bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of genetics in resistance to type 1 diabetes
Authors: Chen Jing , Gusdon Aaron M. , Mathews Clayton E. 
Published: November 2011

AbstractBackgroundA single nucleotide polymorphism in the mitochondrial gene encoding NADH dehydrogenase subunit 2 (mt‐ND2) has been associated with reduced incidence of human type 1 diabetes (T1D). We identified the orthologue of this mitochondrial single nucleotide polymorphism in mouse and using NOD mouse models linked this genetic polymorphism to T1D resistance. The mechanism how this single nucleotide polymorphism affects the development of diabetes is studied using mouse models and beta cell lines.MethodsThe impact of this single nucleotide polymorphism on mitochondrial function and resistance to reactive oxygen species was assessed. For these studies we measured oxygen consumption by isolated mitochondria under different doses of nitric oxide. In addition, alloxan sensitivity of beta cell lines was tested using the MTT method to measure cell survival.Resultsmt‐Nd2a is associated with protection against mouse T1D and alloxan‐induced diabetes. Mice with mt‐Nd2a exhibited resistance to transfer of diabetes by single clone of diabetogenic CD4+ or CD8+ T cells. Beta cell line with mt‐Nd2a resist in vitro attack of diabetogenic CD8+ cytotoxic T cells, as well as free radicals generated by alloxan; isolated mitochondria with mt‐Nd2a showed lower reactive oxygen species production and were more resistant to nitric oxide.Conclusionmt‐Nd2a protects against T1D in mouse models. The protection is at beta cell level and is associated with resistance against reactive oxygen species‐mediated damage and death. Copyright © 2011 John Wiley & Sons, Ltd.
Characterization of the regulatory roles of the SUMO
Authors: Hwang Kwang Woo , Won Tae Joon , Kim Hyunok , Chun Ha‐Jung , Chun Taehoon , Park Yongsoo 
Published: November 2011

AbstractBackgroundType 1 diabetes is a multi‐factorial autoimmune disease that results from the destruction of insulin‐producing β cells of the pancreas; both genetic and environmental factors are thought to contribute to its development. Recently, a novel gene encoding small ubiquitin‐like modifier protein 4 (SUMO4) was cloned and a single nucleotide substitution (M55V) was found to be strongly associated with type 1 diabetes. SUMO4 was shown to interact with IκBα and inhibit NFκB transcriptional activity. The M55V substitution of SUMO4 may affect its ability to modify IκBα by sumoylation, and so lead to activation of NFκB and transcription of genes implicated in the development of type 1 diabetes. However, the effects of sumoylation on immune cells are poorly understood.MethodsHuman SUMO1, 2, 3, 4 and mouse SUMO2 (mSUMO2) were cloned and overexpressed in dendritic, T and B cells using retroviral transduction. We then investigated whether SUMO overexpression affected their functions in vitro. To study the function of mSUMO2 in vivo, we made transgenic mice overexpressing mSUMO2 in T cells and pancreatic β cells and compared them with transgenic mice expressing a super‐repressor of NFκB (a dominant negative form of NFκB, IκBαΔN) in T cells. Diabetes was induced in the two groups of mice by i.p. injection of streptozotocin.ResultsHuman SUMO1, 2, 3, 4 and mSUMO2 were all found to negatively regulate the transcriptional activity of T, B and dendritic cells. Although mSUMO2 overexpression in dendritic cells did not alter the expression of major histocompatibility complex class II proteins or B7, IL‐1, IL‐6 and IL‐7, IL‐12 expression decreased, switching Th1‐directed immune responses into Th2 responses. Unlike T cells from the IκBαΔN mice, mSUMO2 overexpression in T cells suppressed the production of both Th1 and Th2 cytokines. Whereas the mice overexpressing IκBαΔN were completely protected against diabetes, those expressing mSUMO2 had the same susceptibility to diabetes as wild type.ConclusionThese results indicate that at least in T cells, whereas NFκB has pro‐apoptotic activity, mSUMO2 plays a more complex role in the development of autoimmune diabetes. The relative influence of NFκB and sumoylation on the development of autoimmune diabetes in vivo may vary depending on the developmental stage and cell type. Copyright © 2011 John Wiley & Sons, Ltd.
Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population
Authors: Park Yongsoo , Lee Hye‐Soon , Park Youngjoo , Min Dongsoo , Yang Seiwon , Kim Dukhee , Cho Boyoun 
Published: November 2011

