The Incidence of Type-1 Diabetes in NOD Mice Is Modulated by Restricted Flora Not Germ-Free Conditions

In the NOD mouse, the incidence of type-1 diabetes is thought to be influenced by the degree of cleanliness of the mouse colony. Studies collectively demonstrate that exposure to bacterial antigen or infection in the neonatal period prevents diabetes [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], supporting the notion that immunostimulation can benefit the maturation of the postnatal immune system [11]. A widely accepted extrapolation from this data has been the notion that NOD mice maintained under germ-free conditions have an increased incidence of diabetes. However, evidence supporting this influential concept is surprisingly limited [12]. In this study, we demonstrate that the incidence of diabetes in female NOD mice remained unchanged under germ-free conditions. By contrast, a spontaneous monoculture with a gram-positive aerobic spore-forming rod delayed the onset and reduced the incidence of diabetes. These findings challenge the view that germ-free NOD mice have increased diabetes incidence and demonstrate that modulation of intestinal microbiota can prevent the development of type-1 diabetes

Interleukin-21 Is Critically Required in Autoimmune and Allogeneic Responses to Islet Tissue in Murine Models

OBJECTIVE-Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. RESEARCH DESIGN AND METHODS-NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed. RESULTS-Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. CONCLUSIONS-Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes. Diabetes 60:867-875, 20111151sciescopu

Audio versus written feedback: exploring learners’ preference and the impact of feedback format on students’ academic performance

Very little is known about the impact of the different types of feedback on students’ academic performance. This paper explores students’ preference in the use of audio and written feedback and how each type of feedback received by students impact on their academic performance in subsequent assignments. The study involved 68 students who were divided into two groups that received either audio or written feedback in their first assignment which was then recalled and applied into the second assignment. An analysis of results obtained in the second assignment was conducted and comparisons made between students in the audio and written feedback group. Students were also surveyed using an online questionnaire to ascertain their perceptions about the type of feedback they had received. The study established that the type of feedback received did not impact on students’ grades in the subsequent assignment. In addition, while students were broadly positive about audio feedback, they indicated a strong preference for written feedback in future assignments. The study recommends, among other things, further investigation into the link between students’ learning styles and their preferences for different types of feedback

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation

RNA-seq and ChIP-seq Identification of Unique and Overlapping Targets of GLI Transcription Factors in Melanoma Cell Lines

Background: Despite significant progress in therapy, melanoma still has a rising incidence worldwide, and novel treatment strategies are needed. Recently, researchers have recognized the involvement of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and its consistent crosstalk with the MAPK pathway. In order to further investigate the link between the two pathways and to find new target genes that could be considered for combination therapy, we set out to find transcriptional targets of all three GLI proteins in melanoma. Methods: We performed RNA sequencing on three melanoma cell lines (CHL-1, A375, and MEL224) with overexpressed GLI1, GLI2, and GLI3 and combined them with the results of ChIP-sequencing on endogenous GLI1, GLI2, and GLI3 proteins. After combining these results, 21 targets were selected for validation by qPCR. Results: RNA-seq revealed a total of 808 differentially expressed genes (DEGs) for GLI1, 941 DEGs for GLI2, and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. A total of 15 of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq. Conclusions: Our study provides insight into the unique and overlapping transcriptional output of the GLI proteins in melanoma. We suggest that our findings could provide new potential targets to consider while designing melanoma-targeted therapy

Exploiting the ANN Potential in Estimating Snow Depth and Snow Water Equivalent From the Airborne SnowSAR Data at X- and Ku-Bands

