Compound heterozygous mutations in RIPPLY2 associated with vertebral segmentation defects

Segmentation defects of the vertebrae (SDV) are caused by aberrant somite formation during embryogenesis and result in irregular formation of the vertebrae and ribs. The Notch signal transduction pathway plays a critical role in somite formation and patterning in model vertebrates. In humans, mutations in several genes involved in the Notch pathway are associated with SDV, with both autosomal recessive (MESP2, DLL3, LFNG, HES7) and autosomal dominant (TBX6) inheritance. However, many individuals with SDV do not carry mutations in these genes. Using whole-exome capture and massive parallel sequencing, we identified compound heterozygous mutations in RIPPLY2 in two brothers with multiple regional SDV, with appropriate familial segregation. One novel mutation (c.A238T:p.Arg80*) introduces a premature stop codon. In transiently transfected C2C12 mouse myoblasts, the RIPPLY2 mutant protein demonstrated impaired transcriptional repression activity compared with wild-type RIPPLY2 despite similar levels of expression. The other mutation (c.240-4T>G), with minor allele frequency <0.002, lies in the highly conserved splice site consensus sequence 5' to the terminal exon. Ripply2 has a well-established role in somitogenesis and vertebral column formation, interacting at both gene and protein levels with SDV-associated Mesp2 and Tbx6. We conclude that compound heterozygous mutations in RIPPLY2 are associated with SDV, a new gene for this condition. © The Author 2014.

Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin

Missense and frameshift mutations in TRAF family member-associated NF-kappa-B activator (TANK)-binding kinase 1 (TBK1) have been reported in European sporadic and familial amyotrophic lateral sclerosis (ALS) cohorts. To assess the role of TBK1 in ALS patient cohorts of wider ancestry, we have analyzed whole-exome sequence data from an Australian cohort of familial ALS (FALS) patients and controls. We identified a novel TBK1 deletion (c.1197delC) in a FALS patient of Chinese origin. This frameshift mutation (p.L399fs) likely results in a truncated protein that lacks functional domains required for adapter protein binding, as well as protein activation and structural integrity. No novel or reported TBK1 mutations were identified in FALS patients of European ancestry. This is the first report of a TBK1 mutation in an ALS patient of Asian origin and indicates that sequence variations in TBK1 are a rare cause of FALS in Australia. © 2015 Elsevier Inc.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF

Grand Push Auto: A car based exertion game

Grand Push Auto is an exertion game in which players aim to push a full sized car to ever increasing speeds. The re-appropriation of a car as essentially a large weight allows us to create a highly portable and distributable exertion game in which the main game element has a weight of over 1000 kilograms. In this paper we discuss initial experiences with GPA, and present 3 questions for ongoing study which have been identified from our early testing: How might we appropriate existing objects in exertion game design, and does appropriation change how we think about these objects in different contexts, for example environmental awareness? How does this relate to more traditional sled based weight training? How can we create exertion games that allow truly brutal levels of force?

Essential nursing care of the critically ill patient

This chapter is about essential nursing care. Because it is often referred to as basic nursing, nurses may not always perceive it as deserving of priority. Yet, how well patients are cared for has a direct effect on their sense of wellbeing and their recovery. ‘Interventional patient hygiene’ is a systematic, evidence-based approach to nursing actions designed to improve patient outcomes using a framework of hygiene, catheter care, skin care, mobility and oral care.1 This chapter focuses on the physical care, infection control, preventative therapies and transport of critically ill patients. The first two areas are closely linked: poor-quality physical care increases the risk of infection. The final areas are essential features of critical care nursing.

Kansalaisuus ja yhteiskunnallinen yhteisö : T. H. Marshallin ja Talcott Parsonsin perintö nykyaikaiselle kansalaisuustutkimukselle

This work examines the concept of citizenship of TH Marshall and the societal community concept of Talcott Parsons. I am especially interested in whether Marshall s concept of citizenship or Parsons s concept of societal community enable to develop such an analytical framework that creates a basis for relevant examination of how the mechanisms that include or exclude citizenship into the society constitute. The focus is in societal heterogeneity, which will easily introduce multicultural issues in the form of diversity-based conflicts in values, norms and identities. The focus of the review is in the religious orientation and in the examination of the backgrounds of ethnic groups. The research method is the thorough examination of the texts and commenting of the literature of TH Marshall and Talcott Parson, based on which I build my own argumentation and interpretation. As research findings I propose that especially the late works of Talcott Parsons offer analytical tools to study societal pluralism in a way that gives fruitful basis also to the thinking of the 21st century researchers. Parsons s analytical frames of reference form relevant starting points in relation with the social analyses that are made based on inclusion and exclusion. Parsons describes the societal community as differentiated and segmented network, in which different customs and operation models are accepted. Cultural understanding differentiates how and in which context these will be applied. In the conditions of open systems culture can, however, not operate as a connector of the variations of actors neither as a common code that fades away conflicts. Parsons s thinking opens a view into the multicultural world, which is a world society and which consists of ethnic groups that are not internally monolithic but instead in a status of constant cultural redefinition. Individuals and groups are differentiated based on sex, age, different capacities, place of residence, belonging into different collectivities, etc. The late works of Talcott Parsons provide a realistic and an effective, theoretical framework for research of citizenship problems in multicultural conditions. Keywords: citizenship, societal community, society, community, religion, ethnic background, inclusion, exclusion, values and norms.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Power Optimal Network-on-Chip Interconnect Design

