bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid three-dimensional imaging of individual insulin release events by Nipkow disc confocal microscopy
Authors: Rutter G.A. , Loder M.K. , Ravier M.A. 
Published: October 2006

Minute-to-minute control of the release of insulin by pancreatic β-cells in response to glucose or other stimuli requires the precise delivery of large dense-core vesicles to the plasma membrane and regulated exocytosis. At present, the precise spatial organization at the cell surface and the nature of these events (‘transient’ versus ‘full fusion’) are debated. In order to monitor secretory events simultaneously over most of the surface of clusters of single MIN6 β-cells, we have expressed recombinant neuropeptide Y-Venus (an enhanced and vesicle-targeted form of yellow fluorescent protein) as an insulin surrogate. Individual exocytotic events were monitored using Nipkow spinning disc confocal microscopy, with acquisition of a three-dimensional complete image (eight to twelve confocal slices) in &lt;1 s, in response to cell depolarization. Corroborating earlier studies using TIRF (total internal reflection fluorescence) microscopy, this approach indicates that events occur with roughly equal probability over the entire cell surface, with only minimal clustering in individual areas, and provides no evidence for multiple events at the same site. Nipkow disc confocal imaging may thus provide a useful tool to determine whether event types occur at different sites at the cell surface and to explore the role of endocytic proteins including dynamin-1 and -2 in terminating individual exocytotic events.
Interactions between Rabs, tethers, SNAREs and their regulators in exocytosis
Authors: Novick P. , Medkova M. , Dong G. , Hutagalung A. , Reinisch K. , Grosshans B. 
Published: October 2006

Sec2p is the exchange factor that activates Sec4p, the Rab GTPase controlling the final stage of the yeast exocytic pathway. Sec2p is recruited to secretory vesicles by Ypt32-GTP, a Rab controlling exit from the Golgi. Sec15p, a subunit of the octameric exocyst tethering complex and an effector of Sec4p, binds to Sec2p on secretory vesicles, displacing Ypt32p. Sec2p mutants defective in the region 450–508 amino acids bind to Sec15p more tightly. In these mutants, Sec2p accumulates in the cytosol in a complex with the exocyst and is not recruited to vesicles by Ypt32p. Thus the region 450–508 amino acids negatively regulates the association of Sec2p with the exocyst, allowing it to recycle on to new vesicles. The structures of one nearly full-length exocyst subunit and three partial subunits have been determined and, despite very low sequence identity, all form rod-like structures built of helical bundles stacked end to end. These rods may bind to each other along their sides to form the assembled complex. While Sec15p binds Sec4-GTP on the vesicle, other subunits bind Rho GTPases on the plasma membrane, thus tethering vesicles to exocytic sites. Sec4-GTP also binds Sro7p, a yeast homologue of the Drosophila lgl (lethal giant larvae) tumour suppressor. Sro7 also binds to Sec9p, a SNAP25 (25 kDa synaptosome-associated protein)-like t-SNARE [target-membrane-associated SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor)], and can form a Sec4p–Sro7p–Sec9p ternary complex. Overexpression of Sec4p, Sro7p or Sec1p (another SNARE regulator) can bypass deletions of three different exocyst subunits. Thus promoting SNARE function can compensate for tethering defects.
Molecular misreading: the occurrence of frameshift proteins in different diseases
Authors: van Leeuwen F.W. , Kros J.M. , Kamphorst W. , van Schravendijk C. , de Vos R.A.I. 
Published: October 2006

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin–proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.
Gankyrin, the 26 S proteasome, the cell cycle and cancer
Authors: Mayer R.J. , Fujita J. 
Published: October 2006

The known molecular players in cell-cycle control are much studied, not only to learn more about this intricate system, but also to understand the molecular features of oncogenic transformation. Infrequently, new players are discovered that change the interpretation of cell-cycle control. Gankyrin is one such player and was discovered in yeast two-hybrid screens as a new proteasomal subunit that interacts specifically with the S6b (rpt3) AAA (ATPase associated with various cellular activities) ATPase, which, with five other AAAs, are present in the so-called base of the 19 S regulator of the 26 S proteasome. Gankyrin is also the first liver oncogene. Gankyrin is found in other complexes that contain Rb (retinoblastoma protein) and the ubiquitin protein ligase Mdm2 (murine double minute 2). Gankyrin increases the hyperphosphorylation of Rb and therefore activates E2F-dependent transcription of DNA synthesis genes. Additionally, gankyrin, by binding to Mdm2, increases the ubiquitylation and degradation of p53 and prevents apoptosis. Gankyrin controls the functions of two major tumour suppressors and, when overexpressed, causes hepatocellular carcinoma.
Maternal nutrition during pregnancy and health of the offspring
Authors: Martin-Gronert M.S. , Ozanne S.E. 
Published: October 2006