Within the framework of European Space Agency (ESA) activities, several campaigns were carried out in the last decade with the purpose of exploiting the capabilities of multifrequency synthetic aperture radar (SAR) data to retrieve snow information. This article presents the results obtained from the ESA SnowSAR airborne campaigns, carried out between 2011 and 2013 on boreal forest, tundra and alpine environments, selected as representative of different snow regimes. The aim of this study was to assess the capability of X- and Ku-bands SAR in retrieving the snow parameters, namely snow depth (SD) and snow water equivalent (SWE). The retrieval was based on machine learning (ML) techniques and, in particular, of artificial neural networks (ANNs). ANNs have been selected among other ML approaches since they are capable to offer a good compromise between retrieval accuracy and computational cost. Two approaches were evaluated, the first based on the experimental data (data driven) and the second based on data simulated by the dense medium radiative transfer (DMRT). The data driven algorithm was trained on half of the SnowSAR dataset and validated on the remaining half. The validation resulted in a correlation coefficient R ≃ 0.77 between estimated and target SD, a root-mean-square error (RMSE) ≃ 13 cm, and bias = 0.03 cm. ANN algorithms specific for each test site were also implemented, obtaining more accurate results, and the robustness of the data driven approach was evaluated over time and space. The algorithm trained with DMRT simulations and tested on the experimental dataset was able to estimate the target parameter (SWE in this case) with R = 0.74, RMSE = 34.8 mm, and bias = 1.8 mm. The model driven approach had the twofold advantage of reducing the amount of in situ data required for training the algorithm and of extending the algorithm exportability to other test sites

Introducing a new breed of wine yeast: interspecific hybridisation between a commercial Saccharomyces cerevisiae wine yeast and Saccharomyces mikatae

Interspecific hybrids are commonplace in agriculture and horticulture; bread wheat and grapefruit are but two examples. The benefits derived from interspecific hybridisation include the potential of generating advantageous transgressive phenotypes. This paper describes the generation of a new breed of wine yeast by interspecific hybridisation between a commercial Saccharomyces cerevisiae wine yeast strain and Saccharomyces mikatae, a species hitherto not associated with industrial fermentation environs. While commercially available wine yeast strains provide consistent and reliable fermentations, wines produced using single inocula are thought to lack the sensory complexity and rounded palate structure obtained from spontaneous fermentations. In contrast, interspecific yeast hybrids have the potential to deliver increased complexity to wine sensory properties and alternative wine styles through the formation of novel, and wider ranging, yeast volatile fermentation metabolite profiles, whilst maintaining the robustness of the wine yeast parent. Screening of newly generated hybrids from a cross between a S. cerevisiae wine yeast and S. mikatae (closely-related but ecologically distant members of the Saccharomyces sensu stricto clade), has identified progeny with robust fermentation properties and winemaking potential. Chemical analysis showed that, relative to the S. cerevisiae wine yeast parent, hybrids produced wines with different concentrations of volatile metabolites that are known to contribute to wine flavour and aroma, including flavour compounds associated with non-Saccharomyces species. The new S. cerevisiae x S. mikatae hybrids have the potential to produce complex wines akin to products of spontaneous fermentation while giving winemakers the safeguard of an inoculated ferment.Jennifer R. Bellon, Frank Schmid, Dimitra L. Capone, Barbara L. Dunn, Paul J. Chamber

Multiple mantle upwellings in the transition zone beneath the northern East-African Rift system from relative P-wave travel-time tomography

Mantle plumes and consequent plate extension have been invoked as the likely cause of East African Rift volcanism. However, the nature of mantle upwelling is debated, with proposed configurations ranging from a single broad plume connected to the large low-shear-velocity province beneath Southern Africa, the so-called African Superplume, to multiple lower-mantle sources along the rift. We present a new P-wave travel-time tomography model below the northern East-African, Red Sea, and Gulf of Aden rifts and surrounding areas. Data are from stations that span an area from Madagascar to Saudi Arabia. The aperture of the integrated data set allows us to image structures of 100 km length-scale down to depths of 700– 800 km beneath the study region. Our images provide evidence of two clusters of low-velocity structures consisting of features with diameter of 100–200 km that extend through the transition zone, the first beneath Afar and a second just west of the Main Ethiopian Rift, a region with off-rift volcanism. Considering seismic sensitivity to temperature, we interpret these features as upwellings with excess temperatures of 100 6 50 K. The scale of the upwellings is smaller than expected for lower mantle plume sources. This, together with the change in pattern of the low-velocity anomalies across the base of the transition zone, suggests that ponding or flow of deep-plume material below the transition zone may be spawning these upper mantle upwellings