bluuebunny/crossref_metadata_2025 huggingface dataset:
Mouse Hepatitis Coronavirus A59 Nucleocapsid Protein Is a Type I Interferon Antagonist
Authors: Ye Ye , Hauns Kevin , Langland Jeffrey O. , Jacobs Bertram L. , Hogue Brenda G.
Published: December 2006

The recent emergence of several new coronaviruses, including the etiological cause of severe acute respiratory syndrome, has significantly increased the importance of understanding virus-host cell interactions of this virus family. We used mouse hepatitis virus (MHV) A59 as a model to gain insight into how coronaviruses affect the type I alpha/beta interferon (IFN) system. We demonstrate that MHV is resistant to type I IFN. Protein kinase R (PKR) and the alpha subunit of eukaryotic translation initiation factor are not phosphorylated in infected cells. The RNase L activity associated with 2′,5′-oligoadenylate synthetase is not activated or is blocked, since cellular RNA is not degraded. These results are consistent with lack of protein translation shutoff early following infection. We used a well-established recombinant vaccinia virus (VV)-based expression system that lacks the viral IFN antagonist E3L to screen viral genes for their ability to rescue the IFN sensitivity of the mutant. The nucleocapsid (N) gene rescued VVΔE3L from IFN sensitivity. N gene expression prevents cellular RNA degradation and partially rescues the dramatic translation shutoff characteristic of the VVΔE3L virus. However, it does not prevent PKR phosphorylation. The results indicate that the MHV N protein is a type I IFN antagonist that likely plays a role in circumventing the innate immune response.
In Vitro Treatment of Human Monocytes/Macrophages with Myristoylated Recombinant Nef of Human Immunodeficiency Virus Type 1 Leads to the Activation of Mitogen-Activated Protein Kinases, IκB Kinases, and Interferon Regulatory Factor 3 and to the Release of Beta Interferon
Authors: Mangino Giorgio , Percario Zulema A. , Fiorucci Gianna , Vaccari Gabriele , Manrique Santiago , Romeo Giovanna , Federico Maurizio , Geyer Matthias , Affabris Elisabetta
Published: December 2006

The viral protein Nef is a virulence factor that plays multiple roles during the early and late phases of human immunodeficiency virus (HIV) replication. Nef regulates the cell surface expression of critical proteins (including down-regulation of CD4 and major histocompatibility complex class I), T-cell receptor signaling, and apoptosis, inducing proapoptotic effects in uninfected bystander cells and antiapoptotic effects in infected cells. It has been proposed that Nef intersects the CD40 ligand signaling pathway in macrophages, leading to modification in the pattern of secreted factors that appear able to recruit and activate T lymphocytes, rendering them susceptible to HIV infection. There is also increasing evidence that in vitro cell treatment with Nef induces signaling effects. Exogenous Nef treatment is able to induce apoptosis in uninfected T cells, maturation in dendritic cells, and suppression of CD40-dependent immunoglobulin class switching in B cells. Previously, we reported that Nef treatment of primary human monocyte-derived macrophages (MDMs) induces a cycloheximide-independent activation of NF-κB and the synthesis and secretion of a set of chemokines/cytokines that activate STAT1 and STAT3. Here, we show that Nef treatment is capable of hijacking cellular signaling pathways, inducing a very rapid regulatory response in MDMs that is characterized by the rapid and transient phosphorylation of the α and β subunits of the IκB kinase complex and of JNK, ERK1/2, and p38 mitogen-activated protein kinase family members. In addition, we have observed the activation of interferon regulatory factor 3, leading to the synthesis of beta interferon mRNA and protein, which in turn induces STAT2 phosphorylation. All of these effects require Nef myristoylation.
Dendritic Cell-Mediated
trans
-Enhancement of Human Immunodeficiency Virus Type 1 Infectivity Is Independent of DC-SIGN
Authors: Boggiano Cesar , Manel Nicolas , Littman Dan R.
Published: December 2006

Dendritic cells (DCs) enhance human immunodeficiency virus type 1 (HIV-1) infection of CD4
+
T lymphocytes in
trans
. The C-type lectin DC-SIGN, expressed on DCs, binds to the HIV-1 envelope glycoprotein gp120 and confers upon some cell lines the capacity to enhance
trans
-infection. Using a short hairpin RNA approach, we demonstrate that DC-SIGN is not required for efficient
trans
-enhancement by DCs. In addition, the DC-SIGN ligand mannan and an anti-DC-SIGN antibody did not inhibit DC-mediated enhancement. HIV-1 particles were internalized and were protected from protease treatment following binding to DCs, but not from binding to DC-SIGN-expressing Raji cells. Thus, DC-SIGN is not required for DC-mediated
trans
-enhancement of HIV infectivity.
Tissue-Specific Regulation of CD8+T-Lymphocyte Immunodominance in Respiratory Syncytial Virus Infection
Authors: Lee Sujin , Miller Scott A. , Wright David W. , Rock Michael T. , Crowe James E.
Published: December 2006

