bluuebunny/crossref_metadata_2025 huggingface dataset:
Heuristics and biases in a purported counter-example to the acyclicity of 'better than'
Authors: Voorhoeve Alex
Published: July 2008

Stuart Rachels and Larry Temkin have offered a purported counter-example to the acyclicity of the relationship 'all things considered better than'. This example invokes our intuitive preferences over pairs of alternatives involving a single person's painful experiences of varying intensity and duration. These preferences, Rachels and Temkin claim, are confidently held, entirely reasonable, and cyclical. They conclude that we should drop acyclicity as a requirement of rationality. I argue that, together with the findings of recent research on the way people evaluate episodes of pain, the use of a heuristic known as similarity-based decision-making explains why our intuitive preferences may violate acyclicity in this example. I argue that this explanation should lead us to regard these preferences with suspicion, because it indicates that they may be the result of one or more biases. I conclude that Rachels' and Temkin's example does not provide sufficient grounds for rejecting acyclicity.
Friendship and commercial societies
Authors: Badhwar Neera K.
Published: July 2008

Critics of commercial societies complain that the free-market system of property rights and freedom of contract tends to commodify relationships, thus eroding the bonds of personal and civic friendship. I argue that this thesis rests on a misunderstanding of both markets and friendship. As voluntary, reciprocal relationships, market relationships and friendship share important properties. Like all relations and activities that exercise important human capacities and play an important role in a meaningful life, market relations and activities are essentially structured and supported by ethical norms and, in turn, support these norms. The so-called norms of the market, such as instrumentality and fungibility, come in varying degrees and characterize not only market, but also nonmarket, relationships, including friendship. Furthermore, although market relationships are primarily instrumental, the individuals involved are not. The virtues of markets have their counterparts in friendship, as do their vices. For these and other reasons, market societies are not only not inimical to friendship, they create a more secure matrix for civic and personal friendship, as well as for other important values such as art, science, or philosophy, than any other developed form of society.
Spelling Assessment of Students With Disabilities
Authors: Beirne-Smith Mary , Riley Tamar F.
Published: July 2008

Accurate spelling is a complex act that requires cognitive and linguistic knowledge of the phonological, morphological, syntactical, and semantic principles of our language. Students with disabilities frequently exhibit spelling difficulties related to language learning disorders and inefficient cognitive processing. These difficulties often are developmental in nature. Remediation of spelling disorders in students with disabilities requires accurate, comprehensive assessment. Accurate, comprehensive assessment involves the use of both formal and informal assessment measures. In this article, we discuss the theory and research that support the assessment of spelling in students with disabilities and we describe formal and informal spelling assessment procedures.
Profile of Communication Disorders in HIV-Infected Individuals: A Preliminary Study
Authors: Mathew Mili Mary , Bhat Jayashree S.
Published: July 2008

Communication is the very essence of life for humans. This is made possible by the highly complex neurophysiological mechanisms governing humans. Any disturbance to this system can result in impairments of communication. HIV infection is one such disease. In India, the management of such individuals is usually restricted to life sustenance. Little importance is given to their communication problems, which play a vital role in day-to-day functioning. It is with this background that this study was conducted. Eight HIV-infected individuals participated in the study. They were subjected to assessment procedures that included the following tests: Western Aphasia Battery, Frenchay Dysarthria Assessment, Standard Articulation test, Fluency test, and subjective assessment of vocal parameters by a speech language pathologist. The results of the study reveal that individuals with HIV-1 infection show a varied picture of affected parameters of voice, swallowing, and oral motor functioning
Acute Kidney Disease Due to Immune Reconstitution Inflammatory Syndrome in an HIV-Infected Patient With Tuberculosis
Authors: Salliot Carine , Guichard Isabelle , Daugas Eric , Lagrange Marie , Verine Jérôme , Molina Jean-Michel
Published: July 2008

This study reports the case of an HIV-infected patient with disseminated tuberculosis who presented an immune reconstitution inflammatory syndrome (IRIS) revealed by an acute kidney disease 45 and 15 days after initiation of antituberculosis therapy and HAART, respectively. Prednisone therapy and the transient withdrawal of HAART improved the renal function and the clinical condition of this patient. All published case reports of IRIS revealed by acute renal failure in HIV-infected patients are also reviewed.
Characteristics of Patients Accessing Care and Treatment for HIV/AIDS at Public and Nongovernmental Sites in South Africa
Authors: Rosen Sydney , Ketlhapile Mpefe , Sanne Ian , DeSilva Mary Bachman
Published: July 2008

Little is known about the characteristics of patients accessing antiretroviral therapy (ART) in South Africa. In a random sample of 1069 pre-ART and ART patients attending an urban public hospital, a periurban nongovernmental organization (NGO) clinic, and a rural NGO clinic, 79% were female; average age was 34 for women and 37 for men. Two thirds reported having 1 long-term partner, but most did not live with their partner. Three fourths had completed some secondary school or higher; 47% were employed formally (26%) or informally (21%), and 40% lived in informal housing or shacks. Patients at the rural site were less likely to be employed and more likely to receive government grant support. Relative to the HIV-positive population as a whole, ART patients are older, more likely to be female and have 1 long-term partner, live in informal housing, have reached secondary school, and earn an income from formal or informal employment.
Targeting Points for Further Intervention: A Review of HIV-Infected Infants Born in Ireland in the 7 Years Following Introduction of Antenatal Screening
Authors: Ferguson Wendy , Cafferkey Mary , Walsh Amanda , Butler Karina
Published: July 2008

