bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytokine signalling in the β-cell: a dual role for IFNγ
Authors: Gysemans Conny , Callewaert Hanne , Overbergh Lutgart , Mathieu Chantal 
Published: June 2008

IFNγ (interferon γ), a cytokine typically secreted by infiltrating immune cells in insulitis in Type 1 diabetes, is by itself not detrimental to β-cells, but, together with other cytokines, such as IL-1β (interleukin 1β) and TNFα (tumour necrosis factor α), or dsRNA (double-stranded RNA), it induces β-cell apoptosis. The complex gene and protein networks that are altered by the combination of cytokines clearly point towards synergisms between these agents. IFNγ acts mostly via JAK (Janus kinase) activation, with the transcription factors STAT-1 (signal transducer and activator of transcription-1) and IRF-1 (IFNγ regulatory factor-1) playing a central role in the downstream pathway. The study of mice with a disruption of these transcription factors has revealed a possible dual role for IFNγ in β-cell destruction by cytokines or dsRNA. We demonstrated that the absence of STAT-1 from β-cells completely protects against IFNγ+IL-1β- and IFNγ+dsRNA-mediated β-cell death in vitro, whereas absence of IRF-1 does not prevent cytokine-induced β-cell apoptosis. In vivo, a lack of the IRF-1 gene in pancreatic islets even promotes low-dose streptozotocin-induced diabetes, whereas lack of STAT-1 confers resistance against β-cell death following low-dose streptozotocin-induced diabetes. Additionally, IRF-1−/− islets are more sensitive to PNF (primary islet non-function) after transplantation in spontaneously diabetic NOD (non-obese diabetic) mice, whereas STAT-1−/− islets are fully protected. Moreover, proteomic analysis of β-cells exposed to IFNγ or IFNγ+IL-1β confirms that very different pathways are activated by IFNγ alone compared with the combination. We conclude that IFNγ may play a dual role in immune-induced β-cell destruction. Transcription factors drive this dual role, with STAT-1 driving β-cell destruction and IRF-1 possibly playing a role in up-regulation of protective pathways induced by IFNγ.
Role of NF-κB in β-cell death
Authors: Melloul Danielle 
Published: June 2008

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.
Oxidative stress: the vulnerable β-cell
Authors: Lenzen Sigurd 
Published: June 2008

Antioxidative defence mechanisms of pancreatic β-cells are particularly weak and can be overwhelmed by redox imbalance arising from overproduction of reactive oxygen and reactive nitrogen species. The consequences of this redox imbalance are lipid peroxidation, oxidation of proteins, DNA damage and interference of reactive species with signal transduction pathways, which contribute significantly to β-cell dysfunction and death in Type 1 and Type 2 diabetes mellitus. Reactive oxygen species, superoxide radicals (O2•−), hydrogen peroxide (H2O2) and, in a final iron-catalysed reaction step, the most reactive and toxic hydroxyl radicals (OH•) are produced during both pro-inflammatory cytokine-mediated β-cell attack in Type 1 diabetes and glucolipotoxicity-mediated β-cell dysfunction in Type 2 diabetes. In combination with NO•, which is toxic in itself, as well as through its reaction with the O2•− and subsequent formation of peroxynitrite, reactive species play a central role in β-cell death during the deterioration of glucose tolerance in the development of diabetes.
Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes
Authors: Cnop Miriam 
Published: June 2008

