bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of peptide–major histocompatibility complex tetramers and dextramers for the identification of antigen-specific T cells
Authors: Dolton G , Lissina A , Skowera A , Ladell K , Tungatt K , Jones E , Kronenberg-Versteeg D , Akpovwa H , Pentier J M , Holland C J , Godkin A J , Cole D K , Neller M A , Miles J J , Price D A , Peakman M , Sewell A K 
Published: March 2014

SummaryFluorochrome-conjugated peptide–major histocompatibility complex (pMHC) multimers are widely used for flow cytometric visualization of antigen-specific T cells. The most common multimers, streptavidin–biotin-based ‘tetramers’, can be manufactured readily in the laboratory. Unfortunately, there are large differences between the threshold of T cell receptor (TCR) affinity required to capture pMHC tetramers from solution and that which is required for T cell activation. This disparity means that tetramers sometimes fail to stain antigen-specific T cells within a sample, an issue that is particularly problematic when staining tumour-specific, autoimmune or MHC class II-restricted T cells, which often display TCRs of low affinity for pMHC. Here, we compared optimized staining with tetramers and dextramers (dextran-based multimers), with the latter carrying greater numbers of both pMHC and fluorochrome per molecule. Most notably, we find that: (i) dextramers stain more brightly than tetramers; (ii) dextramers outperform tetramers when TCR–pMHC affinity is low; (iii) dextramers outperform tetramers with pMHC class II reagents where there is an absence of co-receptor stabilization; and (iv) dextramer sensitivity is enhanced further by specific protein kinase inhibition. Dextramers are compatible with current state-of-the-art flow cytometry platforms and will probably find particular utility in the fields of autoimmunity and cancer immunology.
A gluten-free diet lowers NKG2D and ligand expression in BALB/c and non-obese diabetic (NOD) mice
Authors: Adlercreutz E H , Weile C , Larsen J , Engkilde K , Agardh D , Buschard K , Antvorskov J C 
Published: March 2014

SummaryThe interplay between diet and immune parameters which could affect type 1 diabetes (T1D) pathogenesis is not sufficiently clarified. Intestinal up-regulation of the activating receptor natural killer group 2D (NKG2D) (CD314) and its ligands is a hallmark of coeliac disease. However, the direct effect of gluten on NKG2D expression is not known. We studied, by fluorescence activated cell sorter (lymphoid tissues) and reverse transcription–quantitative polymerase chain reaction (intestine and pancreatic islets), if a gluten-free diet (GF diet) from 4 weeks of age or a gluten-free diet introduced in breeding pairs (SGF diet), induced changes in NKG2D expression on DX5+(CD49b) natural killer (NK) cells, CD8+T cells and in intestinal and islet levels of NKG2D and ligands in BALB/c and non-obese diabetic (NOD) mice. Gluten-free NOD mice had lower insulitis (P &lt; 0·0001); reduced expression of NKG2D on DX5+NK cells in spleen and auricular lymph nodes (P &lt; 0·05); and on CD8+T cells in pancreas-associated lymph nodes (P = 0·04). Moreover, the level of CD71 on DX5+NK cells and CD8+T cells (P &lt; 0·005) was markedly reduced. GF and SGF mice had reduced expression of NKG2D and DX5 mRNA in intestine (P &lt; 0·05). Differences in intestinal mRNA expression were found in mice at 8, 13 and 20 weeks. Intestinal expression of NKG2D ligands was reduced in SGF mice with lower expression of all ligands. In isolated islets, a SGF diet induced a higher expression of specific NKG2D ligands. Our data show that a gluten-free diet reduces the level of NKG2D and the expression of NKG2D ligands. These immunological changes may contribute to the lower T1D incidence associated with a gluten-free diet.
Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren's syndrome
Authors: Aqrawi L A , Kvarnström M , Brokstad K A , Jonsson R , Skarstein K , Wahren-Herlenius M 
Published: March 2014