The ability of mother to provide nutrients and oxygen for her baby is a critical factor for fetal health and its survival. Failure in supplying the adequate amount of nutrients to meet fetal demand can lead to fetal malnutrition. The fetus responds and adapts to undernutrition but by doing so it permanently alters the structure and function of the body. Maternal overnutrition also has long-lasting and detrimental effects on the health of the offspring. There is growing evidence that maternal nutrition can induce epigenetic modifications of the fetal genome. Only relatively recently has evidence from epidemiological and animal studies emerged suggesting that fetal responses to the intrauterine environment may underlie the prevalence of many chronic diseases of adulthood including Type 2 (non-insulin-dependent) diabetes. It is now of crucial importance to gain the understanding of the molecular mechanisms underlying the relationship between fetal alterations to the intra-uterine environment and their long-term effects on the health of an individual.
The role of GABAA receptor biogenesis, structure and function in epilepsy
Authors: Mizielinska S. , Greenwood S. , Connolly C.N. 
Published: October 2006

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.
The structural biology of voltage-gated calcium channel function and regulation
Authors: Van Petegem F. , Minor D.L. 
Published: October 2006

Voltage-gated calcium channels (CaVs) are large (∼0.5 MDa), multisubunit, macromolecular machines that control calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, calcium-dependent gene transcription and synaptic transmission. CaVs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, calcium-dependent inactivation and calcium-dependent facilitation. These processes arise from the concerted action of different channel domains with CaV β-subunits and the soluble calcium sensor calmodulin. Until recently, nothing was known about the CaV structure at high resolution. Recent crystallographic work has revealed the first glimpses at the CaV molecular framework and set a new direction towards a detailed mechanistic understanding of CaV function.
Do voltage-gated calcium channel α2δ subunits require proteolytic processing into α2 and δ to be functional?
Authors: Douglas L. , Davies A. , Wratten J. , Dolphin A.C. 
Published: October 2006

The accessory α2δ subunits of voltage-gated calcium channels are type 1 transmembrane proteins that are highly glycosylated and possess multiple disulfide bonds. From studies of the topology and processing of skeletal-muscle α2δ-1, it has been shown to be post-translationally cleaved into an α2 and a δ subunit, which remain disulfide-bonded. In the present study, we have examined the processing of α2δ-2 subunits when stably or transiently expressed, in tsA (temperature-sensitive A)-201, Cos-7 and NG108-15 cells, and compared it with that observed in the cerebellum. Despite showing full functionality and being expressed on the plasma membrane, the vast majority of heterologously expressed α2δ-2 is not cleaved into α2-2 and δ-2, unlike endogenous α2δ-2 in the cerebellum. It remains an open question for future research whether α2δ-2 is functional in its calcium channel trafficking role in its proteolytically cleaved or non-cleaved state.
An Econometric Model of Migration Between US Metropolitan Areas
Authors: Alperovich Gershon , Bergsman Joel , Ehemann Christian 
Published: October 2006

We test a model of inter-metropolitan migration using 1965-70 data for 284 metropolitan areas from the 1970 Census of Population. Innovations in model specification permit us to derive estimatable equations for gross in- and out-migration from a point-to-point hypothesis. Measures of economic conditions (the unemployment rate, the growth rate in employment, and the wage rate) are shown to affect migration behaviour both at origins and destinations, as economic theory predicts. Expected effects of past migration on both subsequent in-migration and out-migration are confirmed. In addition, migrants are shown to prefer destination cities that have moderate climates, that are relatively small in size, and that are close to larger cities. The research reported in this paper is part of a larger study of the joint determination of growth in employment in US metropolitan areas and of migration flows between them.
Spatial Choice and Interaction Models: Criteria and Aggregation
Authors: van Lierop Wal , Nijkamp Peter 
Published: October 2006

The paper provides a framework for judging various spatial choice and interaction models on the basis of methodological, theoretical, logical and practical criteria. After a brief discussion of several common models (such as gravity models, entropy models, logit models, probit models and multiproportional Poisson models), the significance of these models is assessed by confronting them with the above-mentioned criteria, so that a qualitative evaluation can be made. The logit model which turns out to be a rather satisfactory spatial interaction model, is dealt with in more detail. Especially the problems of aggregation and disaggregation are analysed, while also a new contribution to logit models is provided by constructing a general probability density function for the population in case of more than two choice alternatives.
A Hierarchical Model of Housing Choice
Authors: Boehm Thomas P. 
Published: October 2006

