Structural Basis for Conserved Regulation and Adaptation of the Signal Recognition Particle Targeting Complex.

The signal recognition particle (SRP) is a ribonucleoprotein complex with a key role in targeting and insertion of membrane proteins. The two SRP GTPases, SRP54 (Ffh in bacteria) and FtsY (SRα in eukaryotes), form the core of the targeting complex (TC) regulating the SRP cycle. The architecture of the TC and its stimulation by RNA has been described for the bacterial SRP system while this information is lacking for other domains of life.

Brain Tumor Genetic Modification Yields Increased Resistance to Paclitaxel in Physical Confinement.

Brain tumor cells remain highly resistant to radiation and chemotherapy, particularly malignant and secondary cancers. In this study, we utilized microchannel devices to examine the effect of a confined environment on the viability and drug resistance of the following brain cancer cell lines: primary cancers (glioblastoma multiforme and neuroblastoma), human brain cancer cell lines (D54 and D54-EGFRvIII), and genetically modified mouse astrocytes (wild type, p53-/-, p53-/- PTEN-/-, p53-/- Braf, and p53-/- PTEN-/- Braf). We found that loss of PTEN combined with Braf activation resulted in higher viability in narrow microchannels.

Whole-exome sequencing in an isolated population from the Dalmatian island of Vis.

We have whole-exome sequenced 176 individuals from the isolated population of the island of Vis in Croatia in order to describe exonic variation architecture. We found 290 577 single nucleotide variants (SNVs), 65% of which are singletons, low frequency or rare variants. A total of 25 430 (9%) SNVs are novel, previously not catalogued in NHLBI GO Exome Sequencing Project, UK10K-Generation Scotland, 1000Genomes Project, ExAC or NCBI Reference Assembly dbSNP.

Progress in methods for rare variant association.

Empirical studies and evolutionary theory support a role for rare variants in the etiology of complex traits. Given this motivation and increasing affordability of whole-exome and whole-genome sequencing, methods for rare variant association have been an active area of research for the past decade. Here, we provide a survey of the current literature and developments from the Genetics Analysis Workshop 19 (GAW19) Collapsing Rare Variants working group.

Cytokeratin 20 positive circulating tumor cells are a marker for response after neoadjuvant chemoradiation but not for prognosis in patients with rectal cancer.

Background: Several studies have shown, that circulating tumor cells (CTC) have a negative prognostic value in colorectal cancer patients. Aim of this study was to evaluate the role of CTC in specifically rectal cancer patients regarding the influence on overall survival and to elucidate the impact of CTC in predicting response after chemoradiation (RCTX).

Methods: In this prospective monocentric study 267 patients with rectal cancer were included.

The Relation Between Child Versus Parent Report of Chronic Fatigue and Language/Literacy Skills in School-Age Children with Cochlear Implants.

Objectives: Preliminary evidence suggests that children with hearing loss experience elevated levels of chronic fatigue compared with children with normal hearing. Chronic fatigue is associated with decreased academic performance in many clinical populations. Children with cochlear implants as a group exhibit deficits in language and literacy skills; however, the relation between chronic fatigue and language and literacy skills for children with cochlear implants is unclear.

Impact of Facial Conformation on Canine Health: Brachycephalic Obstructive Airway Syndrome.

The domestic dog may be the most morphologically diverse terrestrial mammalian species known to man; pedigree dogs are artificially selected for extreme aesthetics dictated by formal Breed Standards, and breed-related disorders linked to conformation are ubiquitous and diverse. Brachycephaly--foreshortening of the facial skeleton--is a discrete mutation that has been selected for in many popular dog breeds e.g.

The UK10K project identifies rare variants in health and disease.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests.

Impact of facial conformation on canine health: corneal ulceration.

