bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell cycle proteins in normal and chemically induced abnormal secondary palate development: a review
Authors: Dhulipala Vamsidhara C , Welshons Wade V , Reddy Chada S
Published: November 2006

Cell cycle progression and thus proper cell number is essential for normal development of organs and organisms. Craniofacial tissues including the secondary palate are vulnerable to disruption of cell cycle progression and proliferation by many chemicals including mycotoxin, secalonic acid D (SAD), glucocorticoids, retinoic acid and 2,3,7,8-tetrachlorodibenzodioxin. Induction of cleft palate (CP) by SAD in mice occurs from a reduction in the size of developing palatal shelves. This is associated with an inhibition of proliferation of murine and human embryonic palatal mesenchymal (MEPM and HEPM) cells as well as a G1/S block of cell cycle. In murine embryonic palates and HEPM cells, SAD inhibited G1/S-phase-specific cyclin-dependent kinase (CDK)2 activity, reduced the level of cyclin E and increased the level of the CDK2 inhibitor, p21. These results, together with those from other laboratories, suggest that common cell cycle protein targets (biomarkers), relevant to the pathogenesis of CP by multiple chemical exposures, that can form the basis for the diagnosis and the development of preventive strategies, are likely to exist.
Effects of Racial Discrimination and Health Behaviors on Mental and Physical Health of Middle-Class African American Men
Authors: Sellers Sherrill L. , Bonham Vence , Neighbors Harold W. , Amell James W.
Published: November 2006

This research is an examination of the effects of racial discrimination and health-promoting behaviors on the physical and mental health of a sample of 399 well-educated African American men. One would think that the attainment of higher education would increase health-promoting behaviors and might decrease discriminatory experiences that impact health. However, regression analysis indicated a more complex picture. Health-promoting behaviors were positively related to mental health, whereas experiences of racial discrimination contributed to poorer mental health. Relationships between health-promoting behaviors and that of racial discrimination to physical health were found to be nonsignificant. In conclusion, the authors discuss the importance of culturally appropriate health-promotion efforts.
Snakes, Skins and the Sphinx: Nietzsche's Ecdysis
Authors: Tyler Tom
Published: November 2006

Foucault claimed that Nietzsche's philosophy constitutes la grande rupture from Kant's conception of knowledge. The break occurred, however, only after Nietzsche had shed his own Kantian skin. This article examines both the debt that early Nietzsche owes to Kant, and the nature of the break evident in his later work. It highlights three key facets of the mature Nietzsche's epistemology: (1) there is no disinterested truth, only a range of evaluative perspectives; (2) these perspectives must continually change and multiply; and (3) the subject of any perspective need not be human. As Nietzsche's own eyesight deteriorated, he saw more, and he saw more clearly.
(un)Housing Aboriginal Possessions in the Virtual Museum: Cultural Practices and Decolonization in civilization.ca and Reservation X
Authors: Emberley Julia
Published: November 2006

This article explores the confluence of various materialities of space and their links to social and representational violence. Specifically, the author examines these forms of violence with reference to two virtual museum exhibitions of indigenous houses and housing practices: the Museum of Civilization's website – civilization.ca – and its permanent exhibit, titled The Grand Hall; and the Reservation X virtual exhibit on the National Museum of the American Indian website. In these museum displays, ideas of ‘house’ and ‘home’ are central to the visual rhetoric on aboriginality.
Language Wants To Be Overlooked: On Software and Ideology
Authors: Galloway Alexander R.
Published: November 2006

This article is a theoretical response to the observation from Wendy Hui Kyong Chun that ‘software is a functional analog to ideology’. Several principles of software design support this claim, the first being the principles of reflection and obfuscation evident in all types of code. At the same time, in contrast to natural language, code is both scriptural and executable, indicating the functional quality of software. In simulating the ideological model, software is an example of technical transcoding without figuration that nevertheless coexists with an exceedingly high level of ideological fetishism and misrecognition.
Laser scattering for particulate fume measurement
Authors: Lucas O. , Linton V. , Alwahabi Z.
Published: November 2006

This paper investigates the use of laser light scattering to determine fume concentration generated by gas metal arc welding (GMAW). The effect of transfer mode on the intensity of scattered laser light was measured to compare the results with those generated by fume box measurements. Good correlation was found between previously measured fume formation rates and scattered light intensity across a range of transfer modes for two wire feed rates. Thus it is proposed that laser light scattering is a viable measurement technique for welding fume and demonstrates several advantages over traditional methods.
CcpA affects expression of the groESL and dnaK operons in Lactobacillus plantarum
Authors: Castaldo Cristiana , Siciliano Rosa A , Muscariello Lidia , Marasco Rosangela , Sacco Margherita
Published: November 2006

Background

Lactic acid bacteria (LAB) are widely used in food industry and their growth performance is important for the quality of the fermented product. During industrial processes changes in temperature may represent an environmental stress to be overcome by starters and non-starters LAB. Studies on adaptation to heat shock have shown the involvement of the chaperon system-proteins in various Gram-positive bacteria. The corresponding operons, namely the dnaK and groESL operons, are controlled by a negative mechanism involving the HrcA repressor protein binding to the cis acting element CIRCE.