Cytotoxic T lymphocytes (CTLs) are critical for control of respiratory syncytial virus (RSV) infection in humans and mice. To investigate cellular immune responses to infection, it is important to identify major histocompatibility complex (MHC) class I-restricted CTL epitopes. In this study, we identified a new RSV-specific, H-2Kd-restricted subdominant epitope in the M2 protein, M2127-135(amino acids 127 to 135). This finding allowed us to study the frequency of T lymphocytes responding to two H-2Kd-presented epitopes in the same protein following RSV infection by enzyme-linked immunospot (ELISPOT) and intracellular cytokine assays for both lymphoid and nonlymphoid tissues. For the subdominant epitope, we identified an optimal nine-amino-acid peptide, VYNTVISYI, which contained an H-2Kdconsensus sequence with Y at position 2 and I at position 9. In addition, an MHC class I stabilization assay using TAP-2-deficient RMA-S cells transfected with Kdor Ldindicated that the epitope was presented by Kd. The ratios of T lymphocytes during the peak CTL response to RSV infection that were specific for M282-90(dominant) to T lymphocytes specific for M2127-135(subdominant) were approximately 3:1 in the spleen and 10:1 in the lung. These ratios were observed consistently in primary or secondary infection by the ELISPOT assay and in secondary infection by MHC/peptide tetramer staining. The number of antigen-specific T lymphocytes dropped in the 6 weeks after infection; however, the proportions of T lymphocytes specific for the immunodominant and subdominant epitopes were maintained to a remarkable degree in a tissue-specific manner. These studies will facilitate investigation of the regulation of immunodominance of RSV-specific CTL epitopes.
Human Immunodeficiency Virus Type 1 Pathobiology Studied in Humanized BALB/c-Rag2
−/−
γ
c
−/−
Mice
Authors: Gorantla Santhi , Sneller Hannah , Walters Lisa , Sharp John G. , Pirruccello Samuel J. , West John T. , Wood Charles , Dewhurst Stephen , Gendelman Howard E. , Poluektova Larisa
Published: December 2006

The specificity of human immunodeficiency virus type 1 (HIV-1) for human cells precludes virus infection in most mammalian species and limits the utility of small animal models for studies of disease pathogenesis, therapy, and vaccine development. One way to overcome this limitation is by human cell xenotransplantation in immune-deficient mice. However, this has proved inadequate, as engraftment of human immune cells is limited (both functionally and quantitatively) following transplantation of mature human lymphocytes or fetal thymus/liver. To this end, a human immune system was generated from umbilical cord blood-derived CD34
+
hematopoietic stem cells in BALB/c-Rag2
−/−
γ
c
−/−
mice. Intrapartum busulfan administration followed by irradiation of newborn pups resulted in uniform engraftment characterized by human T-cell development in thymus, B-cell maturation in bone marrow, lymph node development, immunoglobulin M (IgM)/IgG production, and humoral immune responses following ActHIB vaccination. Infection of reconstituted mice by CCR5-coreceptor utilizing HIV-1
ADA
and subtype C 1157 viral strains elicited productive viral replication and lymphadenopathy in a dose-dependent fashion. We conclude that humanized BALB/c-Rag2
−/−
γ
c
−/−
mice represent a unique and valuable resource for HIV-1 pathobiology studies.
Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression
Authors: Radziewicz Henry , Ibegbu Chris C. , Fernandez Marina L. , Workowski Kimberly A. , Obideen Kamil , Wehbi Mohammad , Hanson Holly L. , Steinberg James P. , Masopust David , Wherry E. John , Altman John D. , Rouse Barry T. , Freeman Gordon J. , Ahmed Rafi , Grakoui Arash
Published: December 2006

The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8
+
antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8
+
T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8
+
T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.
Declining Growth Rate of West Nile Virus in North America
Authors: Snapinn Katherine W. , Holmes Edward C. , Young David S. , Bernard Kristen A. , Kramer Laura D. , Ebel Gregory D.
Published: December 2006

To determine the demographic history of West Nile virus (WNV) in North America, we employed a coalescent method to envelope coding region data sets for the NY99 and WN02 genotypes. Although the observed genetic diversities in both genotypes were of approximately the same age, the mean rate of epidemiological growth of the WN02 population was approximately three times that of the NY99 population, a finding compatible with the recent dominance of the former genotype. However, there has also been a marked decrease in the recent growth rate of WN02, suggesting that WNV has reached its peak prevalence in North America.
Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection
Authors: Williams Brent L. , Yaddanapudi Kavitha , Hornig Mady , Lipkin W. Ian
Published: December 2006