A large part of today's multi-core chips is interconnect. Increasing communication complexity has made essential new strategies for interconnects, such as Network on Chip. Power dissipation in interconnects has become a substantial part of the total power dissipation. Techniques to reduce interconnect power have thus become a necessity. In this paper, we present a design methodology that gives values of bus width for interconnect links, frequency of operation for routers, in Network on Chip scenario that satisfy required throughput and dissipate minimal switching power. We develop closed form analytical expressions for the power dissipation, with bus width and frequency as variables and then use Lagrange multiplier method to arrive at the optimal values. We present a 4 port router in 90 nm technology library as case study. The results obtained from analysis are discussed.

Generic Routing Rules and a Scalable Access Enhancement for the Network-on-Chip RECONNECT

RECONNECT is a Network-on-Chip using a honeycomb topology. In this paper we focus on properties of general rules applicable to a variety of routing algorithms for the NoC which take into account the missing links of the honeycomb topology when compared to a mesh. We also extend the original proposal [5] and show a method to insert and extract data to and from the network. Access Routers at the boundary of the execution fabric establish connections to multiple periphery modules and create a torus to decrease the node distances. Our approach is scalable and ensures homogeneity among the compute elements in the NoC. We synthesized and evaluated the proposed enhancement in terms of power dissipation and area. Our results indicate that the impact of necessary alterations to the fabric is negligible and effects the data transfer between the fabric and the periphery only marginally.

An improved representation of vehicle incompatibility in frontal NCAP tests using a modified rigid barrier

With the objective of better understanding the significance of New Car Assessment Program (NCAP) tests conducted by the National Highway Traffic Safety Administration (NHTSA), head-on collisions between two identical cars of different sizes and between cars and a pickup truck are studied in the present paper using LS-DYNA models. Available finite element models of a compact car (Dodge Neon), midsize car (Dodge Intrepid), and pickup truck (Chevrolet C1500) are first improved and validated by comparing theanalysis-based vehicle deceleration pulses against corresponding NCAP crash test histories reported by NHTSA. In confirmation of prevalent perception, simulation-bascd results indicate that an NCAP test against a rigid barrier is a good representation of a collision between two similar cars approaching each other at a speed of 56.3 kmph (35 mph) both in terms of peak deceleration and intrusions. However, analyses carried out for collisions between two incompatible vehicles, such as an Intrepid or Neon against a C1500, point to the inability of the NCAP tests in representing the substantially higher intrusions in the front upper regions experienced by the cars, although peak decelerations in cars arc comparable to those observed in NCAP tests. In an attempt to improve the capability of a front NCAP test to better represent real-world crashes between incompatible vehicles, i.e., ones with contrasting ride height and lower body stiffness, two modified rigid barriers are studied. One of these barriers, which is of stepped geometry with a curved front face, leads to significantly improved correlation of intrusions in the upper regions of cars with respect to those yielded in the simulation of collisions between incompatible vehicles, together with the yielding of similar vehicle peak decelerations obtained in NCAP tests.

Immunomodulation using agonists and antagonists: potential clinical applications

Introduction: Extensive studies have gone into understanding the differential role of the innate and adaptive arms of the immune system in the context of various diseases. Receptor-ligand interactions are responsible for mediating cross-talk between the innate and adaptive arms of the immune system, so as to effectively counter the pathogenic challenge. While TLRs remain the best studied innate immune receptor, many other receptor families are now coming to the fore for their role in various pathologies. Research has focused on the discovery of novel agonists and antagonists for these receptors as potential therapeutics. Areas covered: In this review, we present an overview of the recent advances in the discovery of drugs targeting important receptors such as G-protein coupled receptors, TRAIL-R, IL-1 beta receptor, PPARs, etc. All these receptors play a critical role in the modulation of the immune response. We focus on the recent paradigms applied for the generation of specific and effective therapeutics for these receptors and their status in clinical trials. Expert opinion: Non-specific activation by antagonist/agonist is a difficult problem to dodge. This demands innovation in ligand designing with the use of strategies such as allosterism and dual-specific ligands. Rigorous preclinical and clinical studies are required in transforming a compound to a therapeutic.

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve `health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.