The prevalence of Type 2 diabetes is increasing dramatically as a result of the obesity epidemic, and poses a major health and socio-economic burden. Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin secretion. This insulin deficiency results from pancreatic β-cell dysfunction and death. Western diets rich in saturated fats cause obesity and insulin resistance, and increase levels of circulating NEFAs [non-esterified (‘free’) fatty acids]. In addition, they contribute to β-cell failure in genetically predisposed individuals. NEFAs cause β-cell apoptosis and may thus contribute to progressive β-cell loss in Type 2 diabetes. The molecular pathways and regulators involved in NEFA-mediated β-cell dysfunction and apoptosis are beginning to be understood. We have identified ER (endoplasmic reticulum) stress as one of the molecular mechanisms implicated in NEFA-induced β-cell apoptosis. ER stress was also proposed as a mechanism linking high-fat-diet-induced obesity with insulin resistance. This cellular stress response may thus be a common molecular pathway for the two main causes of Type 2 diabetes, namely insulin resistance and β-cell loss. A better understanding of the molecular mechanisms contributing to pancreatic β-cell loss will pave the way for the development of novel and targeted approaches to prevent Type 2 diabetes.
Transdifferentiation of pancreatic ductal cells to endocrine β-cells
Authors: Bonner-Weir Susan , Inada Akari , Yatoh Shigeru , Li Wan-Chun , Aye Tandy , Toschi Elena , Sharma Arun 
Published: June 2008

The regenerative process in the pancreas is of particular interest, since diabetes, whether Type 1 or Type 2, results from an inadequate amount of insulin-producing β-cells. Islet neogenesis, or the formation of new islets, seen as budding of hormone-positive cells from the ductal epithelium, has long been considered to be one of the mechanisms of normal islet growth after birth and in regeneration, and suggested the presence of pancreatic stem cells. Results from the rat regeneration model of partial pancreatectomy led us to hypothesize that differentiated pancreatic ductal cells were the pancreatic progenitors after birth, and that with replication they regressed to a less differentiated phenotype and then could differentiate to form new acini and islets. There are numerous supportive results for this hypothesis of neogenesis, including the ability of purified primary human ducts to form insulin-positive cells budding from ducts. However, to rigorously test this hypothesis, we took a direct approach of genetically marking ductal cells using CAII (carbonic anhydrase II) as a duct-cell-specific promoter to drive Cre recombinase in lineage-tracing experiments using the Cre-Lox system. We show that CAII-expressing pancreatic cells act as progenitors that give rise to both new islets and acini after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes either in vivo or ex vivo.
SUMO, hypoxia and the regulation of metabolism
Authors: Agbor Terence A. , Taylor Cormac T. 
Published: June 2008

Post-translational modification is a critical event in the dynamic regulation of protein stability, location, structure, function, activity and interaction with other proteins and as such plays an important role in organism complexity. Over the last 10 years, the extensive and critical role of one such protein modification by SUMO (small ubiquitin-related modifier) has become apparent. The focus of this mini-review will be on recent reports of a possible functional role for the SUMO pathway in the adaptive cellular response to metabolic challenge, such as oxygen deprivation (hypoxia). Here, we will briefly review the evolving evidence for this pathway in the regulation of a number of metabolic regulators and discuss a possible role for SUMOylation in the regulation of basic metabolic function.
Human papillomavirus type 16 late gene expression is regulated by cellular RNA processing factors in response to epithelial differentiation
Authors: Cumming Sarah A. , Cheun-Im Thanaporn , Milligan Stephen G. , Graham Sheila V. 
Published: June 2008

HPV16 (human papillomavirus type 16) is a 7.9 kb double-stranded DNA virus that infects anogenital mucosal epithelia. In some rare cases, in women, infection can progress to cervical cancer. HPV16 gene expression is regulated through use of multiple promoters and alternative splicing and polyadenylation. The virus genome can be divided into an early and a late coding region. The late coding region contains the L1 and L2 genes. These encode the virus capsid proteins L1 and L2; protein expression is confined to the upper epithelial layers and is regulated post-transcriptionally in response to epithelial differentiation. A 79 nt RNA regulatory element, the LRE (late regulatory element), involved in this regulation is sited at the 3′-end of the L1 gene and extends into the late 3′-UTR (3′-untranslated region). This element represses late gene expression in differentiated epithelial cells and may activate it in differentiated cells. The present paper describes our current knowledge of LRE RNA–protein interaction and their possible functions.
Heat-shock protein gene polymorphisms and the risk of nephropathy in patients with Type 2 diabetes
Authors: Buraczynska Monika , Swatowski Andrzej , Buraczynska Kinga , Dragan Michal , Ksiazek Andrzej 
Published: June 2008