Infection of newborn Lewis rats with Borna disease virus (neonatal Borna disease [NBD]) results in cerebellar damage without the cellular inflammation associated with infections in later life. Purkinje cell (PC) damage has been reported for several models of early-life viral infection, including NBD; however, the time course and distribution of PC pathology have not been investigated rigorously. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD cerebella. Real-time PCR at postnatal day 28 (PND28) revealed decreased cerebellar levels of mRNAs encoding the glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase C and the excitatory amino acid transporter 4 (EAAT4). Zebrin II and EAAT4 immunofluorescence analysis in PND21, PND28, PND42, and PND84 NBD rat cerebella revealed a complex pattern of PC degeneration. Early cell loss (PND28) was characterized by preferential apoptotic loss of zebrin II/EAAT4-negative PC subsets in the anterior vermis. Consistent with early preferential loss of zebrin II/EAAT4-negative PCs in the vermis, the densities of microglia and the Bergmann glial expression of metallothionein I/II and the hyaluronan receptor CD44 were higher in zebrin II/EAAT4-negative zones. In contrast, early loss in lateral cerebellar lobules did not reflect a similar discrimination between PC phenotypes. Patterns of vermal PC loss became more heterogeneous at PND42, with the loss of both zebrin II/EAAT4-negative and zebrin II/EAAT4-positive neurons. At PND84, zebrin II/EAAT4 patterning was abolished in the anterior cerebellum, with preferential PC survival in lobule X. Our investigation reveals regional discrimination between patterns of PC subset loss, defined by zebrin II/EAAT4 expression domains, following neonatal viral infection. These findings suggest a differential vulnerability of PC subsets during the early stages of virus-induced neurodegeneration.
Posttranslational Acetylation of the Human Immunodeficiency Virus Type 1 Integrase Carboxyl-Terminal Domain Is Dispensable for Viral Replication
Authors: Topper Michael , Luo Yang , Zhadina Maria , Mohammed Kevin , Smith Leonard , Muesing Mark A.
Published: December 2006

A recent report sought to demonstrate that acetylation of specific lysines within integrase (IN) by the histone acetyltransferase (HAT) p300 regulates human immunodeficiency virus type 1 (HIV-1) integration and is essential for viral replication (A.
Cereseto, L. Manganaro, M. I. Gutierrez, M. Terreni, A. Fittipaldi, M. Lusic, A. Marcello, and M. Giacca
, EMBO J.
24:
3070-3081, 2005). We can corroborate the efficient and specific acetylation of the IN carboxyl-terminal domain (CTD) (amino acids 212 to 288) by p300 using purified recombinant components. Although arginine substitution mutagenesis of the isolated CTD confirms that the majority of p300 acetylation occurs at lysine residues 264, 266, and 273, the pattern of acetylation is not uniform and a hierarchy of reactivity can be established. Several combinatorial mutations of the CTD lysines modified by p300 in vitro were reconstructed into an otherwise infectious proviral plasmid clone and examined for viral growth and frequency of productive chromosomal integration. In contrast to the findings of Cereseto and coworkers, who used epitope-tagged viruses for their experiments, we find that an untagged mutant virus, IN K(264/266/273)R, is fully replication competent. This discrepancy may be explained by the use of an acidic epitope tag placed at the extreme carboxyl terminus of integrase, near the target site for acetylation. Although the tagged, wild-type virus is viable, the combination of this epitope tag with the RRR substitution mutation results in a replication-defective phenotype. Although IN belongs to the very small set of nonhistone proteins modified by HAT-mediated activity, an obligate role for acetylation at the reactive CTD lysines in HIV-1 IN cannot be confirmed.
Role of the TSG101 Gene in Epstein-Barr Virus Late Gene Transcription
Authors: Chua Huey-Huey , Lee Heng-Huan , Chang Shih-Shin , Lu Chih-Chung , Yeh Te-Huei , Hsu Tsuey-Ying , Cheng Tzu-Hao , Cheng Jiin-Tsuey , Chen Mei-Ru , Tsai Ching-Hwa
Published: December 2006

Rta, an Epstein-Barr virus (EBV)-encoded immediate-early protein, governs the reactivation of the viral lytic program by transactivating a cascade of lytic gene expression. Cellular transcription factors such as Sp1, ATF2, E2F, and Akt have been demonstrated to mediate Rta transactivation of lytic genes. We report herein that Rta associates with another potent transcription factor, tumor susceptibility gene 101 (TSG101), to promote the activation of EBV late genes. Results from an EBV cDNA array reveal that depletion of TSG101 by siRNA potently inhibits the transcription of five Rta-responsive EBV late genes, BcLF1, BDLF3, BILF2, BLLF1, and BLRF2. Depletion of TSG101 impairs the Rta transactivation of these late promoters severely. Moreover, a concordant augmentation of Rta transactivating activity is observed when TSG101 is overexpressed following ectopic transfection. Mechanistically, Rta interaction with TSG101 causes the latter to accumulate principally in the nuclei, wherein the proteins colocalize and are recruited to the viral promoters. Of note, TSG101 is crucial for the efficient binding of Rta to these late promoters. As a result, cells with defective TSG101 fail to express late viral proteins, leading to a decrease in the yield of virus particles. Thus, the contribution of TSG101 to Rta-mediated late gene activation is of great importance for completion of the EBV productive lytic cycle. These observations consolidate a role for TSG101 in the replication of EBV, a DNA virus, that differs from what is observed for RNA viruses, where TSG101 aids mainly in the endosomal sorting of enveloped late viral proteins for assembly at the plasma membrane.
Human Papillomavirus E7 Repression in Cervical Carcinoma Cells Initiates a Transcriptional Cascade Driven by the Retinoblastoma Family, Resulting in Senescence
Authors: Johung Kimberly , Goodwin Edward C. , DiMaio Daniel
Published: December 2006