SummaryRo52 is an E3 ubiquitin ligase with a prominent regulatory role in inflammation. The protein is a common target of circulating autoantibodies in rheumatic autoimmune diseases, particularly Sjögren's syndrome (SS). In this study we aimed to investigate the expression of the SS target autoantigen Ro52 in salivary glands of patients with primary Sjögren's syndrome (pSS). Ro52 expression was assessed by immunohistochemical staining of paraffin-embedded and frozen salivary gland biopsies from 28 pSS patients and 19 non-pSS controls from Swedish and Norwegian registries, using anti-human Ro52 monoclonal antibodies. The degree and pattern of staining and inflammation was then evaluated. Furthermore, secreted Ro52 protein was measured in saliva and serum samples from the same individuals through a catch-enzyme-linked immunosorbent assay (ELISA). Ro52 was highly expressed in all the focal infiltrates in pSS patients. Interestingly, a significantly higher degree of Ro52 expression in ductal epithelium was observed in the patients compared to the non-pSS controls (P &lt; 0·03). Moreover, the degree of ductal epithelial expression of Ro52 correlated with the level of inflammation (Spearman's r = 0·48, P &lt; 0·0120). However, no secreted Ro52 protein could be detected in serum and saliva samples of these subjects. Ro52 expression in ductal epithelium coincides with degree of inflammation and is up-regulated in pSS patients. High expression of Ro52 might result in the breakage of tolerance and generation of Ro52 autoantibodies in genetically susceptible individuals. We conclude that the up-regulation of Ro52 in ductal epithelium might be a triggering factor for disease progression in SS.
Influence of Vertical Soft Tissue Thickness on Crestal Bone Changes Around Implants with Platform Switching: A Comparative Clinical Study
Authors: Linkevicius Tomas , Puisys Algirdas , Steigmann Marius , Vindasiute Egle , Linkeviciene Laura 
Published: March 2014

AbstractBackgroundNumerous studies have shown the superiority of platform‐switched implants in preserving crestal bone as compared with platform‐matched implants. However, the influence of initial soft tissue thickness on development of crestal bone loss has not been addressed in previous studies; thus, further research is needed.PurposeTo evaluate crestal bone levels around platform‐switched implants placed in thin and thick mucosal tissue.Materials and MethodsEighty patients (38 male and 42 female, mean age 44 ± 3.34 years) received 80 bone‐level implants of 4.1 mm in diameter with platform switching (Institut Straumann AG, Basel, Switzerland). Tissue thickness was measured, and cases were distributed to Group 1, with thin soft tissue (2 mm or less, n = 40), and Group 2, with thick tissue (more than 2 mm, n = 40). Implants were placed with a one‐stage approach and restored with screw‐retained restorations. Radiographic examination was performed after implant placement, 2 months after healing, after restoration, and at 1‐year follow‐up post‐reconstruction. Crestal bone loss was calculated. The Mann‐Whitney U‐test was applied, and significance was set to p ≤ .05.ResultsImplants in Group 1 (thin tissue) showed 0.79 mm of bone loss after 2 months. After 1‐year follow‐up, bone loss was 1.17 mm. Implants in Group 2 (thick tissue) showed bone loss of 0.17 mm after 2 months of implant placement and 0.21 mm after 1‐year follow‐up. The differences between groups were significant (p < .001) at both time points.ConclusionsIt can be concluded that platform switching does not prevent crestal bone loss if, at the time of implant placement, mucosal tissue is thin. In thick soft tissue, use of platform‐switched implants maintained crestal bone level with minimal remodeling.
Identifying conservation units after large‐scale land clearing: a spatio‐temporal molecular survey of endangered white‐tailed black cockatoos (Calyptorhynchus spp.)
Authors: White Nicole E. , Bunce Michael , Mawson Peter R. , Dawson Rick , Saunders Denis A. , Allentoft Morten E. 
Published: March 2014