Concern has arisen in recent years that selection for extreme facial morphology in the domestic dog may be leading to an increased frequency of eye disorders. Corneal ulcers are a common and painful eye problem in domestic dogs that can lead to scarring and/or perforation of the cornea, potentially causing blindness. Exaggerated juvenile-like craniofacial conformations and wide eyes have been suspected as risk factors for corneal ulceration.

Symportin 1 chaperones 5S RNP assembly during ribosome biogenesis by occupying an essential rRNA-binding site.

During 60S biogenesis, mature 5S RNP consisting of 5S RNA, RpL5 and RpL11, assembles into a pre-60S particle, where docking relies on RpL11 interacting with helix 84 (H84) of the 25S RNA. How 5S RNP is assembled for recruitment into the pre-60S is not known. Here we report the crystal structure of a ternary symportin Syo1-RpL5-N-RpL11 complex and provide biochemical and structural insights into 5S RNP assembly.

Hope thinking and past trauma mediate the relationships of body mass index with perceived mental health treatment need and mental health treatment use.

Unlabelled: Greater body mass is associated with a greater risk of mental health conditions and more frequent mental health treatment use. However, factors that might influence perceived mental health treatment need and mental health treatment use among those of greater weight, including hope thinking, trauma history and perceived mental health treatment stigma, are not well understood.

Objective: The objective of this study was to determine if hope thinking, trauma history and/or perceived mental health treatment stigma mediate the relationships of body mass index [BMI] with perceived mental health treatment need and mental health treatment use.

Collapsing focal segmental glomerulosclerosis resulting from a single dose of zoledronate.

Bisphosphonates are commonly used for the treatment of osteoporosis, Paget's disease, multiple myeloma and hypercalcemia. Collapsing focal segmental glomerulosclerosis (FSGS) is known to occur uncommonly with exposure to bisphosphonates, specifically pamidronate and alendronate; it has rarely and equivocally been reported with zoledronate therapy. We describe the case of a 36-year-old African American female with metastatic breast cancer who presented with nephrotic-range proteinuria and acute kidney injury within 2 weeks of exposure to a single dose of zoledronate.

Evaluation of red cell distribution width in dogs with pulmonary hypertension.

Objectives: To compare red cell distribution width (RDW) between dogs with different causes of pulmonary hypertension (PH) and a control dog population to determine whether RDW was correlated with severity of PH as measured by echocardiography. A further aim was to determine the prognostic significance of increased RDW for dogs with PH.

Animals: Forty-four client-owned dogs with PH and 79 control dogs presented to a single tertiary referral institution.

Prescribing practices of primary-care veterinary practitioners in dogs diagnosed with bacterial pyoderma.

Background: Concern has been raised regarding the potential contributions of veterinary antimicrobial use to increasing levels of resistance in bacteria critically important to human health. Canine pyoderma is a frequent, often recurrent diagnosis in pet dogs, usually attributable to secondary bacterial infection of the skin. Lesions can range in severity based on the location, total area and depth of tissue affected and antimicrobial therapy is recommended for resolution.

Determinants of utilization and cost of VHA care by OEF/OIF Veterans screened for mild traumatic brain injury.

Objective: To determine the demographic and service characteristics that differentially impact utilization and cost of Veterans Health Administration (VHA) services for Operation Enduring Freedom and Operation Iraq Freedom (OEF/OIF) Veterans screened or evaluated for traumatic brain injury (TBI).

Setting: We examined Department of Defense (DoD) and VHA administrative records of OEF/OIF Veterans who were screened or evaluated for TBI.

Participants: Our study population was OEF/OIF Veterans who separated from DoD in Fiscal Years 2003-2009 and who were screened or evaluated in VHA for TBI between October 2008 and July 2009.

The Los Angeles County Community Disaster Resilience Project - a community-level, public health initiative to build community disaster resilience.

Public health officials need evidence-based methods for improving community disaster resilience and strategies for measuring results. This methods paper describes how one public health department is addressing this problem. This paper provides a detailed description of the theoretical rationale, intervention design and novel evaluation of the Los Angeles County Community Disaster Resilience Project (LACCDR), a public health program for increasing community disaster resilience.