HSPs (heat-shock proteins) are molecular chaperones synthesized under stress conditions, and are involved in renal cell survival and matrix remodelling in acute and chronic renal diseases. In the present study, we investigated whether the HSP70 gene polymorphisms affect susceptibility to DN (diabetic nephropathy) in patients with T2DM (Type 2 diabetes mellitus). The study group consisted of 452 patients with nephropathy. Two control subgroups involved 340 healthy individuals and 132 patients with T2DM lasting ≥10 years who were free of nephropathy. Subjects were genotyped for the HSP70-1 +190 G/C and −110 A/C, HSP70-2 +1267 A/G and HSP70-hom +2437 T/C polymorphisms by PCR, followed by digestion with restriction endonucleases. There were no statistically significant differences in genotype distribution between patients with T2DM with DN and controls for the HSP70-hom polymorphism. Significant differences were observed for HSP70-1 and HSP70-2 polymorphisms. CC homozygotes of the −110 and +190 HSP70-1 polymorphisms were more frequent in patients with T2DM with DN compared with healthy controls (22 compared with 6% and 15 compared with 6.5% respectively; P&lt;0.01). The OR (odds ratio) for the risk allele was 2.17 [95% CI (confidence interval), 1.73–2.72] for the −110 A/C and 1.74 (95% CI, 1.40–2.15) for +190 G/C polymorphisms. A strong association with DN was found for the +1267 HSP70-2 polymorphism. The GG genotype and the G allele were associated with DN, with the OR for the G allele being 4.77 (95% CI, 3.81–5.96). All GG homozygotes in the patient group had higher LDL (low-density lipoprotein)-cholesterol levels than AA homozygotes (P&lt;0.01), suggesting that the observed effect might be associated with this cardiovascular risk factor. These patients progressed faster to end-stage renal failure than those with other genotypes. In conclusion, our results indicate that the HSP70-1 and HSP70-2 polymorphisms are associated with renal complications in T2DM and may be useful in identifying patients with increased risk of DN.
Injury to rat carotid arteries causes time-dependent changes in gene expression in contralateral uninjured arteries
Authors: Forte Amalia , Finicelli Mauro , de Luca Pasquale , Nordström Ina , Onorati Francesco , Quarto Cesare , Santè Pasquale , Renzulli Attilio , Galderisi Umberto , Berrino Liberato , de Feo Marisa , Hellstrand Per , Rossi Francesco , Cotrufo Maurizio , Cascino Antonino , Cipollaro Marilena 
Published: June 2008

Vascular surgery aimed at stenosis removal induces local reactions often leading to restenosis. Although extensive analysis has been focused on pathways activated in injured arteries, little attention has been devoted to associated systemic vascular reactions. The aim of the present study was to analyse changes occurring in contralateral uninjured rat carotid arteries in the acute phase following unilateral injury. WKY (Wistar–Kyoto) rats were subjected to unilateral carotid arteriotomy. Contralateral uninjured carotid arteries were harvested from 4 h to 7 days after injury. Carotid arteries were also harvested from sham-operated rats and uninjured rats. Carotid morphology and morphometry were examined. Affymetrix microarrays were used for differential analysis of gene expression. A subset of data was validated by real-time RT–PCR (reverse transcription–PCR) and verified at the protein level by Western blotting. A total of 1011 genes were differentially regulated in contralateral uninjured carotid arteries from 4 h to 7 days after arteriotomy (P&lt;0.0001; fold change, ≥2) and were classified into 19 gene ontology functional categories. To a lesser extent, mRNA variations also occurred in carotid arteries of sham-operated rats. Among the changes, up-regulation of members of the RAS (renin–angiotensin system) was detected, with possible implications for vasocompensative mechanisms induced by arteriotomy. In particular, a selective increase in the 69 kDa isoform of the N-domain of ACE (angiotensin-converting enzyme), and not the classical somatic 195 kDa isoform, was observed in contralateral uninjured carotid arteries, suggesting that this 69 kDa isoenzyme could influence local AngII (angiotensin II) production. In conclusion, systemic reactions to injury occur in the vasculature, with potential clinical relevance, and suggest that caution is needed in the choice of controls during experimental design in vivo.
Impact of an Environmental Cleaning Intervention on the Presence of Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci on Surfaces in Intensive Care Unit Rooms
Authors: Goodman Eric R. , Piatt Richard , Bass Richard , Onderdonk Andrew B. , Yokoe Deborah S. , Huang Susan S. 
Published: June 2008