Results

We studied adaptation to heat shock in the lactic acid bacterium Lactobacillus plantarum. The LM3-2 strain, carrying a null mutation in the ccpA gene, encoding the catabolite control protein A (CcpA), showed a lower percent of survival to high temperature with respect to the LM3 wild type strain. Among proteins differentially expressed in the two strains, the GroES chaperon was more abundant in the wild type strain compared to the mutant strain under standard growth conditions. Transcriptional studies showed that class I heat shock operons were differentially expressed upon heat shock in both strains. Indeed, the dnaK and groESL operons were induced about two times more in the LM3 strain compared to the LM3-2 strain. Analysis of the regulatory region of the two operons showed the presence of cre sequences, putative binding sites for the CcpA protein.

Conclusion

The L. plantarum dnaK and groESL operons are characterized by the presence of the cis acting sequence CIRCE in the promoter region, suggesting a negative regulation by the HrcA/CIRCE system, which is a common type of control among the class I heat shock operons of Gram-positive bacteria. We found an additional system of regulation, based on a positive control exerted by the CcpA protein, which would interact with cre sequences present in the regulatory region of the dnaK and groESL operons. The absence of the CcpA protein results in a lower induction of the chaperon coding operons, with a consequent lower percent of survival of the LM3-2 mutant strain population with respect to the wild type when challenged with a heat insult.
RETRACTED ARTICLE: Small interfering RNA targeted to stem-loop II of the 5' untranslated region effectively inhibits expression of six HCV genotypes
Authors: Prabhu Ramesh , Garry Robert F , Dash Srikanta
Published: November 2006

Background

The antiviral action of interferon alpha targets the 5' untranslated region (UTR) used by hepatitis C virus (HCV) to translate protein by an internal ribosome entry site (IRES) mechanism. Although this sequence is highly conserved among different clinical strains, approximately half of chronically infected hepatitis C patients do not respond to interferon therapy. Therefore, development of small interfering RNA (siRNA) targeted to the 5'UTR to inhibit IRES mediated translation may represent an alternative approach that could circumvent the problem of interferon resistance.

Results

Four different plasmid constructs were prepared for intracellular delivery of siRNAs targeting the stem loop II-III of HCV 5' UTR. The effect of siRNA production on IRES mediated translation was investigated using chimeric clones between the gene for green fluorescence protein (GFP) and IRES sequences of six different HCV genotypes. The siRNA targeted to stem loop II effectively mediated degradation of HCV IRES mRNA and inhibited GFP expression in the case of six different HCV genotypes, where as siRNAs targeted to stem loop III did not. Furthermore, intracytoplasmic expression of siRNA into transfected Huh-7 cells efficiently degraded HCV genomic RNA and inhibited core protein expression from infectious full-length infectious clones HCV 1a and HCV 1b strains.

Conclusion

These in vitro studies suggest that siRNA targeted to stem-loop II is highly effective inhibiting IRES mediated translation of the major genotypes of HCV. Stem-loop II siRNA may be a good target for developing an intracellular immunization strategy based antiviral therapy to inhibit hepatitis C virus strains that are not inhibited by interferon.
Cross-priming of cyclin B1, MUC-1 and survivin-specific CD8+T cells by dendritic cells loaded with killed allogeneic breast cancer cells
Authors: Saito Hiroaki , Dubsky Peter , Dantin Carole , Finn Olivera J , Banchereau Jacques , Palucka A Karolina
Published: November 2006

Introduction

The ability of dendritic cells (DCs) to take up whole tumor cells and process their antigens for presentation to T cells ('cross-priming') is an important mechanism for induction of tumor specific immunity.

Methods

In vitro generated DCs were loaded with killed allogeneic breast cancer cells and offered to autologous naïve CD8+ T cells in 2-week and/or 3-week cultures. CD8+ T cell differentiation was measured by their capacity to secrete effector cytokines (interferon-γ) and kill breast cancer cells. Specificity was measured using peptides derived from defined breast cancer antigens.

Results

We found that DCs loaded with killed breast cancer cells can prime naïve CD8+ T cells to differentiate into effector cytotoxic T lymphocytes (CTLs). Importantly, these CTLs primed by DCs loaded with killed HLA-A*0201- breast cancer cells can kill HLA-A*0201+ breast cancer cells. Among the tumor specific CTLs, we found that CTLs specific for HLA-A2 restricted peptides derived from three well known shared breast tumor antigens, namely cyclin B1, MUC-1 and survivin.

Conclusion

This ability of DCs loaded with killed allogeneic breast cancer cells to elicit multiantigen specific immunity supports their use as vaccines in patients with breast cancer.
The Type 1 Diabetes Genetics Consortium
Authors: RICH STEPHEN S. , CONCANNON PATRICK , ERLICH HENRY , JULIER CECILE , MORAHAN GRANT , NERUP JORN , POCIOT FLEMMING , TODD JOHN A.
Published: November 2006