AbstractAimWe examined how the threatened and endemic white‐tailed black cockatoos of Western Australia have responded genetically to recent and comprehensive habitat loss with the ultimate aim of identifying units for conservation. We assessed the population structure, connectivity and genetic diversity at spatial and temporal scales for Calyptorhynchus baudinii and C. latirostris, which have undergone dramatic population declines. Genetic comparisons of pre‐ and post‐population decline were carried out by including historical samples dating back to 1920. We examined samples collected from across 700 km of their distribution and sampled approximately 1% of the current population census size to produce significant insights into the population genetics of white‐tailed black cockatoos and generate genetic information crucial for conservation management.LocationSouthwest corner of Western Australia.MethodsSix hundred and eighty‐four cockatoo samples were collected from 1920 to 2010 and profiled with 19 microsatellites to identify spatial population structure and loss of genetic diversity.ResultsThe temporal and spatial microsatellite data illustrated that the geographically defined genetic structuring in white‐tailed black cockatoos is likely to represent a recent phenomenon. We identified: (1) spatial population substructure east and west of extensively cleared habitat (>95,800 km2), but the historical samples clustered with the current western population, regardless of origin, (2) a regional loss of allelic diversity over 3–4 generations for the current eastern population, (3) a lack of a genetic signal of the recent population decline, but perhaps a mid‐Holocene population collapse and lastly, (4) limited genetic differentiation between the two currently recognized white‐tailed black‐cockatoo species suggests a review of taxonomy and/or management units should be undertaken.Main conclusionBased on extensive spatio‐temporal sampling, we have demonstrated that recent anthropogenic habitat modifications have affected the genetic structure of a long‐lived and highly mobile species. Our results have identified areas of high conservation value and the importance of maintaining native vegetation migration corridors.
Antifungal properties of terpenoids in Picea abies against Heterobasidion parviporum
Authors: Kusumoto N. , Zhao T. , Swedjemark G. , Ashitani T. , Takahashi K. , Borg‐Karlson A.‐K. 
Published: March 2014

SummaryThe antifungal properties of 14 major oleoresin‐constitutive terpenoids of Norway spruce (Picea abies) against Heterobasidion parviporum were evaluated in vitro at three gradient concentrations, 0.1, 0.2 and 0.4 μmol/cm2, on potato dextrose agar medium. Eight monoterpene hydrocarbons (+)‐ and (−)‐α‐pinene, (−)‐β‐pinene, (+)‐3‐carene, myrcene, (+)‐ and (−)‐limonene, terpinolene; four oxygenated monoterpenes α‐terpineol, terpinen‐4‐ol, 1,8‐cineole, bornyl acetate; and two resin acids abietic acid and dehydroabietic acid were selected. Abietic and dehydroabietic acids showed the highest antifungal activities at all concentrations. Among oxygenated monoterpenes, bornyl acetate and α‐terpineol showed antifungal activity at the highest concentration. Among monoterpene hydrocarbons, (+)‐α‐pinene showed similar activity to terpinen‐4‐ol and 1,8‐cineole at the highest concentration; however, it was lower than α‐terpineol and bornyl acetate. Other monoterpene hydrocarbons inhibited mycelial growth by <10%. Re‐extraction of medium surfaces after the test period revealed that most α‐terpineol and terpinen‐4‐ol remained unchanged on the surface but monoterpene hydrocarbons completely disappeared. However, notable fungal transformed products were observed on surfaces applied with 1,8‐cineole and bornyl acetate. Thus, mycelial growth inhibition of monoterpenoids might be caused by complex functions such as biodegradation and/or detoxification by interaction between mycelium and compound. These results provide a basis for future studies considering the role of chemodiversity in the comprehensive chemical defence of P. abies.
Resistance and tolerance in juvenile interior Douglas‐fir trees Pseudotsuga menziesii var. glauca artificially inoculated with Armillaria ostoyae
Authors: Cruickshank M. G. , Jaquish B. 
Published: March 2014

SummaryPlants utilize two general strategies to cope with pathogen attack. They either limit or resist the pathogen (termed ‘resistance’) or they cope with the disease by surviving and growing (termed ‘tolerance’). Both strategies tend to increase plant fitness; however, there are possible costs, trade‐offs and interactions associated with each strategy. This study focused on five half‐sib interior Douglas‐fir families [Pseudotsuga menziesii var. glauca (Beissn.) Franco] that were putatively classified as either resistant or susceptible to Armillaria ostoyae in a previous greenhouse study of seedling families challenged with A. ostoyae. We compared their survival rates in the greenhouse study with results of juvenile trees from the same five families that were artificially inoculated in field conditions. Both resistance and tolerance appeared to be operating in the field test trees, and a possible trade‐off between resistance and tolerance was detected. Significant differences were detected among the five families for stem radial growth following infection at the tree root collar. Compared with the putatively susceptible families, resistant families had smaller lesions and lower proportional root collar girdling. Tolerant families generally had larger lesions but demonstrated better growth when diseased than resistant families. One tolerant family that was a good survivor in the greenhouse survival study presented vertically shaped lesions that were large in area but had greatly reduced proportional root collar girdling. While a second family showed tolerant traits in the field study, its poor survival in the greenhouse study agreed with the large horizontally spreading lesions associated with high root collar girdling in the field study trees. Survival rankings of the five families in the greenhouse study mostly agreed with results from the field study based on the proportion of collar girdling among families. These host responses are discussed with respect to stability, quantity and quality of stands and products.
Novel nanosome delivery system combined with siRNA targeting the antimicrobial gene DFB4: a new approach for psoriasis management?
Authors: Keren Aviad , David Michael , Gilhar Amos 
Published: March 2014

