frailty, is common in older adults and associated with increased healthcare service use and adverse health outcomes. Currently, there is no overview of available interventions to prevent or reduce the level of frailty (as defined by study's authors) which will help healthcare providers in community settings caring for older adults.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci.

Evolutionary and developmental implications of asymmetric brain folding in a large primate pedigree.

Bilateral symmetry is a fundamental property of the vertebrate central nervous system. Local deviations from symmetry provide various types of information about the development, evolution, and function of elements within the CNS, especially the cerebral hemispheres. Here, we quantify the pattern and extent of asymmetry in cortical folding within the cerebrum of Papio baboons and assess the evolutionary and developmental implications of the findings.

Similarity of wh-Phrases and Acceptability Variation in wh-Islands.

In wh-questions that form a syntactic dependency between the fronted wh-phrase and its thematic position, acceptability is severely degraded when the dependency crosses another wh-phrase. It is well known that the acceptability degradation in wh-island violation ameliorates in certain contexts, but the source of this variation remains poorly understood. In the syntax literature, an influential theory - Featural Relativized Minimality - has argued that the wh-island effect is modulated exclusively by the distinctness of morpho-syntactic features in the two wh-phrases, but psycholinguistic theories of memory encoding and retrieval mechanisms predict that semantic properties of wh-phrases should also contribute to wh-island amelioration.

Depression and Oropharynx Cancer Outcome.

Background: Studies have shown a modest relationship between depression and mortality in patients with cancer. Our study addressed methodological weaknesses in the literature by restricting the sample to patients with one cancer type, adjusting for factors known to affect outcome, and following up patients for a sufficient period.

Methods: We prospectively followed patients newly diagnosed with squamous cell oropharyngeal cancer from the start of radiation therapy until death or until date of last clinical visit.

Prediction using hierarchical data: Applications for automated detection of cervical cancer.

Although the Papanicolaou smear has been successful in decreasing cervical cancer incidence in the developed world, there exist many challenges for implementation in the developing world. Quantitative cytology, a semi-automated method that quantifies cellular image features, is a promising screening test candidate. The nested structure of its data (measurements of multiple cells within a patient) provides challenges to the usual classification problem.

Effects of Age and Estrogen on Skeletal Gene Expression in Humans as Assessed by RNA Sequencing.

Unlabelled: Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining pre-specified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome.

Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis.

Objective: To evaluate the relationship between early relapse recovery and onset of progressive multiple sclerosis (MS).

Methods: We studied a population-based cohort (105 patients with relapsing-remitting MS, 86 with bout-onset progressive MS) and a clinic-based cohort (415 patients with bout-onset progressive MS), excluding patients with primary progressive MS. Bout-onset progressive MS includes patients with single-attack progressive and secondary progressive MS.

Myostatin as a mediator of sarcopenia versus homeostatic regulator of muscle mass: insights using a new mass spectrometry-based assay.

Background: Myostatin is a protein synthesized and secreted by skeletal muscle that negatively regulates muscle mass. The extent to which circulating myostatin levels change in the context of aging is controversial, largely due to methodological barriers.

Methods: We developed a specific and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay to measure concentrations of myostatin and two of its key inhibitors, follistatin-related gene (FLRG) protein and growth and serum protein-1 (GASP-1) in 80 younger (<40 years), 80 older (>65 years), and 80 sarcopenic older women and men.

The association of copy number variation and percent mammographic density.

Background: Percent mammographic density (PD) estimates the proportion of stromal, fat, and epithelial breast tissues on the mammogram image. Adjusted for age and body mass index (BMI), PD is one of the strongest risk factors for breast cancer. Inherited factors are hypothesized to explain between 30 and 60% of the variance in this trait.

Crop rotational diversity enhances belowground communities and functions in an agroecosystem.

Biodiversity loss, an important consequence of agricultural intensification, can lead to reductions in agroecosystem functions and services. Increasing crop diversity through rotation may alleviate these negative consequences by restoring positive aboveground-belowground interactions. Positive impacts of aboveground biodiversity on belowground communities and processes have primarily been observed in natural systems.

TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect.

Cortical Folding of the Primate Brain: An Interdisciplinary Examination of the Genetic Architecture, Modularity, and Evolvability of a Significant Neurological Trait in Pedigreed Baboons (Genus Papio).

Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume.

Global transcriptional profiling using RNA sequencing and DNA methylation patterns in highly enriched mesenchymal cells from young versus elderly women.

Age-related bone loss in humans is associated with a decrease in bone formation relative to bone resorption, although the mechanisms for this impairment in bone formation with aging are not well understood. It is known that the precursors for the bone-forming osteoblasts reside in the mesenchymal cell population in bone marrow. Thus, in an effort to identify relevant genetic pathways that are altered with aging, we examined the gene expression and DNA methylation patterns from a highly enriched bone marrow mesenchymal cell population from young (mean age, 28.

A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease.

Background: The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown.

Aim: To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients.

Methods: We performed a multicenter, case-control analysis utilising self-administered questionnaires.

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Background: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.