bluuebunny/crossref_metadata_2025_split huggingface dataset:
β-Cell Dysfunctional ERAD/Ubiquitin/Proteasome System in Type 2 Diabetes Mediated by Islet Amyloid Polypeptide–Induced UCH-L1 Deficiency
Authors: Costes Safia , Huang Chang-jiang , Gurlo Tatyana , Daval Marie , Matveyenko Aleksey V. , Rizza Robert A. , Butler Alexandra E. , Butler Peter C. 
Published: October 2010

OBJECTIVE
The islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum–associated degradation/ubiquitin/proteasome system.

RESEARCH DESIGN AND METHODS
We used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.

RESULTS
We report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis.

CONCLUSIONS
Our results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell viability.
Congenital Hyperinsulinism and Glucose Hypersensitivity in Homozygous and Heterozygous Carriers of Kir6.2 (KCNJ11) Mutation V290M Mutation
Authors: Loechner Karen J. , Akrouh Alejandro , Kurata Harley T. , Dionisi-Vici Carlo , Maiorana Arianna , Pizzoferro Milena , Rufini Vittoria , de Ville de Goyet Jean , Colombo Carlo , Barbetti Fabrizio , Koster Joseph C. , Nichols Colin G. 
Published: October 2010

OBJECTIVE
The ATP-sensitive K+ channel (KATP) controls insulin secretion from the islet. Gain- or loss-of-function mutations in channel subunits underlie human neonatal diabetes and congenital hyperinsulinism (HI), respectively. In this study, we sought to identify the mechanistic basis of KATP-induced HI in two probands and to characterize the clinical course.

RESEARCH DESIGN AND METHODS
We analyzed HI in two probands and characterized the course of clinical treatment in each, as well as properties of mutant KATP channels expressed in COSm6 cells using Rb efflux and patch-clamp methods.

RESULTS
We identified mutation V290M in the pore-forming Kir6.2 subunit in each proband. In vitro expression in COSm6 cells supports the mutation resulting in an inactivating phenotype, which leads to significantly reduced activity in intact cells when expressed homomerically, and to a lesser extent when expressed heteromerically with wild-type subunits. In one heterozygous proband, a fluoro-DOPA scan revealed a causal focal lesion, indicating uniparental disomy with loss of heterozygosity. In a second family, the proband, homozygous for the mutation, was diagnosed with severe diazoxide–unresponsive hypersinsulinism at 2 weeks of age. The patient continues to be treated successfully with octreotide and amlodipine. The parents and a male sibling are heterozygous carriers without overt clinical HI. Interestingly, both the mother and the sibling exhibit evidence of abnormally enhanced glucose tolerance.

CONCLUSIONS
V290M results in inactivating KATP channels that underlie HI. Homozygous individuals may be managed medically, without pancreatectomy. Heterozygous carriers also show evidence of enhanced glucose sensitivity, consistent with incomplete loss of KATP channel activity.
mt-Nd2aModifies Resistance Against Autoimmune Type 1 Diabetes in NOD Mice at the Level of the Pancreatic β-Cell
Authors: Chen Jing , Gusdon Aaron M. , Piganelli Jon , Leiter Edward H. , Mathews Clayton E. 
Published: October 2010