This work demonstrates a central role for the retinoblastoma (Rb) family in driving the transcriptional program of induced and replicative senescence. HeLa cervical carcinoma cells rapidly undergo senescence when the human papillomavirus (HPV) type 18 E7 gene in these cells is repressed by the bovine papillomavirus (BPV) E2 protein. This senescence response requires the endogenous Rb pathway but not the p53 pathway. Microarray analysis 6 days after BPV E2 introduction into HeLa cells identified 224 cellular genes induced by E7 repression and 354 repressed genes. Many repressed genes were involved in cell cycle progression, and numerous induced genes encoded lysosomal proteins. These gene expression changes were blocked by constitutive expression of the wild-type HPV16 E7 or adenovirus E1A gene, but not by E7 or E1A mutants defective for Rb binding. Short hairpin RNAs targeting the Rb family also inhibited these gene expression changes and blocked senescence. Therefore, surprisingly, the transcriptional response to BPV E2 expression was entirely dependent on E7 repression and activation of the Rb family, and the BPV E2 protein did not directly affect the expression of cellular genes. Activation of the Rb family repressed E2F-responsive genes and stimulated transcriptional activators, thereby mobilizing multiple signals, such as repression of B-MYB and DEK, that were independently sufficient to induce senescence. There was extensive overlap between the transcriptional profiles of senescent, late-passage primary human fibroblasts and senescent cervical carcinoma cells, suggesting that this Rb family-mediated transcriptional cascade also plays a central role in replicative senescence.
Non-operative breast pathology: columnar cell lesions
Authors: Pinder S E , Reis-Filho J S
Published: December 2006

The term “columnar cell lesions” encompasses a spectrum of processes, characterised by variably dilated acini, lined by one to several layers of tightly packed, columnar-shaped epithelial cells. These lesions have received renewed attention in the literature due to their high prevalence in biopsy specimens taken for assessment of mammographically detected microcalcification. In addition, increasing interest has been directed at the sub-set of columnar cell lesions with varying degrees of cytological atypia. Recent observational and molecular genetic studies have provided strong circumstantial evidence to suggest that at least some of these lesions may represent the earliest morphologically identifiable, non-obligate precursor of low grade breast carcinomas. However, the risk of both local recurrence and progression to invasive cancer appears to be exceedingly low. This review provides an update on recent clinicopathological and molecular data on columnar cell lesions and how these have changed our perception of, and the classification system for, these lesions. In addition, guidelines for the management of patients with columnar cell lesions diagnosed in core needle biopsy specimens are provided.
Use of multiple displacement amplification in the investigation of human papillomavirus physical status
Authors: Evans Mark Francis , Adamson Christine Stewart-Crawford , von Walstrom Genevieve Montagu , Cooper Kumarasen
Published: December 2006

Background and Aims:

The investigation of human papillomavirus (HPV) physical status in pre-invasive cervical lesions has been restricted by the small amounts of tissue available for study. Multiple displacement amplification (MDA), a phi29 DNA polymerase based whole genome amplification technique, has the potential to help resolve this problem by yielding large amounts of high molecular weight DNA from tiny starting quantities.

Methods:

Firstly, a comparison was made of restriction endonuclease fragment patterns of DNA from seven different HPV types and corresponding MDA products. Secondly,E6/E7and LCR sequencing data from HPV16 recombinant plasmid and MDA copy DNA were correlated. Thirdly, DNA and MDA products from cervical cell lines (CaSki, HeLa, and SiHa that contain integrated HPV) and an invasive cervical carcinoma were analysed by Southern blot hybridisation. Fourthly, MDA product from CaSki cell DNA mixed with HPV18-plasmid DNA was tested for the demonstration of both episomal and integrated HPV. Finally, MDA products from HPV16 positive abnormal cervical cytological samples were assayed for integration by Southern blot hybridisation.

Results:

DNA templates and MDA products yielded analogous data. Episomal and integrated HPV DNA were successfully detected by Southern blot assay of the cell line/HPV-plasmid model, and in MDA products of clinical samples.

Conclusions:

These data show that MDA has considerable potential to assist in the investigation of HPV physical status; abundant (>40 μg) DNA can be generated with high fidelity from minuscule (50 ng) starting quantities, and both episomal and integrated HPV DNA are distinguishable in MDA products from solid tumours and cytological materials.
Melanoma histopathology reporting: are we complying with the National Minimum Dataset?
Authors: Kaur Manjit R , Colloby Peter S , Martin-Clavijo Agustin , Marsden Jerry R
Published: December 2006

Baclground:

The Royal College of Pathologists introduced the National Minimum Dataset (NMDS) for the histopathological reporting of cutaneous melanoma in February 2002.

Aim:

To determine if histological reporting of invasive primary cutaneous melanoma in the West Midlands region of the UK was compliant with the NMDS.

Methods:

Reports were identified from March 2002 to March 2003 via the regional Cancer Intelligence Unit, and compared with the NMDS. If all items of the NMDS were adhered to, the report was considered compliant. If not compliant, the report was checked to see if it included selected clinical and staging parameters.

Results:

543 cases of invasive cutaneous melanoma were identified, but only 407 reports were analysed. 69/407 (17%) (95% CI 14% to 20%) reports were fully compliant with the NMDS. Of the non-complaint reports, 45/361 (12%) (95% CI 9% to 16%) reported all staging and clinically relevant parameters; 62/361 (17%) (95% CI 59% to 65%) reported all staging parameters. Breslow thickness was reported in all but one of the reports (99.7%), Clark’s level was reported in 344/407 (85%), ulceration in 280/407 (69%), and microsatellites in 146/407 (36%).