AbstractIn a recently published issue of the journal, Bracke et al. demonstrate an impressive improvement in psoriasiform features in allogeneic human skin grafts transplanted onto immune‐deficient mice. This improvement was achieved using a novel nanosome (SECosome) as a vehicle for delivering topically applied siRNA to human epidermis. Targeting the gene DFB4 with this delivery system, they prevented translation of the antimicrobial peptide, human β defensin‐2(hBD2), thus normalizing the psoriasiform epidermal phenotype of siRNA/SECosome‐treated human skin grafts. This study encourages the exploration of topical gene silencing strategies in dermatology and refocuses our attention on both, the role of hBD2 in psoriasis pathogenesis and the thorny question which animal model reflects human psoriasis most faithfully.
A transgenic zebrafish model for monitoring glucocorticoid receptor activity
Authors: Krug R. G. , Poshusta T. L. , Skuster K. J. , Berg M. R. , Gardner S. L. , Clark K. J. 
Published: March 2014

AbstractGene regulation resulting from glucocorticoid receptor and glucocorticoid response element interactions is a hallmark feature of stress response signaling. Imbalanced glucocorticoid production and glucocorticoid receptor activity have been linked to socioeconomically crippling neuropsychiatric disorders, and accordingly there is a need to developin vivomodels to help understand disease progression and management. Therefore, we developed the transgenicSR4Gzebrafish reporter line with six glucocorticoid response elements used to promote expression of a short half‐life green fluorescent protein following glucocorticoid receptor activation. Herein, we document the ability of this reporter line to respond to both chronic and acute exogenous glucocorticoid treatment. The green fluorescent protein expression in response to transgene activation was high in a variety of tissues including the brain, and provided single‐cell resolution in the effected regions. The specificity of these responses is demonstrated using the partial agonist mifepristone and mutation of the glucocorticoid receptor. Importantly, the reporter line also modeled the temporal dynamics of endogenous stress response signaling, including the increased production of the glucocorticoid cortisol following hyperosmotic stress and the fluctuations of basal cortisol concentrations with the circadian rhythm. Taken together, these results characterize our newly developed reporter line for elucidating environmental or genetic modifiers of stress response signaling, which may provide insights to the neuronal mechanisms underlying neuropsychiatric disorders such as major depressive disorder.
Robbins and Advanced Further Education
Authors: Parry Gareth 
Published: March 2014

AbstractIn appraising existing patterns and assessing future needs, the Robbins inquiry broke new ground in treating British higher education as a system. In so doing, it went beyond its terms of reference to consider the situation of part‐time higher education. This brought into view the scale, scope and character of provision and participation in the further education sector of higher education. While the need to focus its thinking and recommendations on full‐time courses was never in doubt, the inquiry insisted that central policy decisions take account of all sectors of higher education and that sources of evidence be comprehensive in range and reach.
Student Numbers and Funding: Does Robbins Add Up?
Authors: Callender Claire 
Published: March 2014

AbstractThis article explores how the Robbins Report's recommendations for a massive expansion in higher education alongside a comprehensive system of student financial support, both financed by the public purse, came about and were translated into policy. It argues that these policies, including the Robbins principle, the desire for expanding educational opportunities plus the Reports' emphasis upon the public and social benefits of higher education, can only be understood within the context of the Welfare State and the values and ideas enshrined in its post‐war development. In addition, the article examines some of the Robbins Reports' projections about the number of student places demanded and compares these with the actual number of students enrolled, highlighting the changes in the composition of the student body overtime. It concludes by exploring issues concerning student funding and highlights the shifts in thinking about the role of higher education, who benefits and so who pays; changes associated with the end of the post‐war consensus about the Welfare State.
Remembering Robbins: Context and Process
Authors: Shattock Michael 
Published: March 2014