AbstractBackgroundRecently, the association of a common STAT4 haplotype with type 1 diabetes (T1D) as well as rheumatoid arthritis has been documented in Caucasians and Koreans. STAT4 is involved in the signalling of interleukin‐12 and γIFN, as well as interleukin‐23. To discover genes affecting the susceptibility of common autoimmune diseases, we studied the association of polymorphisms in STAT4 with autoimmune thyroid disease (AITD) as well as T1D in the Korean population.Subjects and methodsFour single‐nucleotide polymorphisms on the chromosome 2q (rs11889341, rs7574865, rs8179673, and rs10181656), which were found to associate with rheumatoid arthritis were examined for association in a Korean sample of 428 AITD, 418 T1D patients, and 1060 controls.ResultsThe minor alleles of all four single‐nucleotide polymorphisms and the reconstructed STAT4 haplotypes conferred significant degree of risk for AITD (p = 10−2 to 10−4). Although we found a weak association of rs11889341 with T1D (p < 0.05), the same haplotypes were not associated with T1D susceptibility. When we stratified T1D patients according to the age of onset, the minor alleles of all four single‐nucleotide polymorphisms and the same haplotypes showed significant association with the susceptibility of T1D in the early‐onset subgroup (p < 0.01), not in the late‐onset subgroup.ConclusionSTAT4 alleles and the same haplotypes might influence cytokine signalling, and therefore the development of AITD as well as T1D. These results reinforce the influence of STAT4 gene as a general autoimmune gene. Copyright © 2011 John Wiley & Sons, Ltd.
Discordant association of islet autoantibodies with high‐risk HLA genes in Chinese type 1 diabetes
Authors: Gu Yong , Zhang Mei , Chen Heng , Wang Zhixiao , Xing Chunyan , Yang Hui , Xu Xinyu , Liu Yu , Zhou Zhiguang , Yu Liping , Hutton John , Eisenbarth George , Yang Tao 
Published: November 2011

AbstractBackgroundTo reveal the aetiology of diabetes, the relationships between the islet autoantibodies, human leukocyte antigen (HLA)‐A and DRB1 genotypes in the Chinese patients with type l diabetes (T1D) were investigated in our study.MethodsIn the cross‐sectional and case‐control study, peripheral blood samples were collected from 600 T1D patients and 102 healthy controls. The genetic polymorphisms of HLA‐A and DRB1 are examined with polymerase chain reaction‐sequence oligonucleotide probe method. The zinc transporter 8 antibody (ZnT8A), glutamic acid decarboxylase antibody (GADA) and protein‐tyrosine‐phosphatase‐2 autoantibody (IA2A) were detected by radioligand assay.ResultsThe A*2402, DRB1*0301, DRB1*0405 and DRB1*0901 alleles, and A*1101‐DRB1*0901, A*2402‐DRB1*0405 and A*2402‐DRB1*0901 haplotypes were associated with T1D (all p < 0.05). The positive rates of ZnT8A in patients carried DRB1*0901, IA2A in patients carried DRB1*0405 and A*1101‐DRB1*0901 and GADA in patients carried DRB1*0901 and A*2402‐DRB1*0901 were significantly higher than those not carried (p < 0.05). HLA‐DRB1*0901 was the independent risk factor of positive antibody in T1D patients. In addition, higher body mass index is also related with the loss of islet function besides high‐risk HLA gene and islet autoantibody (p < 0.05).ConclusionsThe discordant association of autoantibodies with high‐risk HLA gene may indicate the different immunology mechanisms of those autoantibodies. And metabolic burden resulting from overweight may accelerate apoptosis of beta cells. Copyright © 2011 John Wiley & Sons, Ltd.
Encapsulated pancreatic progenitors derived from human embryonic stem cells as a therapy for insulin‐dependent diabetes
Authors: Tuch Bernard E. , Hughes Timothy C. , Evans Margaret D. M. 
Published: November 2011