Abstract:  The Type 1 Diabetes Genetics Consortium (T1DGC) is an international, multicenter program organized to promote research to identify genes and their alleles that determine an individual's risk for type 1 diabetes (T1D). The primary goal of the T1DGC is to establish resources and data that can be used by, and that is fully accessible to, the research community in the study of T1D. All the information on T1DGC can be accessed at the following web address: http://www.t1dgc.org. A resource base of well‐characterized families is being assembled that will facilitate the localization and characterization of T1D susceptibility genes. From these families, the T1DGC is establishing banks of DNA, serum, plasma, and cell lines, as well as useful databases. The T1DGC also sponsors training opportunities (bioinformatics) and technology transfer (HLA genotyping).
A Mini Meta‐Analysis of Studies on CD4+CD25+ T cells in Human Type 1 Diabetes
Authors: TREE TIMOTHY I.M. , ROEP BART O. , PEAKMAN MARK
Published: November 2006

Abstract:  Type 1 diabetes mellitus (T1DM) is characterized by a loss of self‐tolerance to islet antigens. In health, immunological tolerance is maintained by multiple central and peripheral mechanisms including the action of a specialized set of regulatory T cells characterized by expression of CD4 and CD25 (CD4+CD25+ Treg). It has been suggested that a defect in this cell population, either numerically or functionally, could contribute to the development of autoimmune diseases, such as T1DM. To investigate this possibility, several research groups have studied the frequency and suppressive capacity of this cell population in individuals with T1DM and, to date, there are four such studies published. We therefore performed a mini meta‐analysis to compare the results in the four published studies, account for differences in their findings, and draw a consensus view on the role of this important cell subset in human T1DM.
HLA Class I Epitope Discovery in Type 1 Diabetes
Authors: PINKSE GABRIELLE G.M. , BOITARD CHRISTIAN , TREE TIMOTHY I.M. , PEAKMAN MARK , ROEP BART O.
Published: November 2006

Abstract:  Islet autoreactive CD8 T cells are plausible candidates for direct beta cell toxicity in type 1 diabetes (T1DM). In 2005, cellular studies in the pathogenesis of this disease have reached a new milestone. Autoreactive CD8 T cells have been defined and several target islet epitopes of these have been discovered and validated simultaneously in three independent studies. The insulin B10–B18 peptide that displays exceptional binding affinity for HLA‐A2 has been reported in all three studies, and its recognition shows an association with autoimmune beta cell destruction and T1DM. These studies imply that CD8 T cell‐based HLA tetramers and ELISPOT analyses can be useful to monitor T1DM as well as islet transplantation, and may provide useful tools to assess immunological efficacy of immune intervention trials.
Genetics of Fulminant Type 1 Diabetes
Authors: KAWASAKI EIJI , EGUCHI KATSUMI
Published: November 2006

Abstract:  Fulminant type 1 diabetes exhibits distinct clinical futures from “classic” autoimmune type 1 diabetes. Although the etiology of fulminant type 1 diabetes is not fully elucidated, class II HLA could contribute to the development of fulminant type 1 diabetes. In Japanese patients with “classic” type 1 diabetes, DRB1*0405‐DQB1*0401 and DRB1*0901‐DQB1*0303 are major susceptible HLA‐DR‐DQ haplotypes, whereas DRB1*1502‐DQB1*0601 and DRB1*1501‐DQB1*0602 are protective. In contrast, only DRB1*0405‐DQB1*0401, but not DRB1*0901‐DQB1*0303, is a susceptible haplotype in fulminant type 1 diabetes. In addition, neither DRB1*1502‐DQB1*0601 nor DRB1*1501‐DQB1*0602 are protective haplotypes in fulminant type 1 diabetes. In genotypic combination analysis, the homozygotes of DRB1*0405‐DQB1*0401 are associated with both fulminant type 1 diabetes and “classic” type 1 diabetes, whereas the homozygotes of DRB1*0901‐DQB1*0303 are associated with only “classic” type 1 diabetes. These findings suggest a different contribution of class II HLA in the mechanisms of beta cell damage between fulminant and “classic” type 1 diabetes. To further address the pathogenesis of fulminant type 1 diabetes, HNF‐1α gene mutation and mutation of the mitochondrial DNA were analyzed in patients with fulminant type 1 diabetes admitted to our department during the period from 1990 to 2000. Neither mutations of HNF‐1α gene nor A‐to‐G mutation at nucleotide position 3,243 of the mitochondrial tRNALEU(UUR) gene were identified in these patients. These results suggest that the HNF‐1α gene mutation and mutation of the mitochondrial DNA are not likely associated with diabetic patients with fulminant clinical symptoms at disease onset. In this article we will summarize the current findings on the genetics of Japanese patients with fulminant type 1 diabetes.
Genes Influencing Innate and Acquired Immunity in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults
Authors: SANJEEVI CARANI B.
Published: November 2006

Abstract: DQ8 and DQ2 are associated with susceptibility to and DQ6 with protection from type 1 diabetes mellitus (T1DM). A set of polymorphic genes, called MHC class I chain‐related genes (MIC‐A) in HLA class I region interact with NK cells. In Italians, MICA allele 5 increases T1DM risk by 6.1. Together with HLA‐DQ8 and DQ2 the risk increases severalfold. HLA class I genes, also identified as susceptibility genes for T1DM, interact with polymorphic killer immunoglobulin‐like receptors (KIR) on NK cells. HLA‐DQ8 and DQ2 and MICA‐5 in Swedish and other populations also show positive association with disease. Studies on KIR in Latvian patients with T1DM also suggest a role for KIR in the etiology of T1DM. The results from MICA and KIR studies suggest that polymorphism of these genes of the innate immune system identify possible defects in the first line of antiviral defense in the etiology of T1DM. Screening for these genes could be important in the prediction strategies for T1DM.
Progression of Autoimmune Diabetes
Authors: BEYAN HURIYA , OLA THOMAS , DAVID R. , LESLIE G.
Published: November 2006