OBJECTIVETo investigate whether a single nucleotide polymorphism (SNP) in the mitochondrial gene for NADH dehydrogenase 2 (mt-Nd2) can modulate susceptibility to type 1 diabetes in NOD mice.RESEARCH DESIGN AND METHODSNOD/ShiLtJ mice conplastic for the alloxan resistant (ALR)/Lt-derived mt-Nd2a allele (NOD.mtALR) were created and compared with standard NOD (carrying the mt-Nd2c allele) for susceptibility to spontaneous autoimmune diabetes, or to diabetes elicited by reciprocal adoptive splenic leukocyte transfers, as well as by adoptive transfer of diabetogenic T-cell clones. β-Cell lines derived from either the NOD (NIT-1) or the NOD.mtALR (NIT-4) were also created to compare their susceptibility to cytolysis by diabetogenic CD8+ T-cells in vitro.RESULTSNOD mice differing at this single SNP developed spontaneous or adoptively transferred diabetes at comparable rates and percentages. However, conplastic mice with the mt-Nd2a allele exhibited resistance to transfer of diabetes by the CD4+ T-cell clone BDC 2.5 as well as the CD8+ AI4 T-cell clones from T-cell receptor transgenic animals. NIT-4 cells with mt-Nd2a were also more resistant to AI4-mediated destruction in vitro than NIT-1 cells.CONCLUSIONSConplastic introduction into NOD mice of a variant mt-Nd2 allele alone was not sufficient to prevent spontaneous autoimmune diabetes. Subtle nonhematopoietic type 1 diabetes resistance was observed during adoptive transfer experiments with T-cell clones. This study confirms that genetic polymorphisms in mitochondria can modulate β-cell sensitivity to autoimmune T-cell effectors.
Impact of Positive Family History and Genetic Risk Variants on the Incidence of Diabetes
Authors: Uusitupa Matti I. , Stančáková Alena , Peltonen Markku , Eriksson Johan G. , Lindström Jaana , Aunola Sirkka , Ilanne-Parikka Pirjo , Keinänen-Kiukaanniemi Sirkka , Tuomilehto Jaakko , Laakso Markku 
Published: October 2010

OBJECTIVE
We aimed to investigate the influence of positive family history (FH+) of diabetes and 19 known genetic risk loci on the effectiveness of lifestyle changes and their predictive value on the incidence of type 2 diabetes in the Finnish Diabetes Prevention Study (DPS).

RESEARCH DESIGN AND METHODS
A total of 522 subjects with impaired glucose tolerance (IGT) were randomized into the control (n = 257) and intervention (n = 265) groups. The mean follow-up was 6.2 years (median 7 years), and the lifestyle intervention, aimed at weight reduction, healthy diet, and increased physical activity, lasted for 4 years (range 1–6 years). An oral glucose tolerance test (OGTT) and assessment of basic clinical variables were performed annually.

RESULTS
The effect of intervention on the incidence of diabetes was almost similar in subjects with FH+ compared with subjects with a negative family history (FH−) of diabetes during the entire follow-up. In the Cox model, including FH, genetic risk SNPs, and randomization group, and adjusted for the effects of age, sex, BMI, and study center, only lifestyle intervention had a significant effect (hazard ratio 0.55, 95% CI 0.41–0.75, P &lt; 0.001) on the incidence of diabetes. Further analyses showed that in addition to the baseline glucose and insulin values, 1-year changes in 2-h glucose and 2-h insulin achieved by lifestyle intervention had a significant effect on the incidence of diabetes.

CONCLUSIONS
These results emphasize the effectiveness of lifestyle intervention in reducing the risk of diabetes in high-risk individuals independently of genetic or familial risk of type 2 diabetes.
Low HDL Cholesterol, Metformin Use, and Cancer Risk in Type 2 Diabetes
Authors: Yang Xilin , So Wing Yee , Ma Ronald C.W. , Kong Alice P.S. , Lee Heung Man , Yu Linda W.L. , Chow Chun-Chung , Ozaki Risa , Ko Gary T.C. , Chan Juliana C.N. 
Published: October 2010

OBJECTIVE
The AMP-activated protein kinase (AMPK) pathway is a master regulator in energy metabolism and may be related to cancer. In type 2 diabetes, low HDL cholesterol predicts cancer, whereas metformin usage is associated with reduced cancer risk. Both metformin and apolipoprotein A1 activate the AMPK signaling pathway. We hypothesize that the anticancer effects of metformin may be particularly evident in type 2 diabetic patients with low HDL cholesterol.

RESEARCH DESIGN AND METHODS
In a consecutive cohort of 2,658 Chinese type 2 diabetic patients enrolled in the study between 1996 and 2005, who were free of cancer and not using metformin at enrollment or during 2.5 years before enrollment and who were followed until 2005, we measured biological interactions for cancer risk using relative excess risk as a result of interaction (RERI) and attributable proportion (AP) as a result of interaction. A statistically significant RERI &gt;0 or AP &gt;0 indicates biological interaction.