Objectives.To evaluate the adequacy of discharge room cleaning and the impact of a cleaning intervention on the presence of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) on environmental surfaces in intensive care unit (ICU) rooms.Design.Prospective environmental study.Setting and sample.Convenience sample of ICU rooms in an academic hospital.Methods and intervention.The intervention consisted of (1) a change from the use of pour bottles to bucket immersion for applying disinfectant to cleaning cloths, (2) an educational campaign, and (3) feedback regarding adequacy of discharge cleaning. Cleaning of 15 surfaces was evaluated by inspecting for removal of a preapplied mark, visible only with an ultraviolet lamp (“black light”). Six surfaces were cultured for MRSA or VRE contamination. Outcomes of mark removal and culture positivity were evaluated by X2 testing and generalized linear mixed models, clustering by room.Results.The black-light mark was removed from 44% of surfaces at baseline, compared with 71 % during the intervention (P < .001). The intervention increased the likelihood of removal of black-light marks after discharge cleaning (odds ratio, 4.4; P < .001), controlling for ICU type (medical vs surgical) and type of surface. The intervention reduced the likelihood of an environmental culture positive for MRSA or VRE (proportion of cultures positive, 45% at baseline vs 27% during the intervention; adjusted odds ratio, 0.4; P = .02). Broad, flat surfaces were more likely to be cleaned than were doorknobs and sink or toilet handles.Conclusions.Increasing the volume of disinfectant applied to environmental surfaces, providing education for Environmental Services staff, and instituting feedback with a black-light marker improved cleaning and reduced the frequency of MRSA and VRE contamination.
MINS2: Revisiting the molecular code for transmembrane-helix recognition by the Sec61 translocon
Authors: Park Yungki , Helms Volkhard 
Published: June 2008

Abstract
Summary: To be fully functional, membrane proteins should not only fold, but also get inserted into the membrane, which is mediated by the Sec61 translocon. Recent experimental studies have attempted to elucidate how the Sec61 translocon accomplishes this delicate task by measuring the translocon-mediated membrane insertion free energies of 357 systematically designed peptides. On the basis of this data set, we have developed MINS2, a novel sequence-based computational method for predicting the membrane insertion free energies of protein sequences. A benchmark analysis of MINS2 shows that MINS2 significantly outperforms previously proposed methods. Importantly, the application of MINS2 to known membrane protein structures shows that a better prediction of membrane insertion free energies does not lead to a better prediction of transmembrane segments of polytopic membrane proteins.
Availability: A web server for MINS2 is publicly available at http://service.bioinformatik.uni-saarland.de/mins.
Contact: volkhard.helms@bioinformatik.uni-saarland.de
Supplementary information: Supplementary data are available at Bioinformatics online.
DNAlive: a tool for the physical analysis of DNA at the genomic scale
Authors: Goñi J. Ramon , Fenollosa Carlos , Pérez Alberto , Torrents David , Orozco Modesto 
Published: June 2008