Abstract:  Autoimmune diabetes is due to destruction of insulin‐secreting beta islet cells by an immune‐mediated process, which is induced and promoted by the interaction of genetic and environmental factors.
This form of diabetes is one of a group of autoimmune diseases that affect about 10% of the population in the developed world.
The detection of diabetes‐associated autoantibodies, including glutamic acid decarboxylase antibodies (GADA), islet cell antibodies (ICA), and insulinoma‐associated (IA‐2) autoantibodies is widely held to reflect an underlying autoimmune pathology but the clinical features associated with the presence of these diabetes‐associated autoantibodies is highly variable ranging from lack of symptoms with normal glucose tolerance to catastrophic and potentially fatal diabetic ketoacidosis. It is the purpose of this article to establish the range of metabolic features associated with diabetes‐associated autoimmune changes and discuss how this metabolic spectrum itself reflects a spectrum of immune and clinical changes that cast light on the nature of autoimmune diabetes.
Immunomodulation for the Prevention of SPIDDM and LADA
Authors: POZZILLI P. , GUGLIELMI C.
Published: November 2006

Abstract:  Type 1 diabetes may occur at any age, in young individuals before or after adolescence, during middle age life, or even in the elderly. When diagnosed in adults it is characterized by the presence of islet cell‐related autoantibodies (ICA), in particular GAD and IA2 (less common) and very rarely insulin autoantibodies (IAA). Baseline C‐peptide at diagnosis of type 1 diabetes can identify different patient populations according to when the disease is diagnosed depending on age. A key question is whether the process of beta cell destruction follows the same pattern in patients diagnosed in young age, soon after adolescence, or in adult age. The terms SPIDDM—slowly progressive insulin‐dependent diabetes mellitus and LADA—latent autoimmune diabetes in adults have been considered synonymous on most grounds based on the fact that with this form of diabetes we intend a form of diabetes that has an autoimmune basis that eventually will require insulin for its treatment sometime after diagnosis. Therapeutic approaches are similar for prevention and treatment of SPIDDM or LADA, including both specific and nonspecific immunomodulation. For specific immunomodulation the attention is focused on DiaPep277, GAD, and insulin, and for nonspecific immunomodulation on 1,25 dihydroxy‐vitamin D3 (calcitriol) and thiazolidinediones. Current trials in SPIDDM/LADA with both specific and nonspecific immunomodulation seem promising. Response to therapy varies according to age and residual beta cell function at diagnosis of SPIDMM/LADA. Results in beta cell protection with different agents can also help to identify differences, if any, between SPIDMM and LADA.
Heightened Interferon‐α/β Response Causes Myeloid Cell Dysfunction and Promotes T1D Pathogenesis in NOD Mice
Authors: PENG RUI HUA , PAEK EDWARD , XIA CHANQING Q. , TENNYSON NATHAN , CLARE‐SALZLER MICHAEL J.
Published: November 2006

Abstract:  Increasing attention is drawn to the contributions of abnormalities in both innate and acquired immune responses to the pathogenesis of autoimmune diseases, such as type 1 diabetes (T1D). Dendritic cells (DC) are critical immune cells linking innate and acquired immune responses and previous studies in NOD mice suggest abnormalities in these cells.
To address DC dysregulation we examined kinetic global gene expression in NOD and B6 GM‐CSF/IL‐4‐induced bone marrow‐derived DC following lipopolysaccharide (LPS)‐stimulation. We identified expression differences in over 300 genes including a cluster of 16 interferon (IFN‐α/β) target genes overexpressed in NOD DC. Mechanistically, heightened IFN‐α/β responses were not due to increased production of this cytokine, IFN‐γ priming or increased Syk kinase activity. We found, however, heightened responses to IFN‐α/β in NOD versus B6 as demonstrated by increased type 1 IFN target gene expression, for example, IRF‐7, in NOD DC and macrophages. Analysis of multiple congenic strains demonstrated that the Idd5 susceptibility region largely governed heightened IFN‐α responses. Of interest, heightened IFN‐α/β response in NOD mice was not confined to hematopoietic cells but was also seen in the pancreas and β cells. Compounding the IFN‐α response defect, NOD mice harbor significantly more PDC in spleen in comparison to B6 and produce four‐ to sixfold more IFN‐α when stimulated with CpG. Finally, treatment of NOD mice with IFN‐α inducing agents, for example, high‐dose poly I:C accelerates diabetes in both female and male mice. The abnormalities in the IFN‐α/β axis appear to play a significant role in T1D pathogenesis.
Young NOD Mice Show Increased Diabetes Sensitivity to Low Doses of Streptozotocin
Authors: REDDY SHIVA , CHANG MIKE , ROBINSON ELIZABETH
Published: November 2006