The main objective of this paper is the construction of an expanded model of housing choice that includes not only tenure choice, which has traditionally been the subject of analysis, but also other housing characteristic choices. In this model the probability of the household making a given tenure choice is estimated at the first level of a choice hierarchy. The family's choices over dwelling size and quality are then estimated at succeeding levels of that hierarchy, conditionally on the choices which precede them. These conditional probabilities can be combined with the probability of tenure choice to produce eight joint probabilities of housing choice. In addition, for a particular household or group of households, we can determine the effect of a change in any of the systems variables on the probability of the families making a given housing choice. In the empirical section it is demonstrated that this model provides much greater insight than the conventional tenure choice study regarding the effects of income, relative prices, and other socioeconomic variables on the family's housing choices. Consequently, it is concluded that models of this type should provide a superior tool for designing effective housing policy.
The Fiscal Condition of American and Canadian Cities
Authors: Mercer John , Goldberg Michael A. 
Published: October 2006

The fiscal condition of American and Canadian cities is examined in this paper using municipal bond ratings from Moody's Investors Service for the period 1970-1980. Two hypotheses are posited: that Canadian central cities will exhibit greater fiscal health than will American central cities; over time Canadian and US cities will exhibit differences in changes in bond ratings with changes being more positive for the Canadian case. Neither hypothesis is refuted by the bond rating evidence presented in the paper. While the limited size of the Canadian sample of cities with Moody's bond rating precludes rigorous statistical tests, the findings are consistent with previous work which suggests that there are significant differences between Canadian and US cities and that the North American City concept must be used with care.
Duration of Methicillin-Resistant Staphylococcus aureus Carriage, According to Risk Factors for Acquisition
Authors: Marschall Jonas , Mühlemann Kathrin 
Published: October 2006

Objective.To examine the duration of methicillin-resistant Staphylococcus aureus (MRSA) carriage and its determinants and the influence of eradication regimens.Design.Retrospective cohort study.Setting.A 1,033-bed tertiary care university hospital in Bern, Switzerland, in which the prevalence of methicillin resistance among S. aureus isolates is less than 5%.Patients.A total of 116 patients with first-time MRSA detection identified at University Hospital Bern between January 1, 2000, and December 31, 2003, were followed up for a mean duration of 16.2 months.Results.Sixty-eight patients (58.6%) cleared colonization, with a median time to clearance of 7.4 months. Independent determinants for shorter carriage duration were the absence of any modifiable risk factor (receipt of antibiotics, use of an indwelling device, or presence of a skin lesion) (hazard ratio [HR], 0.20 [95% confidence interval {CI}, 0.09-0.42]), absence of immunosuppressive therapy (HR, 0.49 [95% CI, 0.23-1.02]), and hemodialysis (HR, 0.08 [95% CI, 0.01-0.66]) at the time MRSA was first MRSA detected and the administration of decolonization regimen in the absence of a modifiable risk factor (HR, 2.22 [95% CI, 1.36-3.64]). Failure of decolonization treatment was associated with the presence of risk factors at the time of treatment (P = .01). Intermittent screenings that were negative for MRSA were frequent (26% of patients), occurred early after first detection of MRSA (median, 31.5 days), and were associated with a lower probability of clearing colonization (HR, 0.34 [95% CI, 0.17-0.67]) and an increased risk of MRSA infection during follow-up.Conclusions.Risk factors for MRSA acquisition should be carefully assessed in all MRSA carriers and should be included in infection control policies, such as the timing of decolonization treatment, the definition of MRSA clearance, and the decision of when to suspend isolation measures.
Community-Acquired Infection With Healthcare-Associated Methicillin-Resistant Staphylococcus aureus: The Role of Home Nursing Care
Authors: Lescure François-Xavier , Locher Gwenaelle , Eveillard Mathieu , Biendo Maurice , Agt Stéphanie Van , Loup Guillaume Le , Douadi Youcef , Ganry Olivier , Vandenesch François , Eb François , Schmit Jean-Luc , Etienne Jerome 
Published: October 2006