Conclusion:

There was slow uptake of the NMDS in this region in the year following its introduction. Although major parameters required for staging were more consistently reported, ulceration and microsatellites were less frequently reported.
Influenza immunisation: attitudes and beliefs of UK healthcare workers
Authors: Smedley Julia , Poole Jason , Waclawski Eugene , Stevens Anthony , Harrison John , Watson John , Hayward Andrew , Coggon David
Published: December 2006

Aim:To explore attitudes to influenza immunisation and rates of uptake among staff working in acute hospitals in the UK.

Method:A cross-sectional survey of 11 670 healthcare workers in six UK hospitals was carried out using a postal questionnaire.

Results:Among 6302 responders (54% of those mailed), 19% had taken up influenza immunisation during winter 2002/3. Vaccination was well tolerated, with a low prevalence of side effects (13%) and associated time off work (2%). The majority of subjects who accepted vaccination (66%) were most strongly influenced by the personal benefits of protection against influenza. Prevention of sickness absence and protection of patients were the prime motivation for only 10% and 7% of subjects, respectively. Among 3967 who declined vaccination, the most common primary demotivators were concern about safety (31%) and efficacy (29%). 22% were most strongly deterred by lack of time to attend for vaccination. Free text answers indicated that 37% declined because of a perceived low ratio of personal benefits to adverse effects. Subjects said they would be persuaded to take up vaccination in future by easier access (36%), more information about personal benefit and risk (34%) and more information about effects on staff absence (24%).

Conclusions:These findings indicate that the uptake of influenza immunisation among UK healthcare workers remains low. There is some scope for increasing uptake by improving accessibility and encouragement from professional peers. However, the results suggest that perception of small personal benefit in relation to risk mitigates, importantly, against higher uptake of routine annual influenza vaccination. Thus, resource might better be allocated to ensuring efficient management in epidemic years. The effect of publicity about pandemic influenza on risk perception and vaccine uptake among healthcare workers during winter 2005/6 warrants further study.
Air pollution and doctors’ house calls for respiratory diseases in the Greater Paris area (2000–3)
Authors: Chardon Benoit , Lefranc Agnès , Granados Denis , Grémy Isabelle
Published: December 2006

This study describes the short-term relationships between the daily levels of PM10, PM2.5, NO2and the number of doctors’ house calls for asthma, upper respiratory diseases (URD) and lower respiratory diseases (LRD) in Greater Paris for the years 2000–3. Doctors’ house calls are a relevant health indicator for the study of short-term health effects of air pollution. Indeed, it is potentially more sensitive than indicators such as general hospital admissions due to the severity of diseases motivating the call. In this study, time-series analysis was used. The daily numbers of doctor’s house calls were adjusted for time trends, seasonal factors, day of the week, influenza, weather and pollen. Up to 15 days of lag between exposure and health effects was considered using distributed lag models. A total of about 1 760 000 doctors’ house calls for all causes occurred during the study period, among which 8027 were for asthma, 52 928 for LRD and 74 845 for URD. No significant increase in risk was found between air pollution and doctors’ house calls for asthma. No significant association was found between NO2and doctors’ house calls. An increase of 10 μg/m3in the mean levels of PM10and PM2.5encountered during the 3 previous days was associated with an increase of 3% (0.8% and 5.3%) and 5.9% (2.9% and 9.0%) in the number of doctor’s house calls for URD and LRD, respectively. Considering up to 15 days between exposure and health outcomes, effects persist until 4 days after exposure and then decrease progressively. No morbidity displacement was observed. This study shows a significant heath effect of ambient particles (PM2.5and PM10). When compared to the RRs obtained for mortality or hospital admissions in the same area, the values of the RRs obtained in this study confirm the higher sensibility of doctor’s house calls for respiratory diseases as a health indicator.
Hospital injury rates in relation to socioeconomic status and working conditions
Authors: d’Errico A , Punnett L , Cifuentes M , Boyer J , Tessler J , Gore R , Scollin P , Slatin C
Published: December 2006

Objectives:To describe the risk of work injury by socioeconomic status (SES) in hospital workers, and to assess whether SES gradient in injury risk is explained by differences in psychosocial, ergonomic or organisational factors at work.

Methods:Workforce rosters and Occupational Safety and Health Administration injury logs for a 5-year period were obtained from two hospitals in Massachusetts. Job titles were classified into five SES strata on the basis of educational requirements and responsibilities: administrators, professionals, semiprofessionals, skilled and semiskilled workers. 13 selected psychosocial, ergonomic and organisational exposures were assigned to the hospital jobs through the national O*NET database. Rates of injury were analysed as frequency records using the Poisson regression, with job title as the unit of analysis. The risk of injury was modelled using SES alone, each exposure variable alone and then each exposure variable in combination with SES.

Results:An overall annual injury rate of 7.2 per 100 full-time workers was estimated for the two hospitals combined. All SES strata except professionals showed a significant excess risk of injury compared with the highest SES category (administrators); the risk was highest among semiskilled workers (RR 5.3, p<0.001), followed by nurses (RR 3.7, p<0.001), semiprofessionals (RR 2.9, p = 0.006) and skilled workers (RR 2.6, p = 0.01). The risk of injury was significantly associated with each exposure considered except pause frequency. When workplace exposures were introduced in the regression model together with SES, four remained significant predictors of the risk of injury (decision latitude, supervisor support, force exertion and temperature extremes), whereas the RR related to SES was strongly reduced in all strata, except professionals.