Abstract:  In type 1 diabetes, environmentally induced early‐limited beta cell damage may pre‐empt the subsequent immune‐mediated beta cell destruction. Low doses of streptozotocin (Stz), given early to diabetes‐prone mice, may cause limited beta cell destruction during the early phase and precipitate diabetes. Here, we aimed to see if young NOD mice are more diabetes‐sensitive to various multiple low doses of Stz than nondiabetes‐prone mice. We also determined the molecular pathology of islets following administration of the diabetogen. Female NOD and CD‐1 mice received 5 daily doses of Stz at day 21 (20, 30, and 40 mg/kg body weight; 18 mice per group) or diluent, and diabetes was monitored. Pancreas were studied histochemically and immunohistochemically at various time points after Stz administration. Following administration of Stz, NOD mice showed a much earlier onset and increased diabetes rate, at all three doses, than CD‐1 mice. By day 80, the final diabetes rates following the 40, 30, and 20 mg dose in NOD mice were 95%, 85%, and 33%, respectively, compared with 33%, 28%, and 5.5%, respectively, in CD‐1 mice. However, following the 20 mg dose, only 2 of the 12 remaining NOD mice developed the disease between 90 and 250 days compared with 19 of 24 NOD mice that did not receive Stz at day 21. Stz‐administered NOD and CD‐1 mice showed an initial loss of beta cells, with redistribution of islet endocrine cells, early macrophage infiltration, and increasing insulitis.
Pancreatic Autoimmunity Induction with Insulin B:9–23 Peptide and Viral Mimics in the NZB Mouse
Authors: DEVENDRA DEVASENAN , MIAO DONGMEI , NAKAYAMA MAKI , EISENBARTH GEORGE S. , LIU EDWIN
Published: November 2006

Abstract:  To create a new experimental model of diabetes, we used the New Zealand Black (NZB) mouse as a potential model. NZB mice were immunized with B:9–23 insulin peptide in IFA and the viral mimic, poly(A:U).
No diabetes was observed but blood glucose was significantly higher in the B:9–23 peptide group compared to controls. Insulin autoantibodies (IAA) were only induced in groups given the B:9–23 peptide. B:9–23 alone induced peri‐insulitis. We demonstrate insulin autoimmunity in the NZB mouse using the insulin peptide B:9–23 and viral mimics. The reason for the protection from diabetes despite the presence of autoimmunity is currently not established.
Glutamic Acid Decarboxylase‐Specific CD4+ Regulatory T Cells
Authors: LIU CHIH‐PIN
Published: November 2006

Abstract:  It is known that CD4+ regulatory T cells (Tr cells) play a central role in inducing immune tolerance in animals and humans. Compared to polyclonal Tr cells, autoantigen‐specific Tr cells are more potent at blocking pathogenic immune responses. In order to better understand the role of Tr cells in controlling type 1 diabetes development and to help design effective antigen‐specific cell‐based therapeutic methods to treat the disease, it is necessary to: (a) determine the antigen specificity of Tr cells; (b) study how antigen‐specific Tr cells behave in vivo; (c) investigate the interaction of Tr cells with pathogenic T cells (Tpath cells) and determine whether such interaction correlates with the progression or inhibition of diabetes; and (d) determine the cellular and molecular mechanisms underlying the regulation of diabetes by Tr cells. We have addressed these questions with a focus on the studies of glutamic acid decarboxylase (GAD)‐specific T cells. Previous studies have suggested that GAD‐specific T cells play a key role in type 1 diabetes. Treatment of NOD mice with GAD or its peptides can prevent the progression toward overt disease. The preventive effect could be due to either the deletion of antigen‐specific pathogenic T cells or the induction of potent antigen‐specific Tr cells. Using antigen‐specific I‐Ag7 tetramers we have isolated several populations of GAD peptide‐specific T cells from diabetes‐prone NOD and diabetes‐resistant NOR mice. Herein, we summarize our studies on the role of these GAD peptide‐specific T cells in type 1 diabetes. We present evidence that supports the hypothesis that the repertoire of T cells specific for these GAD peptides is biased toward Tr cells that inhibit diabetes rather than toward pathogenic T cells that induce diabetes.
HLA Class I Epitope Discovery in Type 1 Diabetes
Authors: VAN ENDERT PETER , HASSAINYA YOUSRA , LINDO VIVIAN , BACH JEAN‐MARIE , BLANCOU PHILIPPE , LEMONNIER FRANÇOIS , MALLONE ROBERTO
Published: November 2006

Abstract:  Type 1 diabetes mellitus (T1DM) results from the destruction of β cells by autoantigen‐specific T cells. In the non‐obese diabetic (NOD) mouse model, CD8+ T cells play an essential role in both the initial triggering of insulitis and its destructive phase, and proinsulin (PI) is one of the dominant target antigens (Ags). However, little is known about the beta cell epitopes presented by HLA class I molecules and recognized by human CD8+ T cells. We and other groups recently applied reverse immunology approaches to identify HLA class I‐restricted PI epitopes. To establish an inventory of potential naturally processed epitopes, whole human PI or the transitional region between the B‐chain and C‐peptide were digested with purified proteasome complexes. By combining proteasome digestion data with epitope prediction algorithms, candidate epitopes restricted by HLA‐A2.1 and other HLA class I molecules were identified. We validated immunogenicity and natural processing of the identified PI epitopes in HLA‐A2.1‐transgenic mice, while others demonstrated recognition of multiple PI epitopes by CD8+ T cells from T1DM and healthy subjects in the context of different HLA class I molecules. These results demonstrate the power of reverse immunology strategies for epitope discovery. DNA vaccination of HLA‐transgenic mice may be another rapid and efficient reverse immunology approach to map additional epitopes derived from other T1DM Ags, such as IA‐2 and glutamic acid decarboxylase 65 (GAD 65). Transfer of this information to Elispot‐ and MHC tetramer‐based assay formats should allow to reliably detect and characterize autoreactive CD8+ T cell responses in T1DM, and may open new avenues for early T1DM diagnosis and immune intervention.
Association of SUMO4 M55V Polymorphism with Autoimmune Diabetes in Latvian Patients
Authors: SEDIMBI SAIKIRAN K. , SHASTRY ARUN , PARK YONGSOO , RUMBA INGRIDA , SANJEEVI CARANI B.
Published: November 2006