RESULTS
During 13,808 person-years of follow-up (median 5.51 years), 129 patients developed cancer. HDL cholesterol &lt;1.0 mmol/L was associated with increased cancer risk among those who did not use metformin, but the association was not significant among those who did. Use of metformin was associated with reduced cancer risk in patients with HDL cholesterol &lt;1.0 mmol/L and, to a lesser extent, in patients with HDL cholesterol ≥1.0 mmol/L. HDL cholesterol &lt;1.0 mmol/L plus nonuse of metformin was associated with an adjusted hazard ratio of 5.75 (95% CI 3.03–10.90) compared with HDL cholesterol ≥1.0 mmol/L plus use of metformin, with a significant interaction (AP 0.44 [95% CI 0.11–0.78]).

CONCLUSIONS
The anticancer effect of metformin was most evident in type 2 diabetic patients with low HDL cholesterol.
Genetic diversity of Avena strigosa Schreb. ecotypes on the basis of isoenzyme markers
Authors: Kubiak Katarzyna 
Published: October 2010

Genetic diversity of Avena strigosa Schreb. ecotypes on the basis of isoenzyme markers
Genetic diversity was analyzed in 19 ecotypes of the diploid oat A. strigosa originating from various geographical regions of the world. Six isoenzyme systems (AAT, ACP, EST, LAP, MDH, PX) were studied and 16 loci were identified. Only two loci (Est4 and Mdh2) were polymorphic. Ecotypes were characterized by the percentage of polymorphic loci (P=3.3%), the mean number of alleles per locus (A=1.04) and intrapopulation diversity (HS=0.013). Total genetic diversity (HT=0.07) and interpopulation diversity (DST=0.057) were examined as well. The value of the coefficient of gene differentiation (GST=0.821) indicated that diversity among populations was an important contributor to total variability. Genetic similarity between A. strigosa populations was very high (IN=0.94). Cluster analysis did not demonstrate strongly differentiated groups among the ecotypes examined.
A simple technique of random leaf collecting for biometric studies in a tree stand
Authors: Żółkoś Katarzyna , Meissner Włodzimierz 
Published: October 2010

A simple technique of random leaf collecting for biometric studies in a tree stand
The method reflects proportions in the number of leaves of different sizes and shapes, which appear in a tree stand. The study was carried out during autumn leaf fall, in about a hundred years old tree stand, dominated by beech. Leaves were collected three times, altogether with assessment of foliage density. For all gathered leaves, the width and length were measured and the data were statistically analyzed. Differences among all three samples were significant, which indicates different size of falling leaves in the following periods. Thus, only the research carried on at the end of leaves falling allows collecting a sample which represents proportions among leaves of different sizes in the tree stand.
New data on the distribution of dwarf ephemeral wetland vascular plant species and communities in western and north-western Poland
Authors: Popiela Agnieszka , Prajs Bożena , Łysko Andrzej 
Published: October 2010

New data on the distribution of dwarf ephemeral wetland vascular plant species and communities in western and north-western Poland
New phytosociological data are provided on Eleocharito-Caricetum bohemicae occurring on the easternmost range border in Central Europe. The distribution maps of selected character species of Eleocharito-Caricetum in Central Europe are presented.
Man-made habitats - hotspots of evolutionary game between grass, fungus and fly
Authors: Lembicz Marlena , Olejniczak Paweł , Olszanowski Ziemowit , Górzyńska Karolina , Leuchtmann Adrian 
Published: October 2010

Man-made habitats - hotspots of evolutionary game between grass, fungus and fly
The origin and effects of an evolutionary game between species from three different kingdoms (plants, fungi and animals) are presented. We provide scientific evidence that the interaction discovered in man-made habitats leads to an early stage of coevolution. The grass Puccinellia distans was observed to rapidly spread in new man-made habitats, while at the same time, it was colonised by the fungus Epichloë typhina. The invasion of infected grasses is accompanied by alterations in life histories of both species: P. distans developed features promoting long-distance spreading, whereas E. typhina changed its life cycle by forming sexual structures for the second time, later in the vegetative season. This enables the fungus to make use of the late shoots of the grass for sexual reproduction, even though it cannot be completed because the vector of spermatia necessary for fertilisation, female Botanophila flies, is not present at that time. This indicates that such uncoordinated evolutionary processes had taken place before interactions between organisms became so specialised that it is difficult to presume they were the result of natural selection. Moreover, these processes could have been initiated in man-made habitats that, in particular circumstances, can become coevolutionary hotspots.
Development and characterization of microsatellite loci in Taihangia rupestris (Rosaceae), a rare cliff herb
Authors: Wang Hong‐Wei , Zhang Bing , Wang Zhao‐Shan , Cheng Yue‐Qin , Ye Yong‐Zhong 
Published: October 2010