Objective.To better understand the role of indirect transmission in community-acquired infection with methicillin-resistant Staphylococcus aureus (MRSA).Design.Prospective case-control study.Setting.A French teaching hospital.Patients.A total of 198 case patients and 198 control patients with MRSA or methicillin-susceptible S. aureus infection diagnosed between April 2002 and July 2003.Results.Multivariate analysis showed a highly significant independent link between MRSA infection at admission and prior receipt of home nursing care (odds ratio [OR], 3.7; P<.001). Other independent risk factors were prior hospitalization (OR, 3.8; P<.001), transfer from another institution (OR, 2.3; P = .008), and age older than 65 years (OR, 1.6; P = .04). Prior home nursing care showed a frequency dose-response relationship. Eleven MRSA-infected patients had had home nursing procedures but no hospital stay in the previous 3 years. These patients' MRSA strains were related to the prevalent MRSA clone currently spreading in French hospitals.Conclusion.Home nursing care appears to be an independent risk factor for MRSA acquisition in the community. The reservoir probably consists of MRSA carriers discharged from the hospital. Community nurses seem to be a potential vector.
Outbreak of Bloodstream Infection With the Mold Phialemonium Among Patients Receiving Dialysis at a Hemodialysis Unit
Authors: Clark Thomas , Huhn Gregory D. , Conover Craig , Cali Salvatore , Arduino Matthew J. , Hajjeh Rana , Brandt Mary E. , Fridkin Scott K. 
Published: October 2006

BackgroundMolds are a rare cause of disseminated infection among dialysis patients.Objective.We evaluated a cluster of intravascular infections with the mold Phialemonium among patients receiving hemodialysis at the same facility in order to identify possible environmental sources and prevent further infection.Design.Environmental assessment and case-control study.Setting.A hemodialysis center affiliated with a tertiary care hospital.Methods.We reviewed surveillance and clinical microbiology records and performed a blood culture survey for all patients. The following data for case patients were compared with those for control patients: underlying illness, dialysis characteristics, medications, and other possible exposure for 120 days prior to infection. Environmental assessment of water treatment, dialysis facilities, and heating, ventilation, and air-conditioning (HVAC) systems of the current and previous locations of the dialysis center was performed. Samples were cultured for fungus; Phialemonium isolates were confirmed by sequencing of DNA. Investigators observed dialysis access site disinfection technique.Results.Four patients were confirmed as case patients, defined as a patient having intravascular infection with Phialemonium species; 3 presented with fungemia, and 1 presented with an intravascular graft infection. All case patients used a fistula or graft for dialysis access, as did 12 (75%) of 16 of control patients (P = .54). Case and control patients did not differ in other dialysis characteristics, medications received, physiologic findings, or demographic factors. Phialemonium species were not recovered from samples of water or dialysis machines, but were recovered from the condensation drip pans under the blowers of the HVAC system that supplied air to the dialysis center. Observational study of 21 patients detected suboptimal contact time with antiseptic agents used to prepare dialysis access sites.Conclusion.The report of this outbreak adds to previous published reports of Phialemonium infection occurring in immunocompromised patients who likely acquired infection in the healthcare setting. Recovery of this mold from blood culture should be considered indicative of infection until proven otherwise. Furthermore, an investigation into possible healthcare-related environmental reservoirs should be considered.
Optimal Bandaging of Smallpox Vaccination Sites to Decrease the Potential for Secondary Vaccinia Transmission Without Impairing Lesion Healing
Authors: Talbot Thomas R. , Peters Jody , Yan Lihan , Wright Peter F. , Edwards Kathryn M. 
Published: October 2006

Objective.To assess the optimal method for covering smallpox vaccination sites to prevent transmission of vaccinia.Design.Randomized, nonblinded clinical trial.Setting.Tertiary care medical center.Participants.Vaccinia-naive and vaccinia-experienced volunteers.Interventions.After vaccination, study participants were randomized to receive 1 of 3 types of bandage: gauze, occlusive with gauze lining, or foam. Vaccination sites were assessed every 3 to 5 days until the lesion healed. During each visit, specimens were obtained from the vaccination site, the bandage surface before removal, and the index finger contralateral to the vaccination site and were cultured for vaccinia. Time to lesion healing was assessed.Results.All 48 vaccinia-naive and 47 (87%) of 54 vaccinia-experienced participants developed a vesicle or pustule at the injection site 6-11 days after vaccination. Fourteen (14%) of 102 participants had bandage cultures positive for vaccinia. All but 1 of these vaccinia-positive cultures were of a bandage from participants randomized to the gauze bandage group, and all but 3 were of bandages from vaccinia-naive participants. No finger-specimen cultures were positive for vaccinia. One episode of neck autoinoculation occurred in a vaccinia-naive individual who had vaccinia recovered from his gauze bandage on multiple visits. The foam bandage was associated with more local adverse effects (skin irritation and induration). The time to healing did not differ among the bandage groups.Conclusions.The potential for transmission of vaccinia from a vaccination site is greater if the site is covered by gauze than if it is covered by occlusive or foam bandages. Use of an occlusive bandage with a gauze lining is the best choice for coverage of smallpox vaccination sites because of a reduced potential for vaccinia transmission and a lower reactogenicity rate. Bandage choice did not affect vaccination lesion healing.