Abstract:  Small ubiquitin‐related modifier (SUMO4), located in IDDM5, has been identified as a potential susceptibility gene for type 1 diabetes mellitus (T1DM). The novel polymorphism M55V, causing an amino acid change in the evolutionarily conserved met55 residue has been shown to activate the nuclear factor κB (NF‐κB), hence the suspected role of SUMO4 in the pathogenicity of T1DM. The M55V polymorphism has been shown to be associated with susceptibility to T1DM in Asians, but not in Caucasians. Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of T1DM and SUMO4 M55V has not been studied in LADA to date. The current study aims to test whether Latvians are similar to Caucasians in susceptibility to autoimmune diabetes (T1DM and LADA), with respect to SUMO4 M55V. We studied, age‐ and sex‐matched, Latvian T1DM patients (n= 100) and healthy controls (n= 90) and LADA patients (n= 45) and healthy controls (n= 95). SUMO4 M55V polymorphism was analyzed using polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP)
. The allelic frequencies of the A and G alleles were compared with HLA DR3–DR4‐positive and HLA DR3‐DR4‐negative patients to identify any potential relation between HLA DR3–DR4 and SUMO4 M55V. We found no significant association between SUMO4 M55V and T1DM susceptibility in Latvians, the results being in concurrence with the previous studies in Caucasians of British and Canadian origin. Comparison of the A and G alleles with HLA DR3–DR4 did not result in any significant P values. No significant association was found between SUMO4 M55V and LADA. SUMO4 M55V is not associated with susceptibility to T1DM and LADA in Latvians, and Latvians exhibit similarity to other Caucasians with respect to association of SUMO4 M55V with autoimmune diabetes.
Feasibility of a Type 1 Diabetes Primary Prevention Trial Using 2000 IU Vitamin D3 in Infants from the General Population with Increased HLA‐Associated Risk
Authors: WICKLOW BRANDY A. , TABACK SHAYNE P.
Published: November 2006

Abstract:  Recent epidemiologic, immunologic, and NOD mouse studies suggest that intervention in the vitamin D system may be a successful method to prevent type 1 diabetes. Newborns at increased HLA‐associated risk are randomized to receive either 400 or 2000 IU vitamin D3 by 1 month of age. We show that recruitment of babies from the general population for identification of HLA‐associated risk status followed by enrollment to a randomized controlled prevention trial is feasible in Canada.
Why Diabetes Incidence Increases—A Unifying Theory
Authors: LUDVIGSSON JOHNNY
Published: November 2006

Abstract:  There is a wide spectrum within the diabetes syndrome. Type 1 diabetes may have a slow progression with good residual insulin secretion and without autoantibodies, while phenotypic type 2 diabetes may have autoantibodies. A single patient may have traits of both types of diabetes. Their incidence increases in parallel. The etiology is mainly unknown, but environmental factors play an important role in genetically predisposed individuals. The search for just one single cause of manifest diabetes may be confusing. Different mechanism may be important in different parts of the world. Furthermore, certain mechanisms may lead to islet inflammation while other/additional mechanisms may increase insulin demand and cause insulin deficiency with manifestation of clinical diabetes. Several hypothesis of etiology may fit different parts of the disease process. Thus, increased hygiene may contribute to an imbalance of the immune system, facilitating autoimmune reactions when virus infections, or proteins like cow's milk or gluten, provoke. Increased insulin demand because of rapid growth, or insulin resistance caused by stress, infections, puberty, etc., lead to β cell stress, antigen presentation and may cause both an autoimmune reaction in genetically predisposed individuals, and insulin deficiency leading to manifest diabetes in individuals who have lost β cell function. Vitamins may modulate the immune process, but we know too little to give vitamin substitution. However, we do know that low physical exercise, obesity, and stress, increases insulin demand resulting in insulin deficiency. Now we can therefore intervene to prevent the diabetic syndrome.
Preface
Authors: SIDEMAN SAMUEL
Published: November 2006