• Premise of the study: Microsatellite primers were developed for the rare Taihangia rupestris (Rosaceae) to evaluate genetic diversity, population genetic structure, mating system, and demographic events of this species.• Methods and Results: Ten primer sets were developed using an enriched genomic library and were successfully amplified in T. rupestris var. ciliata and T. rupestris var. rupestris. The number of alleles per locus ranged from 2 to 21; the observed and expected heterozygosities ranged from 0.300 to 0.950 and from 0.328 to 0.956, respectively, in the two varieties.• Conclusions: The markers described here will be useful for studies of genetic variation, genetic structure, and mating systems of T. rupestris, which are important for the future conservation of this rare species.
Evaluation of Novel Phosphoramidate ProTides of the 2′-Fluoro Derivatives of a Potent Anti-Varicella Zoster Virus Bicyclic Nucleoside Analogue
Authors: Derudas Marco , Quintiliani Maurizio , Brancale Andrea , Andrei Graciela , Snoeck Robert , Balzarini Jan , McGuigan Christopher 
Published: October 2010

Background: Recently, the synthesis and antiviral activity of a series of 2′-fluoro derivatives of the most potent anti-varicella zoster virus (VZV) agent reported to date, the bicyclic nucleoside analogue Cf1743, have been reported. Methods: Here, we present molecular modelling studies for the interaction of these compounds with VZV-encoded thymidine kinase (TK) and we report the synthesis of a series of phosphoramidate ProTides of these compounds designed to bypass the nucleoside kinase dependence of the parent nucleoside analogues. Results: The phosphoramidate prodrugs were equally effective as their parent compounds against VZV in cell culture, but lost antiviral potency against TK-deficient VZV strains. Conclusions: ProTide-based kinase bypass is not successful in this case.
Amino acid substitutions in core and NS5A regions of the HCV genome can predict virological decrease with pegylated interferon plus ribavirin therapy
Authors: Kitamura Shosuke , Tsuge Masataka , Hatakeyama Tsuyoshi , Abe Hiromi , Imamura Michio , Mori Nami , Saneto Hiromi , Kawaoka Tomokazu , Mitsui Fukiko , Hiraga Nobuhiko , Takaki Shintaro , Kawakami Yoshiiku , Aikata Hiroshi , Takahashi Shoichi , Ohishi Waka , Ochi Hidenori , Hayes C Nelson , Chayama Kazuaki 
Published: October 2010

Background The current standard therapy for chronic hepatitis C is pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. Recently, it has been reported that amino acid (aa) substitutions in the core region, as well as the IFN-sensitivity-determining region (ISDR), were predictive of non-virological response (NVR), sustained virological response (SVR) and early virological response. Despite the importance of these two predictive factors for combination therapy, their interaction is poorly understood. Methods A total of 117 patients who were treated with PEG-IFN-α2b plus RBV combination therapy were selected for participation in this study. We determined the aa sequences in the core region and ISDR by direct sequencing and analysed them along with clinical data to indentify predictive factors for therapeutic response. Results The aa sequences in the core region and γ-glutamyl transpeptidase (GTP) levels were associated with SVR and NVR, but aa sequences in the ISDR were not. However, substitutions at both aa 70 and aa 91 in the core region without substitutions in the ISDR and higher levels of γ-GTP were independent predictive factors for NVR. Wild-type aa 70 and aa 91 in the core region, higher platelet counts and lower levels of γ-GTP were independent predictive factors for SVR. Conclusions These results indicate that analyses of aa substitutions in both the core region and the ISDR are useful for predicting the effectiveness of combination therapy, and could help to avoid therapy exposure for patients who have a low probability of SVR.
TLR-Activated Dendritic Cells Enhance the Response of Aged Naive CD4 T Cells via an IL-6–Dependent Mechanism
Authors: Jones Stephen C. , Brahmakshatriya Vinayak , Huston Gail , Dibble John , Swain Susan L. 
Published: October 2010