AbstractBackgroundCellular‐based therapies for insulin‐dependent diabetes are potential means of achieving and maintaining normal blood glucose levels (BGL) without the need for insulin administration. Islets isolated from donor pancreases have been the most common tissue used to date, but supply is a limiting factor. The use of human embryonic stem cells (hESC) as a therapy became a possibility with the report that these cells could be differentiated to pancreatic progenitors (PP) over 12 days in vitro. Conversion of PP to glucose‐responsive insulin‐secreting cells can be achieved by transplanting the progenitors in vivo where cell maturation occurs. To date this step has not been shown under in vitro conditions.MethodsPrior to transplanting, cells are encapsulated in alginate to prevent the immune cells of recipient attacking the graft. The alginate capsules have pores with a molecular weight cut‐off of 250 kDa. These are too small to allow entry of immune cells, but large enough for passage of nutrients and insulin.ResultsEncapsulated insulin‐producing cells survive and function when transplanted, and have been shown to normalize BGL when allografted into diabetic mice. As few as 750 encapsulated human islets are sufficient to normalize BGL of diabetic non‐obese diabetic severe combined immunodeficient (NOD/SCID) recipient mice for at least 2 months. The safety of transplanting encapsulated human islets as demonstrated by the lack of major adverse events and infection was recently shown in a first‐in‐human clinical trial. Finally, fetal porcine islet‐like cell clusters, which are akin to PP derived from ESC, mature and normalize BGL of diabetic recipient mice with the same efficiency as non‐encapsulated clusters placed under the kidney capsule.ConclusionTransplanting encapsulated PP, derived from hESCs, into diabetic recipients is the strategy that is now being explored in the Australia Diabetes Therapy Project. Copyright © 2011 John Wiley & Sons, Ltd.
MicroCT for molecular imaging: Quantitative visualization of complete three‐dimensional distributions of gene products in embryonic limbs
Authors: Metscher Brian D. , Müller Gerd B. 
Published: November 2011

AbstractMicroCT volume image of acetylated alpha‐tubulin immunostaining in a stage 23 chick embryo, immunostaining shown in yellow within the intact embryo. From Metscher and Müller, Developmental Dynamics 240:2301–2308, 2011.
Ecohydrological interactions in a degraded two‐phase mosaic dryland: implications for regime shifts, resilience, and restoration
Authors: King Elizabeth G. , Franz Trenton E. , Caylor Kelly K. 
Published: November 2011

ABSTRACTIn the semi‐arid rangelands of north central Kenya, the abundance of grasses has declined over recent decades. Concomitantly, the native succulent herb Sansevieria volkensii has greatly proliferated in many areas. Landscape structure has thus shifted from contiguous herbaceous cover to large, dense stands of S. volkensii with interpatches of bare or sparsely vegetated ground. Local pastoralists view this transition as highly undesirable; understanding the mechanisms and reversibility of the transition is necessary to develop management options. Because water availability is a key driver in this dryland ecosystem, we assessed the ecohydrological dynamics that may govern the vegetative spread of S. volkensii patches in a communal landholding in Laikipia District, Kenya. We assessed surface water flow patterns, soil moisture, S. volkensii proliferation, and adjacent vegetation density along the margins of dense patches of S. volkensii. We found that run‐on zones along patch margins had greater soil moisture than runoff zones following a rain event. These run‐on zones also had significantly higher S. volkensii ramet density, more new ramets, and greater leaf water content. New ramet density was negatively affected by the density of adjacent interpatch vegetation. We interpret these findings in the context of scale‐dependent feedbacks and the cusp catastrophe model of ecosystem transitions. We hypothesize that the amount and spatial heterogeneity of plant available moisture governs the reversibility of transitions in this system and discuss the implications of this finding for management and restoration. Copyright © 2011 John Wiley & Sons, Ltd.
A Series of 3D Rare‐Earth‐Metal–Organic Frameworks with Isolated Guest Keggin Silicotungstate Fragments as Anion Templates
Authors: Li Suzhi , Zhang Dongdi , Guo Yuanyuan , Ma Pengtao , Zhao Junwei , Wang Jingping , Niu Jingyang 
Published: November 2011

AbstractSix rare‐earth (RE) metal constructed 3D metal–organic frameworks, [RE(pydc)(H2O)n]4[SiW12O40]·4H2O [RE = TmIII (1), YIII (2), PrIII (3), LaIII (4), SmIII (5), EuIII (6); n = 3 (1, 2), 4 (3–6); H2pydc = pyridine‐2,6‐dicarboxylic acid], have been synthesized and characterized by elemental analyses, inductively coupled plasma techniques, IR and UV spectroscopy, thermogravimetric analyses (for 1 and 3), X‐ray powder diffraction, and single‐crystal X‐ray diffraction. The structural analyses indicate that 1–6 are basically isostructural and show a rare host 3D framework that contains [SiW12O40]4– Keggin polyoxoanions as templates. Photoluminescence measurements reveal that 1–5 show the luminescence of pydc ligands, whereas 6 displays a unique red luminescence.
Lipophilization of dihydrocaffeic acid affects its antioxidative properties in fish‐oil‐enriched emulsions
Authors: Sørensen Ann‐Dorit Moltke , Nielsen Nina Skall , Yang Zhiyong , Xu Xuebing , Jacobsen Charlotte 
Published: November 2011