Abstract:  The goal of clinical cardiology is to obtain an integrated picture of the interacting parameters of muscle and vessel mechanics, blood circulation and myocardial perfusion, oxygen consumption and energy metabolism, and electrical activation and heart rate, thus relating to the true physiological and pathophysiological characteristics of the heart. Scientific insight into the cardiac physiology and performance is achieved by utilizing life sciences, for example, molecular biology, genetics and related intra‐ and intercellular phenomena, as well as the exact sciences, for example, mathematics, computer science, and related imaging and visualization techniques. The tools to achieve these goals are based on the intimate interactions between engineering science and medicine and the developments of modern, medically oriented technology. Most significant is the beneficiary effect of the globalization of science, the Internet, and the unprecedented international interaction and scientific cooperation in facing difficult multidisciplined challenges. This meeting aims to explore some important interactions in the cardiac system and relate to the integration of spatial and temporal interacting system parameters, so as to gain better insight into the structure and function of the cardiac system, thus leading to better therapeutic modalities.
Functional Studies of Individual Myosin Molecules
Authors: DANTZIG JODY A. , LIU TIM Y. , GOLDMAN YALE E.
Published: November 2006

Abstract:  The “conventional” isoform of myosin that polymerizes into filaments (myosin II) is the molecular motor powering contraction in all three types of muscle. Considerable attention has been paid to the developmental progression, isoform distribution, and mutations that affect myocardial development, function, and adaptation. Optical trap (laser tweezer) experiments and various types of high‐resolution fluorescence microscopy, capable of interrogating individual protein motors, are revealing novel and detailed information about their functionally relevant nanometer motions and pico‐Newton forces. Single‐molecule laser tweezer studies of cardiac myosin isoforms and their mutants have helped to elucidate the pathogenesis of familial hypertrophic cardiomyopathies. Surprisingly, some disease mutations seem to enhance myosin function. More broadly, the myosin superfamily includes more than 20 nonfilamentous members with myriad cellular functions, including targeted organelle transport, endocytosis, chemotaxis, cytokinesis, modulation of sensory systems, and signal transduction. Widely varying genetic, developmental and functional disorders of the nervous, pigmentation, and immune systems have been described in accordance with these many roles. Compared to the collective nature of myosin II, some myosin family members operate with only a few partners or even alone. Individual myosin V and VI molecules can carry cellular vesicular cargos much farther distances than their own size. Laser tweezer mechanics, single‐molecule fluorescence polarization, and imaging with nanometer precision have elucidated the very different mechano‐chemical properties of these isoforms. Critical contributions of nonsarcomeric myosins to myocardial development and adaptation are likely to be discovered in future studies, so these techniques and concepts may become important in cardiovascular research.
Recruitment of New Cells into the Postnatal Heart
Authors: VISCONTI RICHARD P. , MARKWALD ROGER R.
Published: November 2006

Abstract:  Establishment of the circulatory system occurs very early in development to support the rapid growth of the embryo. Therefore, the heart is the first functional organ to be formed during both avian and mammalian development. Historically, cardiac development has been considered to occur only during embryogenesis from cell sources located within the primordial structures that generate the myocardium and associated coronary vascular endothelium and smooth muscle and cardiac fibroblasts. Recently, however, contribution to the cardiac structures has been demonstrated to occur during embryonic development from extracardiac sources, like the anterior heart field, raising questions as to whether cardiogenesis may be an ongoing process that extends into adult life. In this brief article, we describe the contribution of circulating adult bone marrow hematopoietic stem cells to the cardiac cell populations and the potential regulation of their differentiation by the extracellular matrix protein, periostin.
Embryonic Heart Induction
Authors: FOLEY ANN C. , GUPTA RUCHIKA W. , GUZZO ROSA M. , KOROL OKSANA , MERCOLA MARK
Published: November 2006

Abstract:  We have characterized two signaling pathways that induce heart tissue during embryonic development. The first is initiated by the Wnt antagonist Dickkopf1 (Dkk1) and involves the homeodomain transcription factor Hex. Other Wnt antagonists are less effective and the potency of Dkk1 might be due to synergy between Wnt antagonizing and another, novel activity emanating from its amino terminal cysteine‐rich domain. The second signal is initiated by Nodal and its co‐receptor Cripto. Importantly, both the Dkk1/Wnt antagonism and Nodal pathways act on the endoderm that underlies the future heart to control secretion of diffusible factors that induce cardiogenesis in adjacent mesoderm.
In this article, we summarize data that Dkk1 induces cardiogenic differentiation cell non‐autonomously through the action of the homeodomain transcription factor Hex. We also discuss recent data showing that Nodal also acts indirectly through stimulation of the secreted protein Cerberus, which is a member of the differential‐screening selected aberrant in neuroblastoma (DAN) family of secreted proteins. Finally, we present the model that signaling from Dkk1 regulates novel activities, in addition to Wnt antagonism, which are essential for progression beyond initiation of cardiogenesis to control later stages of cardiomyocyte differentiation and myocardial tissue organization.
The Role of Basic Leucine Zipper Protein‐Mediated Transcription in Physiological and Pathological Myocardial Hypertrophy
Authors: KEHAT IZHAK , HASIN TAL , ARONHEIM AMI
Published: November 2006