Conclusions:A strong gradient in the risk of injury by SES was reported in a sample population of hospital workers, which was greatly attenuated by adjusting for psychosocial and ergonomic workplace exposures, indicating that a large proportion of that gradient can be explained by differences in working conditions.
The validation of work-related self-reported asthma exacerbation
Authors: Bolen Aimee R , Henneberger Paul K , Liang Xiaoming , Sama Susan R , Preusse Peggy A , Rosiello Richard A , Milton Donald K
Published: December 2006

Objective:To determine the validity of work-related self-reported exacerbation of asthma using the findings from serial peak expiratory flow (PEF) measurements as the standard.

Methods:Adults with asthma treated in a health maintenance organisation were asked to conduct serial spirometry testing at home and at work for 3 weeks. Self-reported respiratory symptoms and medication use were recorded in two ways: a daily log completed concurrently with the serial PEF testing and a telephone questionnaire administered after the PEF testing. Three researchers evaluated the serial PEF records and judged whether a work relationship was evident.

Results:95 of 382 (25%) working adults with asthma provided adequate serial PEF data, and 13 of 95 (14%) were judged to have workplace exacerbation of asthma (WEA) based on these data. Self-reported concurrent medication use was the most valid single operational definition, with a sensitivity of 62% and a specificity of 65%.

Conclusions:A work-related pattern of self-reported asthma symptoms or medication use was usually not corroborated by serial PEF testing and failed to identify many people who had evidence of WEA based on the serial PEF measurements.
CLUSTERING PROTOCOL FOR SENSOR NETWORKS
Authors: DURRESI ARJAN , PARUCHURI VAMSI , DURRESI MIMOZA , BAROLLI LEONARD
Published: December 2006

In this paper we present Clustering Protocol for Sensor networks (CPS). Clustering techniques are used by different protocols and applications to increase scalability and reduce delays in sensor networks. Examples include routing protocols, and applications requiring efficient data aggregation. Our approach is based on the Covering Problem that aims at covering an area with minimum number of circular disks. CPS is a lightweight protocol that does not require any neighborhood information and imposes low communication overhead. We present simulation results to show the efficiency of CPS in both ideal cases and randomly distributed networks. Moreover, CPS is scalable with respect to density and network size.
PARM: A PHYSICALLY-AWARE REFERENCE MODEL FOR PEER-TO-PEER OVERLAY INTERNETWORKING
Authors: LE HANH , HOANG DOAN , SIMMONDS ANDREW
Published: December 2006

Peer-to-Peer (P2P) technologies developed rapidly in different directions with various applications and routing mechanisms. Each of them deals with a particular task, and/or provides a specific service. They were developed separately without a unified architecture taking into account all the performance factors of a P2P system. This makes the P2P systems incomplete and their performances far from optimal. This trend also restricts the interoperability amongst the systems because of the lack of standardization in functional architectures of the P2P systems. As a result, tangible benefits for Internet users are limited because the edge-Internet resources are not sharable amongst the systems. Inspired by TCP/IP model, this paper introduces PARM: a Physically-Aware Reference Model for Overlay Internetworking, which is an open reference structure for designing better performance P2P systems. PARM divides major functional P2P system tasks into layers so that they can be tackled individually and efficiently. A Peer Name Service was developed to evaluate the model. The service interprets peer names into their current locations. Simulation results indicate that PARM helps to produce excellent performance overlays. The overlays can achieve desirable features such as decentralization, self-organization, scalability, low overhead and minimal delay penalty.
EVALUATING PERFORMANCE AND ACCURACY OF A SENTINEL-BASED EXCEPTION DIAGNOSIS APPROACH FOR P2P AGENT SYSTEMS
Authors: SHAH NAZARAF , GODWIN NICK , AKHGAR BABAK , SIDDIQI JAWED
Published: December 2006

Using open Multi-agent systems (MAS) to represent a peer-to-peer (P2P) organization is a complex application of distributed artificial intelligence. These systems are designed to create networked applications where each peer node contributes to the overall functionality of the application. Each agent in such systems acts as a peer and has no fixed role. In other words a peer may assume the role of either service provider or service consumer in a given interaction. The dynamics of these networked applications make them vulnerable to different kinds of exceptions. Also the absence of centralized control and changes in organizational structure gives rise to unpredictable exceptions. It becomes essential to have some exception diagnosis mechanisms in place to be able to diagnose the cause of such exceptions while preserving the autonomy of the peer agents. These mechanisms do come with some overheads. In this paper we present an evaluation of the application of our proposed sentinel based approach to exception diagnosis in P2P based MAS and also discuss the trade offs that arise in using a sentinel based approach to exception diagnosis in such systems.
SERVICE ORIENTED COOPERATION AMONG TRUSTWORTHY PEERS
Authors: WATANABE KENICHI , TAKIZAWA MAKOTO
Published: December 2006