Abstract
Summary: DNAlive is a tool for the analysis and graphical display of structural and physical characteristics of genomic DNA. The web server implements a wide repertoire of metrics to derive physical information from DNA sequences with a powerful interface to derive 3D information on large sequences of both naked and protein-bound DNAs. Furthermore, it implements a mesoscopic Metropolis code which allows the inexpensive study of the dynamic properties of chromatin fibers. In addition, our server also surveys other protein and genomic databases allowing the user to combine and explore the physical properties of selected DNA in the context of functional features annotated on those regions.
Availability: http://mmb.pcb.ub.es/DNAlive/ ; http://www.inab.org/
Contact: modesto@mmb.pcb.ub.es
Supplementary information: Supplementary data are available at Bioinformatics online.
Microarray-based classification and clinical predictors: on combined classifiers and additional predictive value
Authors: Boulesteix Anne-Laure , Porzelius Christine , Daumer Martin 
Published: June 2008

AbstractMotivation: In the context of clinical bioinformatics methods are needed for assessing the additional predictive value of microarray data compared to simple clinical parameters alone. Such methods should also provide an optimal prediction rule making use of all potentialities of both types of data: they should ideally be able to catch subtypes which are not identified by clinical parameters alone. Moreover, they should address the question of the additional predictive value of microarray data in a fair framework.Results: We propose a novel but simple two-step approach based on random forests and partial least squares (PLS) dimension reduction embedding the idea of pre-validation suggested by Tibshirani and colleagues, which is based on an internal cross-validation for avoiding overfitting. Our approach is fast, flexible and can be used both for assessing the overall additional significance of the microarray data and for building optimal hybrid classification rules. Its efficiency is demonstrated through simulations and an application to breast cancer and colorectal cancer data.Availability: Our method is implemented in the freely available R package ‘MAclinical’ which can be downloaded from http://www.stat.uni-muenchen.de/~socher/MAclinicalContact: boulesteix@slcmsr.org
First Report of Lethal Yellowing Group (16Sr IV) of Phytoplasmas in Vernonia cinerea in Jamaica
Authors: Brown S. E. , Been B. O. , McLaughlin W. A. 
Published: June 2008

Coconut lethal yellowing disease (CLY) has had a devastating effect on the coconut (Cocos nucifera L.) industry in Jamaica and Latin America. A study was conducted in Jamaica during 2005 to identify alternate hosts of the CLY phytoplasma. Since weeds are known to act as reservoir hosts of numerous pathogens, Vernonia cinerea (L.) (Asteraceae), a prevalent weed species on coconut farms island-wide, was collected from coconut farms in areas of high and low levels of CLY incidence, although none of the plants displayed disease symptoms. DNA was extracted from plant samples by the method of Dellaporta et al. (1) and analyzed by nested PCR assay employing phytoplasma universal rRNA operon primers P1/P7 (2,4) and LY16Sf/LY16-23Sr (3). DNA derived from CLY-diseased or healthy coconut palm served as positive and negative controls, respectively, in each assay. Amplification of an rDNA product of the expected size (1.7 kb) confirmed phytoplasma infections in 53 of 118 (44.9%) V. cinerea test plants. Twenty-seven of the rDNA PCR products were analyzed by digestion with restriction enducleases RsaI, MspI, MseI, TaqI, HinfI, and HhaI. The restriction fragment length polymorphism profiles obtained were similar to that observed in the CLY-infected coconut palm. V. cinerea rDNA amplicons were cloned and sequenced (in both directions) and a representative sequence was deposited in GenBank (Accession No. EU057983). Blast analysis determined this sequence to be most similar (99%) to that of CLY phytoplasma in Jamaica (Accession No. AF49807) and Florida (Accession No. AF498309). To our knowledge, this is the first report of the 16Sr IV group of phytoplasmas infecting V. cinerea. Presence of the lethal yellowing phytoplasmas in dicotyledonous plant species has important epidemiological implications concerning vector identity and ecology. Futhermore, it is now evident that weed control on coconut farms could assist in the management of CLY disease in Jamaica. References: (1) S. L. Dellaporta et al. Plant Mol. Biol. Rep. 1:19, 1993. (2) S. Deng and C. Hiruki. J. Microbiol. Methods 14:53, 1991. (3) N. A. Harrison et al. Ann. Appl. Biol. 141:183, 2002. (4) C. D. Smart et al. Appl. Environ. Microbiol. 62:2988, 1996.