AbstractThe Robbins Report was the most deeply researched and most highly regarded report ever written on British higher education. By common consent at the time it marked a watershed in the development of higher education in Britain and took its place as one of the most influential contributions to the growth of British society since Beveridge. However, some of its most important recommendations were not accepted and for nearly 30 years the pattern of development that it proposed was in abeyance. This article describes the context of the establishment of the Robbins Committee, considers the processes that it followed in reaching its conclusions and offers an account of why some key recommendations were rejected. The article is intended to provide an historical introduction to the articles in this special issue of the journal.
Timing and intensity of exposure to interferon‐γ critically determines the function of monocyte‐derived dendritic cells
Authors: Kerkar Sid P. , Chinnasamy Dhanalakshmi , Hadi Neima , Melenhorst Jan , Muranski Pawel , Spyridonidis Alexandros , Ito Sawa , Weber Gerrit , Yin Fang , Hensel Nancy , Wang Ena , Marincola Francesco M. , Barrett Austin John 
Published: March 2014

SummaryA growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects of interferon‐γ (IFN‐γ) on the differentiation and maturation of human peripheral blood monocyte‐derived dendritic cells (moDC). Here, we report that following differentiation of monocytes into moDC with granulocyte–macrophage colony‐stimulating factor and interleukin‐4, IFN‐γ induces moDC maturation and up‐regulates the co‐stimulatory markers CD80/CD86/CD95 and MHC Class I, enabling moDC to effectively generate antigen‐specific CD4+ and CD8+ T‐cell responses for multiple viral and tumour antigens. Early exposure of monocytes to high concentrations of IFN‐γ during differentiation promotes the formation of macrophages. However, under low concentrations of IFN‐γ, monocytes continue to differentiate into dendritic cells possessing a unique gene‐expression profile, resulting in impairments in subsequent maturation by IFN‐γ or lipopolysaccharide and an inability to generate effective antigen‐specific CD4+ and CD8+ T‐cell responses. These findings demonstrate that IFN‐γ imparts differential programmes on moDC that shape the antigen‐specific T‐cell responses they induce. Timing and intensity of exposure to IFN‐γ can therefore determine the functional capacity of moDC.
CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model
Authors: Oghumu Steve , Varikuti Sanjay , Terrazas Cesar , Kotov Dmitri , Nasser Mohd W. , Powell Catherine A. , Ganju Ramesh K. , Satoskar Abhay R. 
Published: March 2014

SummaryTumor associated macrophages play a vital role in determining the outcome of breast cancer. We investigated the contribution of the chemokine receptor CXCR3 to antitumor immune responses using a cxcr3 deficient mouse orthotopically injected with a PyMT breast cancer cell line. We observed that cxcr3 deficient mice displayed increased IL‐4 production and M2 polarization in the tumors and spleens compared to WT mice injected with PyMT cells. This was accompanied by larger tumor development in cxcr3−/− than in WT mice. Further, tumor‐promoting myeloid derived immune cell populations accumulated in higher proportions in the spleens of cxcr3 deficient mice. Interestingly, cxcr3−/− macrophages displayed a deficiency in up‐regulating inducible nitric oxide synthase after stimulation by either IFN‐γ or PyMT supernatants. Stimulation of bone marrow derived macrophages by PyMT supernatants also resulted in greater induction of arginase‐1 in cxcr3−/− than WT mice. Further, cxcr3−/− T cells activated with CD3/CD28 in vitro produced greater amounts of IL‐4 and IL‐10 than T cells from WT mice. Our data suggests that a greater predisposition of cxcr3 deficient macrophages towards M2 polarization contributes to an enhanced tumor promoting environment in cxcr3 deficient mice. Although CXCR3 is known to be expressed on some macrophages, this is the first report that demonstrates a role for CXCR3 in macrophage polarization and subsequent breast tumor outcomes. Targeting CXCR3 could be a potential therapeutic approach in the management of breast cancer tumors.