Various types of applications make access to objects distributed in peer-to-peer (P2P) overlay networks. Even if the locations of target objects are discovered by some look-up algorithm such as flooding and distributed hash table (DHT), applications cannot manipulate the target objects without access rights. It is critical to perceive which peer can manipulate an object in which method, i.e. only a peer authorized with an access right is allowed to manipulate an object. Hence, an application has to find peers which can manipulate a target object rather than detect the location of the target object. Due to the scalability, variety, and autonomy of peers, it is difficult, may be impossible to maintain a centralized directory showing in which peer each object is distributed. An acquaintance peer of a peer p is a peer whose service the peer p knows and with which the peer p can directly communicate. We discuss types of acquaintance relations of peers with respect to what objects each peer holds, is allowed to manipulate, and can grant access rights on. Acquaintance peers of a peer may notify the peer of different information on target peers due to communication and propagation delay. Here, it is critical to discuss how much a peer trusts each acquaintance peer. We first define the satisfiability of an acquaintance peer, i.e. how much a peer is satisfied by issuing an access request to the acquaintance peer. For example, if a peer p locally manipulates a target object o and obtains a response, p is mostly satisfied. On the other hand, if the peer p has to ask another peer to manipulate the object o, the peer p is less satisfied. We define the trustworthiness and ranking factor of an acquaintance peer obtained by accumulating the satisfiability of each interaction with the acquaintance peer. Differently from traditional reputation concepts, trustworthiness information only from trustworthy acquaintance peers can be used to obtain the ranking factor. The trustworthiness of an acquaintance peer shows how much a peer can trusts the acquaintance peer while the ranking factor of an acquaintance peer shows how much the acquaintance peer is trusted by other trustworthy acquaintance peers. Then, we evaluate the trustworthiness and ranking factor in presence of faulty peers.
A ROBUST AND EFFICIENT FLOODING-BASED ROUTING FOR WIRELESS SENSOR NETWORKS
Authors: ZHANG YING , FROMHERZ MARKUS
Published: December 2006

Flooding protocols for wireless networks in general have been shown to be very inefficient and therefore are mainly used in network initialization or route discovery and maintenance. In this paper, we propose a framework of constrained flooding protocols. The framework incorporates a reinforcement learning kernel, a differential delay mechanism, and a constrained and probabilistic retransmission policy. This type of protocol takes the advantages of robustness from flooding, but maintains energy efficiency by constraining retransmissions. Without the use of any control packets, such a protocol adapts to the specific routing requirements of the task and the dynamic changes of the network. We analyze this framework in simulation using some real-world applications in sensor networks.
A BROWNIAN-TIME EXCURSION INTO FOURTH-ORDER PDES, LINEARIZED KURAMOTO–SIVASHINSKY, AND BTP-SPDES ON ℝ+ × ℝd
Authors: ALLOUBA HASSAN
Published: December 2006

In recent articles we have introduced the class of Brownian-time processes (BTPs) and the Linearized Kuramoto–Sivashinsky process (LKSP). Probabilistically, BTPs represent a unifying class for some different exciting processes like the iterated Brownian motion (IBM) of Burdzy (a process with fourth-order properties) and the Brownian–snake of Le Gall (a second-order process); they also include many additional new and quite interesting processes. The LKSP is closely connected to the Kuramoto–Sivashinsky PDEs, one of the most celebrated PDEs in modern applied mathematics. We start by surveying the fourth-order PDE connections to BTPs and the LKSP that we uncovered in two recent articles.

In the second part of this paper we introduce BTP-SPDEs, these are SPDEs in which the PDE part is that solved by running a BTP. We consider a BTP-SPDE driven by an additive spacetime white noise on the time-space set ℝ+ × ℝd; and we prove the existence of a unique real-valued, Lp(Ω,ℙ) for all p ≥ 1, BTP solution to such BTP-SPDEs for 1 ≤ d ≤ 3. This contrasts sharply with the standard theory of reaction-diffusion type SPDEs driven by spacetime white noise, in which real-valued solutions are confined to one spatial dimension. Like the PDEs case, BTP-SPDEs also provide a valuable insight into other fourth-order SPDEs of applied science. We carry out such a program in forthcoming articles.
STOCHASTIC DELAY GILPIN–AYALA COMPETITION MODELS
Authors: LIAN BAOSHENG , HU SHIGENG
Published: December 2006

In this paper, we investigate a stochastic Gilpin–Ayala competition system, which is more general and more realistic than the classical Lotka–Volterra competition system. We reveal that the environmental noise will not only suppress a potential population explosion in the stochastic delay Gilpin–Ayala competition system but also make the solutions stochastically ultimately bounded. Comparing the classical Lotka–Volterra with Gilpin–Ayala competition system, we find that the latter has better proprieties.
Mass spectrometric identification of phosphorylation sites of rRNA transcription factor upstream binding factor
Authors: Lin C. Huie , Platt Mark D. , Ficarro Scott B. , Hoofnagle Mark H. , Shabanowitz Jeffrey , Comai Lucio , Hunt Donald F. , Owens Gary K.
Published: December 2006

