Granzyme A Required for Regulatory T-Cell Mediated Prevention of Gastrointestinal Graft-versus-Host Disease

In our previous work we could identify defects in human regulatory T cells (Tregs) likely favoring the development of graft-versus-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA) also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS- FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model

Pathways to passenger resilience during rural transport disruption: A conceptual model development

This paper defines the concept of disruption in travel and transportation, specifically in the rural context. Resilience is introduced as a theoretical tool to model individual and community development in times of change and disruption. Various resilience characteristics that influence passengers during disruptions are identified. A conceptual model - which links passenger behaviour characteristics, identified from expert studies with community resilience characteristics - to identify possible pathways to enhancing passenger resilience is developed. The resilience characteristics presented in the model are formulated and evaluated from existing resilience literature, 60 interviews with passengers and rural dwellers in Scottish borders and rural Lancashire, and consultation and brainstorming discussion within a research group. The developed model can provide a better understanding of resilience in the context of transportation disruption and uncertainty. It can also identify new technology options to lessen disruption impacts; decrease recovery times; and provide transport service planning during disruption

Novel associations for hypothyroidism include known autoimmune risk loci

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the first large genome-wide association study of hypothyroidism, in 2,564 cases and 24,448 controls from the customer base of 23andMe, Inc., a personal genetics company. We identify four genome-wide significant associations, two of which are well known to be involved with a large spectrum of autoimmune diseases: rs6679677 near _PTPN22_ and rs3184504 in _SH2B3_ (p-values 3.5e-13 and 3.0e-11, respectively). We also report associations with rs4915077 near _VAV3_ (p-value 8.3e-11), another gene involved in immune function, and rs965513 near _FOXE1_ (p-value 3.1e-14). Of these, the association with _PTPN22_ confirms a recent small candidate gene study, and _FOXE1_ was previously known to be associated with thyroid-stimulating hormone (TSH) levels. Although _SH2B3_ has been previously linked with a number of autoimmune diseases, this is the first report of its association with thyroid disease. The _VAV3_ association is novel. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the four genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.1

Thermomechanical modelling of laser surface glazing for H13 tool steel

A two-dimensional thermomechanical finite element (FE) model of laser surface glazing (LSG) has been developed for H13 tool steel. The direct coupling technique of ANSYS 17.2 (APDL) has been utilised to solve the transient thermomechanical process. A H13 tool steel cylindrical cross-section has been modelled for laser power 200 W and 300 W at constant 0.2 mm beam width and 0.15 ms residence time. The model can predict temperature distribution, stress–strain increments in elastic and plastic region with time and space. The crack formation tendency also can be assumed by analysing the von Mises stress in the heat-concentrated zone. Isotropic and kinematic hardening models have been applied separately to predict the after-yield phenomena. At 200 W laser power, the peak surface temperature achieved is 1520 K which is below the melting point (1727 K) of H13 tool steel. For laser power 300 W, the peak surface temperature is 2523 K. Tensile residual stresses on surface have been found after cooling, which are in agreement with literature. Isotropic model shows higher residual stress that increases with laser power. Conversely, kinematic model gives lower residual stress which decreases with laser power. Therefore, both plasticity models could work in LSG for H13 tool steel

The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

<p>Abstract</p> <p>Background</p> <p>The protein tyrosine phosphatase nonreceptor type 2 (<it>PTPN22</it>) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA_1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes.</p> <p>Methods</p> <p>The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA_1cand daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset.</p> <p>Results</p> <p>A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between <it>PTPN22 </it>and proinsulin (est.: 1.28, p = 0.03).</p> <p>Conclusions</p> <p>The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.</p

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations

Modelling and analysis of sustainable freight transportation

This is an editorial

Development of a Map-Matching Algorithm for Rural Passenger Information Systems through Mobile Phones and Crowd Sourcing

In this research, a passenger-centric passenger information system is proposed, which uses crowd sourcing and mobile phones so that passengers are not only information consumers but are also providers of information to the system. Passengers can allow the system to track their location through their smart phones when they are traveling on public transportation; this will compensate for the lack of a vehicle tracking system in public transportation, particularly in nonurban areas. Map-matching (MM) algorithms integrate location data (i.e.,latitude and longitude) obtained from positioning sensors (in this case, mobile GPS) with a digital geographic information system (GIS) road map. Any map-matching algorithm first identifies the road link on which a vehicle is traveling and then determines the vehicle's location on that road segment. In the proposed information system, at a given point of time, a number of vehicle locations (latitude and longitude) are received from passengers traveling on a bus. In order to provide a precise vehicle location at a given point of time, a novel map-matching algorithm using fuzzy logic, which integrates multiple vehicle locations (obtained from passenger's smart phones) with a GIS road map, has been developed. The developed map-matching algorithm was tested using real-world data collected on four different bus routes in Aberdeenshire, Scotland, and also GPS data collected in and around Nottingham, United Kingdom. It was identified that the developed MM algorithm is efficient and capable of supporting the proposed passenger information system. (C) 2013 American Society of Civil Engineers