Concordance of clinician judgment of mild traumatic brain injury history with a diagnostic standard.

The concordance of Department of Veterans Affairs (VA) clinician judgment of mild traumatic brain injury (mTBI) history with American Congress of Rehabilitation Medicine (ACRM)-based criteria was examined for Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) Veterans. In order to understand inconsistencies in agreement, we also examined the associations between evaluation outcomes and conceptually relevant patient characteristics, deployment-related events, current self-reported health symptoms, and suspected psychiatric conditions. The Veteran sample comprised 14,026 OIF/OEF VA patients with deployment-related mTBI history (n = 9,858) or no history of mTBI (n = 4,168) as defined by ACRM-based criteria.

Food-specific serum IgE and IgG reactivity in dogs with and without skin disease: lack of correlation between laboratories.

Background: Despite conflicting data on their utility and no reports on interlaboratory reproducibility, serum food-specific antibodies are commonly assayed in first-opinion canine practice.

Hypothesis/objectives: To determine both the variability of test results between two laboratories and the frequencies and magnitudes of food reactivity in dogs of different disease status.

Animals: Sera were obtained from eight dogs with cutaneous adverse food reaction (Group A), 22 with nonfood-induced atopic dermatitis (Group B), 30 with an allergic/inflammatory phenotype (Group C), 12 with miscellaneous skin diseases (Group D) and nine healthy dogs (Group E).

Anticipating the traumatic brain injury-related health care needs of women veterans after the Department of Defense change in combat assignment policy.

Background: Female service members' presence in combat zones during Operation Enduring Freedom and Operation Iraqi Freedom is unprecedented both in terms of the number of women deployed and the nature of their involvement. In light of changing Department of Defense policy governing the deployment of women in combat zones, this article intends to set the groundwork for estimating future combat-related injuries and subsequent Veterans Health Administration (VHA) utilization while focusing on traumatic brain injury (TBI).

Methods: The article summarizes and presents the results of a study that examines veterans who present to VHA for TBI evaluation.

Reconstituting the motility of isolated intracellular cargoes.

Kinesin, dynein, and myosin transport intracellular cargoes including organelles, membrane-bound vesicles, and mRNA along the cytoskeleton. These motor proteins work collectively in teams to transport cargoes over long distances and navigate around obstacles in the cell. In addition, several types of motors often interact on the same cargo to allow bidirectional transport and switching between the actin and microtubule networks.

KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls.

Genetic associations with expression for genes implicated in GWAS studies for atherosclerotic cardiovascular disease and blood phenotypes.

Genome-wide association studies (GWAS) have uncovered many genetic associations for cardiovascular disease (CVD). However, data are limited regarding causal genetic variants within implicated loci. We sought to identify regulatory variants (cis- and trans-eQTLs) affecting expression levels of 93 genes selected by their proximity to SNPs with significant associations in prior GWAS for CVD traits.

Dynein interacts with the neural cell adhesion molecule (NCAM180) to tether dynamic microtubules and maintain synaptic density in cortical neurons.

Cytoplasmic dynein is well characterized as an organelle motor, but dynein also acts to tether and stabilize dynamic microtubule plus-ends in vitro. Here we identify a novel and direct interaction between dynein and the 180-kDa isoform of the neural cell adhesion molecule (NCAM). Optical trapping experiments indicate that dynein bound to beads via the NCAM180 interaction domain can tether projecting microtubule plus-ends.

How long and low can you go? Effect of conformation on the risk of thoracolumbar intervertebral disc extrusion in domestic dogs.

Intervertebral disc extrusion (IVDE) is a common neurological disorder in certain dog breeds, resulting in spinal cord compression and injury that can cause pain and neurological deficits. Most disc extrusions are reported in chondrodystrophic breeds (e.g.