Abstract:  Accumulating evidence suggests that nuclear transcription factors from the basic leucine zipper (bZIP) family play an important role in cardiac development and function. This class includes the CREB/ATF family of transcription factors, namely CREB, cAMP response element modulator (CREM), ATF, and the related AP‐1 and C/EBP families. An effort has been made to elucidate the role of specific bZIP members in the heart. Unfortunately, little insight could be gained from knockout experiments, either due to embryonic lethal phenotypes or functional compensation by other bZIP family members. Surprisingly, cardiac overexpression of several inhibitory transcription factors from the bZIP family, such as a nonphosphorylatable form of CREB (CREBser133), a nonfunctional isoform of CREM, or ATF3 resulted in massive atrial dilatation.
In order to try and characterize this pathway we have expressed the potent bZIP inhibitory protein, Jun dimerization protein 2 (JDP2), specifically in the mouse heart in a temporally controlled manner. Expression of JDP2 resulted in massive biatrial dilatation; loss of connexin 40 (Cx40), connexin43 (C×43), and myosin light chain 2 (MLC2a) expression; atrioventricular defects in conduction; and a lethal phenotype. All these effects were independent of any developmental events acquired during adulthood, and were totally reversible upon abolishing the bZIP inhibition. The results of this article suggest that bZIP inhibition is sufficient to cause atrial dilation, that this dilatation is acquired postnatally, and that it is reversible upon the relief of inhibition. Thus, bZIP repressors may serve as novel drug targets for the prevention of atrial dilatation a major risk of atrial fibrillation (AF).
Hypertrophy and Atrophy of the Heart
Authors: RAZEGHI PETER , TAEGTMEYER HEINRICH
Published: November 2006

Abstract:  The size of a cardiomyocyte is determined by relative rates of protein synthesis and degradation. Signaling pathways regulating myocardial protein synthesis have been extensively investigated, not the least because in patients hypertrophy increases cardiovascular morbidity and mortality. Until now strategies to reverse hypertrophy have relied on the inhibition of prohypertrophic signaling pathways. Here we review signaling pathways of atrophy in the heart and we present evidence in support of the idea that activating proatrophic signaling pathways in the presence of prohypertrophic signaling may be an attractive strategy to reverse hypertrophy.
Role of Cellular Compartmentation in the Metabolic Response to Stress
Authors: ZHOU LUFANG , YU XIN , CABRERA MARCO E. , STANLEY WILLIAM C.
Published: November 2006

Abstract:  The mechanisms controlling ATP generation in the transition from normal resting conditions to either high work states or ischemia are poorly understood. ATP generation depends upon compartmentation between the mitochondria and cytosol of metabolic pathways and key energy transfer species that cannot be easily assessed experimentally. We developed a multicompartment mathematical model of cardiac metabolism to simulate the metabolic responses to ischemia and increased workload. The model is based on mass balances, transport, and metabolic processes in cardiac tissue, and has three distinct compartments (blood, cytosol, and mitochondria). In addition to distinguishing between cytosol and mitochondria, the model includes a cytosolic subcompartment for glycolytic metabolic channeling. The model simulations predict the rapid activation of glycogenolysis and lactate production at the onset of ischemia, and support the concept of localization of glycolysis to a cytosolic subcompartment. In addition, simulations show that mitochondrial NADH/NAD+ is primarily determined by oxygen consumption during ischemia, while cytosolic NADH/NAD+ and lactate production are largely a function of glycolytic flux during the initial phase, and is controlled by mitochondrial NADH/NAD+ and the malate–aspartate shuttle during the steady state. Finally, the model predicts that metabolic activation with an abrupt increase in workload requires parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and ADP phosphorylation. Taken together, these studies demonstrate the importance of metabolic compartmentation in the regulation of cardiac energetics in response to acute stress, and they highlight the usefulness of computational models in this line of investigation.
Maintenance of the Metabolic Homeostasis of the Heart
Authors: BALABAN ROBERT S.
Published: November 2006

Abstract:  The heart is almost unique in the body with a constant requirement to conduct work well beyond the normal maintenance of cellular integrity. With this constant workload, it is not surprising that cardiac energy conversion is highly specialized to maintain a constant supply of energy. This maintenance of cellular metabolites during alterations in workload has been termed metabolic homeostasis. Here we discuss our efforts to understand the cellular and mitochondrial control network that orchestrates the metabolic homeostasis of the heart. This begins with a better definition of the metabolic pathways, acute posttranslational control sites, and proper kinetic evaluation of the reaction steps in the intact mitochondrial environment. First, a quantitative model of mitochondrial energy conversion is presented and demonstrates several serious gaps in our knowledge of this process. Toward filling these gaps, screens of the entire mitochondrial proteome have been conducted to establish the metabolic pathways that need to be considered. In addition, the dynamic phosphoproteome of intact mitochondria, using 2D gel electrophoresis coupled to 32P labeling, has revealed a remarkably extensive protein phosphorylation network throughout the mitochondrial metabolic network that has essentially been overlooked. Initial studies on evaluating the functional significance of these protein phosphorylations and the kinase–phosphatase system involved will be reviewed. One of the major deficits in the consensus quantitative model of oxidative phosphorylation to explain intact mitochondria activities is in complex I, where even the initiation of Nicotinamide Adenine Dinucleotide (reduced) (NADH) oxidation is problematical using

in vitro

kinetic data.
Studies will be described where the NADH binding and oxidation kinetics at complex I in the intact mitochondria were determined using fluorescence lifetime and enzyme dependent‐fluorescence recovery after photo‐oxidation (ED‐FRAP) techniques. These later studies suggest that matrix NADH binding characteristics are much different (>103 binding constant errors) than isolated proteins. In addition, complex I is far from equilibrium and may play an important role in regulating the rate of reducing equivalent delivery to the cytochromes.