AbstractThe aim of the present study was to evaluate the antioxidative effect of lipophilized dihydrocaffeic acid, i.e., octyl dihydrocaffeate and oleyl dihydrocaffeate. Furthermore, the relationship between the measured efficacy of the antioxidants in emulsions, their partitioning into different phases of an emulsion system and their in vitro antioxidant properties was also evaluated. Lipid oxidation in the emulsions was affected by the antioxidants applied. Thus, despite a reduced antioxidant activity of lipophilized dihydrocaffeic acid in the antioxidant assays, lipophilized dihydrocaffeic acid was more efficient than caffeic and dihydrocaffeic acids. Octyl dihydrocaffeate had a significantly higher antioxidative effect than oleyl dihydrocaffeate in emulsions. The results partly supported the polar paradox hypothesis, since lipophilized compounds resulted in increased oxidative stability. However, the decreased antioxidative efficacy with increasing alkyl chain length esterified to dihydrocaffeic acid supported a newly suggested cut‐off effect hypothesis. This hypothesis suggests that when a certain level of hydrophobicity is obtained for lipophilized phenolic acids, the ester forms micelles in the aqueous phase rather than being located at the interface or oil phase. This phenomenon is suggested to explain the reduced antioxidant activity of oleyl dihydrocaffeate compared with octyl dihydrocaffeate.Practical application: The finding that lipophilization of phenolic compounds increase their efficacy opens up new possibilities for producing new and more efficient antioxidants for food systems. However, the results also show that optimization of the chain length for each type of phenolic compound may be necessary. Since these compounds may have a much higher efficacy against lipid oxidation a lower amount of antioxidant will be necessary to obtain the same effect. This would decrease the costs. In addition, the use of synthetic antioxidants, that might have toxic effect in vivo, can be avoided. The raw materials used for the lipophilized compounds are natural compounds, however the fate of the lipophilized compounds in vivo should eventually be evaluated.
On the singularly perturbed character of the turbulent free jet and its robust numerical solution
Authors: Ansari Ali R. , Shishkin Grigori I. 
Published: November 2011

SUMMARYWe consider a numerical approximation of the classical problem of the turbulent free jet. The same boundary layer equation is used for the laminar jet, but with the introduction of the turbulent viscosity. This viscosity depends on the kinematic momentum and the slenderness parameter and varies in space. Here, the problem under consideration is taken to be singularly perturbed, with the slenderness parameter as the perturbation parameter taking arbitrary values from (0,1]. The effective width of the layer depends on the turbulent viscosity and becomes thinner as the slenderness parameter tends to zero. This singularly perturbed character of the turbulent free jet makes this investigation both unique and exploratory. The problem is solved numerically on a finite subdomain by using boundary conditions obtained from the similarity solution. We construct a robust numerical method on the basis of the piecewise‐uniform meshes condensing in the vicinity of the centre of the jet. By numerical experiments, we show that errors for the computed velocity components do not depend on the perturbation parameter. Copyright © 2011 John Wiley & Sons, Ltd.
Predicting Business Failure Using an RSF‐based Case‐Based Reasoning Ensemble Forecasting Method
Authors: Li Hui , Sun Jie 
Published: November 2011

ABSTRACTCase‐based reasoning (CBR) is considered a vital methodology in the current business forecasting area because of its simplicity, competitive performance with modern methods, and ease of pattern maintenance. Business failure prediction (BFP) is an effective tool that helps business people and entrepreneurs make more precise decisions in the current crisis. Using CBR as a basis for BFP can improve the tool's utility because CBR has the potential advantage in making predictions as well as suggestions compared with other methods. Recent studies indicate that an ensemble of various techniques has the possibility of improving the performance of predictive model. This research focuses on an early investigation on predicting business failure using a CBR ensemble (CBRE) forecasting method constructed from the use of random similarity functions (RSF), dubbed RSF‐based CBRE. Four issues are discussed: (i) the reasons for the use of RSF as the basis in the CBRE forecasting method for BFP; (ii) the means to construct the RSF‐based CBRE forecasting method for BFP; (iii) the empirical test on sensitivity of the RSF‐based CBRE to the number of member CBR predictors; and (iv) performance assessment of the ensemble forecasting method. Results of the RSF‐based CBRE forecasting method were statistically validated by comparing them with those of multivariate discriminant analysis, logistic regression, single CBR, and a linear support vector machine. The results from Chinese hotel BFP indicate that the RSF‐based CBRE forecasting method could significantly improve CBR's upper limit of predictive capability. Copyright © 2011 John Wiley & Sons, Ltd.
Increased p75 neurotrophin receptor expression in the canine distemper virus model of multiple sclerosis identifies aldynoglial schwann cells that emerge in response to axonal damage
Authors: Imbschweiler Ilka , Seehusen Frauke , Peck Claas‐Tido , Omar Mohamed , Baumgärtner Wolfgang , Wewetzer Konstantin 
Published: November 2011

AbstractGliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide regeneration‐promoting cells recruitable for therapeutic purposes. There is accumulating evidence that aldynoglial cells with Schwann cell‐like growth‐promoting properties emerge in the lesioned CNS. However, the characterization of these cells and the signals triggering their in situ generation have remained enigmatic. In the present study, we used the p75 neurotrophin receptor (p75NTR) as a marker for Schwann cells to study gliogenesis in the well‐defined canine distemper virus (CDV)‐induced demyelination model. White matter lesions of CDV‐infected dogs contained bi‐ to multipolar, p75NTR‐expressing cells that neither expressed MBP, GFAP, BS‐1, or P0 identifying oligodendroglia, astrocytes, microglia, and myelinating Schwann cells nor CDV antigen. Interestingly, p75NTR‐expression became apparent prior to the onset of demyelination in parallel to the expression of β‐amyloid precursor protein (β‐APP), nonphosphorylated neurofilament (n‐NF), BS‐1, and CD3, and peaked in subacute lesions with inflammation. To study the role of infiltrating immune cells during differentiation of Schwann cell‐like glia, organotypic slice cultures from the normal olfactory bulb were established. Despite the absence of infiltrating lymphocytes and macrophages, a massive appearance of p75NTR‐positive Schwann‐like cells and BS‐1‐positive microglia was noticed at 10 days in vitro. It is concluded that axonal damage as an early signal triggers the differentiation of tissue‐resident precursor cells into p75NTR‐expressing aldynoglial Schwann cells that retain an immature pre‐myelin state. Further studies have to address the role of microglia during this process and the regenerative potential of aldynoglial cells in CDV infection and other demyelinating diseases. © 2011 Wiley Periodicals, Inc.
In vitro and in vivo characterization of a novel hedgehog signaling antagonist in human glioblastoma cell lines
Authors: Ferruzzi Pietro , Mennillo Federica , De Rosa Antonella , Giordano Cinzia , Rossi Marco , Benedetti Giovanni , Magrini Roberta , Mohr Gal.la Pericot , Miragliotta Vincenzo , Magnoni Letizia , Mori Elisa , Thomas Russell , Tunici Patrizia , Bakker Annette 
Published: November 2011

AbstractGlioblastoma multiforme (GBM) is composed of heterogeneous and genetically different cells, which are highly invasive and motile. The standard chemotherapeutic agent, temozolomide, affects GBM cell proliferation but is generally unable to prevent tumor recurrence. Hedgehog pathway activation has been reported to be relevant in GBM and different pharmacological pathway modulators have been identified. We report that by growing a commercially available recurrent GBM cell line (DBTRG‐05MG) without serum and in the presence of defined growth factors; we obtained a less differentiated cell population, growing in suspension as neurospheres, in which the Hedgehog pathway is activated. Furthermore, the expression profile of Hedgehog pathway components found in DBTRG‐05MG neurospheres is similar to primary stem‐like cells derived from recurrent GBM patients. We report the effect of our novel specific Smoothened receptor antagonist (SEN450) on neurosphere growing cells and compared its effect to that of well known benchmark compounds. Finally, we showed that SEN450 is both antiproliferative on its own and further reduces tumor volume after temozolomide pretreatment in a mouse xenograft model using DBTRG‐05MG neurosphere cells. Altogether our data indicate that the Hedgehog pathway is not irreversibly switched off in adherent cells but can be reactivated when exposed to well‐defined culture conditions, thus restoring the condition observed in primary tumor‐derived material, and that pharmacological modulation of this pathway can have profound influences on tumor proliferation. Therefore, pharmacological inhibition of the Hedgehog pathway is a potentially useful therapeutic approach in GBM.