rRNA transcription is a fundamental requirement for all cellular growth processes and is activated by the phosphorylation of the upstream binding factor (UBF) in response to growth stimulation. Even though it is well known that phosphorylation of UBF is required for its activation and is a key step in activation of rRNA transcription, as yet, there has been no direct mapping of the UBF phosphorylation sites. The results of the present studies employed sophisticated nano-flow HPLC-microelectrospray-ionization tandem mass spectrometry (nHPLC-μESI-MS/MS) coupled with immobilized metal affinity chromatography (IMAC) and computer database searching algorithms to identify 10 phosphorylation sites on UBF at serines 273, 336, 364, 389, 412, 433, 484, 546, 584, and 638. We then carried out functional analysis of two of these sites, serines 389 and 584. Serine-alanine substitution mutations of 389 (S389A) abrogated rRNA transcription in vitro and in vivo, whereas mutation of serine 584 (S584A) reduced transcription in vivo but not in vitro. In contrast, serine-glutamate mutation of 389 (S389E) restored transcriptional activity. Moreover, S389A abolished UBF-SL1 interaction in vitro, while S389E partially restored UBF-SL1 interaction. Taken together, the results of these studies suggest that growth factor stimulation induces an increase in rRNA transcriptional activity via phosphorylation of UBF at serine 389 in part by facilitating a rate-limiting step in the recruitment of RNA polymerase I: i.e., recruitment of SL1. Moreover, studies provide critical new data regarding multiple additional UBF phosphorylation sites that will require further characterization by the field.
Role(s) of nucleoli and phosphorylation of ribosomal protein S6 and/or HSP27 in the regulation of muscle mass
Authors: Kawano F. , Matsuoka Y. , Oke Y. , Higo Y. , Terada M. , Wang X. D. , Nakai N. , Fukuda H. , Imajoh-Ohmi S. , Ohira Y.
Published: December 2006

Effects of 14 days of hindlimb unloading or synergist ablation-related overloading with or without deafferentation on the fiber cross-sectional area, myonuclear number, size, and domain, the number of nucleoli in a single myonucleus, and the levels in the phosphorylation of the ribosomal protein S6 (S6) and 27-kDa heat shock protein (HSP27) were studied in rat soleus. Hypertrophy of fibers (+24%), associated with increased nucleolar number (from 1–2 to 3–5) within a myonucleus and myonuclear domain (+27%) compared with the preexperimental level, was induced by synergist ablation. Such phenomena were associated with increased levels of phosphorylated S6 (+84%) and HSP27 (+28%). Fiber atrophy (−52%), associated with decreased number (−31%) and domain size (−28%) of myonuclei and phosphorylation of S6 (−98%) and HSP27 (−63%), and with increased myonuclear size (+19%) and ubiquitination of myosin heavy chain (+33%, P > 0.05), was observed after unloading, which inhibited the mechanical load. Responses to deafferentation, which inhibited electromyogram level (−47%), were basically similar to those caused by hindlimb unloading, although the magnitudes were minor. The deafferentation-related responses were prevented and nucleolar number was even increased (+18%) by addition of synergist ablation, even though the integrated electromyogram level was still 30% less than controls. It is suggested that the load-dependent maintenance or upregulation of the nucleolar number and/or phosphorylation of S6 and HSP27 plays the important role(s) in the regulation of muscle mass. It was also indicated that such regulation was not necessarily associated with the neural activity.
Differential localization of autolyzed calpains 1 and 2 in slow and fast skeletal muscles in the early phase of atrophy
Authors: Vermaelen Marianne , Sirvent Pascal , Raynaud Fabrice , Astier Catherine , Mercier Jacques , Lacampagne Alain , Cazorla Olivier
Published: December 2006

Calpains have been proposed to be involved in the cytoskeletal remodeling and wasting of skeletal muscle. However, limited data are available about the specific involvement of each calpain in the early stages of muscle atrophy. The aims of this study were to determine whether calpains 1 and 2 are autolyzed after a short period of muscle disuse, and, if so, where in the myofibers the autolyzed products are localized. In the rat soleus muscle, 5 days of immobilization increased autolyzed calpain 1 in the particulate and not the soluble fraction. Conversely, autolyzed calpain 2 was not found in the particulate fraction, whereas it was increased in the soluble fraction after immobilization. In the less atrophied plantaris muscle, no difference was noted between the control and immobilized groups whatever the fraction or calpain. Other proteolytic pathways were also investigated. The ubiquitin-proteasome pathway was activated in both skeletal muscles, and caspase 3 was activated only in the soleus muscle. Taken together, our data suggest that calpains 1 and 2 are involved in atrophy development in slow type muscle exclusively and that they have different regulation and protein targets. Moreover, the activation of proteolytic pathways appears to differ in slow and fast muscles, and the proteolytic mechanisms involved in fast-type muscle atrophy remain unclear.
Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice
Authors: Kuboki Satoshi , Schuster Rebecca , Blanchard John , Pritts Timothy A. , Wong Hector R. , Lentsch Alex B.
Published: December 2006

It is well established that liver ischemia-reperfusion induces the expression of heat shock protein (HSP) 70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia-reperfusion injury in mice. Male mice were subjected to 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg iv) was injected before surgery. We found that this dose induced HSP70 expression within 6 h of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment and liver nuclear factor-κB activation, and attenuated serum levels of tumor necrosis factor-α and macrophage inflammatory protein-2, but increased levels of interleukin (IL)-6. In HSP70 knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70 knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected before surgery. Intravenous injection of 10 μg of recombinant HSP70 had no effect on liver injury after ischemia-reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for postischemic liver injury.