AbstractThe most effective immunological adjuvants contain microbial products, such as TLR agonists, which bind to conserved pathogen recognition receptors. These activate dendritic cells (DCs) to become highly effective APCs. We assessed whether TLR ligand-treated DCs can enhance the otherwise defective response of aged naive CD4 T cells. In vivo administration of CpG, polyinosinic-polycytidylic acid, and Pam3CSK4 in combination with Ag resulted in the increased expression of costimulatory molecules and MHC class II by DCs, increased serum levels of the inflammatory cytokines IL-6 and RANTES, and increased cognate CD4 T cell responses in young and aged mice. We show that, in vitro, preactivation of DCs by TLR ligands makes them more efficient APCs for aged naive CD4 T cells. After T–DC interaction, there are enhanced production of inflammatory cytokines, particularly IL-6, and greater expansion of the aged T cells, resulting from increased proliferation and greater effector survival with increased levels of Bcl-2. TLR preactivation of both bone marrow-derived and ex vivo DCs improved responses. IL-6 produced by the activated DCs during cognate T cell interaction was necessary for enhanced aged CD4 T cell expansion and survival. These studies suggest that some age-associated immune defects may be overcome by targeted activation of APCs by TLR ligands.
EBV Latent Membrane Protein 1 Is a Negative Regulator of TLR9
Authors: Fathallah Ikbal , Parroche Peggy , Gruffat Henri , Zannetti Claudia , Johansson Hanna , Yue Jiping , Manet Evelyn , Tommasino Massimo , Sylla Bakary S. , Hasan Uzma A. 
Published: October 2010

Abstract
EBV infects most of the human population and is associated with a number of human diseases including cancers. Moreover, evasion of the immune system and chronic infection is an essential step for EBV-associated diseases. In this paper, we show that EBV can alter the regulation and expression of TLRs, the key effector molecules of the innate immune response. EBV infection of human primary B cells resulted in the inhibition of TLR9 functionality. Stimulation of TLR9 on primary B cells led to the production of IL-6, TNF-α, and IgG, which was inhibited in cells infected with EBV. The virus exerts its inhibitory function by decreasing TLR9 mRNA and protein levels. This event was observed at early time points after EBV infection of primary cells, as well as in an immortalized lymphoblastoid cell line. We determined that the EBV oncoprotein latent membrane protein 1 (LMP1) is a strong inhibitor of TLR9 transcription. Overexpression of LMP1 in B cells reduced TLR9 promoter activity, mRNA, and protein levels. LMP1 mutants altered in activating the NF-κB pathway prevented TLR9 promoter deregulation. Blocking the NF-κB pathway recovered TLR9 promoter activity. Mutating the NF-κB cis element on the TLR9 promoter restored luciferase transcription in the presence of LMP1. Finally, deletion of the LMP1 gene in the EBV genome abolished the ability of the virus to induce TLR9 downregulation. Our study describes a mechanism used by EBV to suppress the host immune response by deregulating the TLR9 transcript through LMP1-mediated NF-κB activation.
Lymphocyte Development RequiresS-nitrosoglutathione Reductase
Authors: Yang Zhiyong , Wang Zhi-En , Doulias Paschalis-Thomas , Wei Wei , Ischiropoulos Harry , Locksley Richard M. , Liu Limin 
Published: October 2010

AbstractNO is critical to immunity, but its role in the development of the immune system is unknown. In this study, we show that S-nitrosoglutathione reductase (GSNOR), a protein key to the control of protein S-nitrosylation, is important for the development of lymphocytes. Genetic deletion of GSNOR in mice results in significant decrease in both T and B lymphocytes in the periphery. In thymus, GSNOR deficiency causes excessive protein S-nitrosylation, increases apoptosis, and reduces the number of CD4 single-positive thymocytes. Lymphopenia and increase in S-nitrosylation and apoptosis in GSNOR-deficient mice are largely abolished by genetic deletion of inducible NO synthase. Furthermore, the protection of lymphocyte development by GSNOR is apparently intrinsic to hematopoietic cells. Thus, GSNOR, likely through regulation of S-nitrosylation and apoptosis, physiologically plays a protective role in the development of the immune system.