Even in countries with well-developed programs for prevention of mother-to-child transmission (MTCT) of HIV, there remains a low level of ongoing transmission. Pregnant, HIV-infected women may not always access screening and available interventions because of circumstances, beliefs, and other influences. Missed opportunities for the prevention of MTCT remains an issue to be addressed. Through a review of HIV-infected children born during the years of antenatal screening in Ireland, we sought to identify further targets for intervention to further reduce MTCT.
Monitoring Adherence and Defaulting for Antiretroviral Therapy in 5 East African Countries: An Urgent Need for Standards
Authors: Chalker John , Andualem Tenaw , Minzi Omary , Ntaganira Joseph , Ojoo Atieno , Waako Paul , Ross-Degnan Dennis
Published: July 2008

Objectives: A cross-sectional survey was performed in 24 systems of care providing antiretroviral medications in Ethiopia, Kenya, Rwanda, Tanzania, and Uganda to examine current practices in monitoring rates of treatment adherence and defaulting.

Results: Only 20 of 48 facilities reported routinely measuring individual patient adherence levels; only 12 measured rates of adherence for the clinic population. The rules for determining which patients were included in the calculation of rates were unclear. Fourteen different definitions of treatment defaulting were in use. Facilities routinely gather potentially useful data, but the frequency of doing so varied widely.

Conclusions: Individual and program treatment adherence and defaulting are not routinely monitored; when done, the operational definitions and methods varied widely, making comparisons across programs unreliable. There is a pressing need to determine which measures are the most feasible and reliable to collect, the most useful for clinical counseling, and most informative for program management.
Hepatic Ultrastructural Mitochondrial Changes Prior to Antiretroviral Therapy in HIV-Infected Patients in Brazil
Authors: Mendes-Corrêa Maria Cássia , Andrade Heitor Franco , Fumica Takakura Cleusa , Seixas Duarte Maria Irma
Published: July 2008

The use of antiretroviral (ARV) medications has been linked to the emergence of severe adverse effects, including mitochondrial toxicity. The liver also appears to be among the affected organs. Nevertheless, different studies suggest that these patients' mitochondrial alterations could be associated to other etiological factors. The goal of this study was to analyze hepatic mitochondria ultrastructural changes in HIV-infected patients under investigation for hepatopathy. Semiquantitative analysis of mitochondria was performed in liver biopsies from 10 patients divided into 2 groups: Group 1 consisted of 5 patients who had never used ARV medications; group 2 consisted of 5 patients who reported previous use of either zidovudine or didanosine. Significant mitochondrial alterations were found in both groups. The summation of the mitochondrial alterations was higher in group 1 ( P < .05) when compared with those who had previously used ARV medications. Therefore, the authors conclude that severe mitochondrial alterations occur in HIV-infected patients who have never been submitted to antiretroviral therapy.
Perceptions of Health, HIV Disease, and HIV Treatment by Patients in 6 Regions: Analysis of the 2555-Person AIDS Treatment for Life International Survey
Authors: Mascolini Mark , Zuniga José M.
Published: July 2008

Background. Antiretroviral therapy (ART) has reached millions of HIV-infected patients worldwide, however very little is known about their perceptions about HIV disease and its treatment. The AIDS Treatment for Life International Survey (ATLIS) is the largest sampling of patient perceptions about HIV disease and its treatment, as well as their behaviors, including HIV status disclosure and ART adherence. Methods. The International Association of Physicians in AIDS Care (IAPAC) and its survey vendor, Ipsos Insight Health, conducted a convenience-sample survey of 2555 treated and untreated HIV-infected adults recruited by diverse means from 6 regions: North America, Latin America, the Caribbean, Europe, Asia/Pacific, and sub-Saharan Africa. Findings. Nearly three quarters of respondents were taking prescription medications for HIV infection or related diseases. Participants reported generally good overall health and high degrees of satisfaction with current antiretroviral drugs, though approximately half of respondents voiced concern about potential ART toxicity and 39.4% reported switching their antiretroviral regimen specifically because of treatment-associated side effects. About 1 in 5 respondents never took medications for HIV and AIDS. Among the three quarters of respondents currently taking medications, 37% are taking their first prescribed antiretroviral regimen, and 24% have switched from a first-line antiretroviral regimen. Three quarters of respondents believe ART will help them live a long life, and treatment-experienced respondents expressed this view significantly more often than untreated respondents. Large majorities of respondents in Latin America, Asia, and South Africa want to know more about ART, while half or fewer in these countries correctly explained the meaning of undetectable HIV RNA (defined as <50 HIV RNA copies/mL of plasma) or knew their CD4 cell count.
The Entrepreneur's Evolution to Philanthropist
Authors: Taylor Marilyn L. , Coates Theresa , Strom Robert , Renz David , Holman Rhonda
Published: July 2008

Entrepreneurs who evolve into philanthropists make contributions on broad fronts, for example, to the economic effects in their communities and nations and to the social issues of various kinds that they embrace as challenges. This article is an early excursion into understanding the process by which entrepreneurs make the transition from entrepreneurs in the economic realm to philanthropists involved in various social issues. The article draws its insights from the evolution of Ewing Marion Kauffman, founder of the successful pharmaceutical company Marion Laboratories and also the Kauffman Foundation, which has had a unique entrepreneurship focus addressing the needs of entrepreneurs, researchers, and educators throughout the United States and beyond. The Kauffman case study demonstrates that the entrepreneur's leave taking of his or her company and the entry into the nonprofit or philanthropic world are processes. The research identifies a number of issues associated with these overlapping and integrated processes.
Gender Differences in Ethnocultural Empathy and Attitudes Toward Men and Women in Authority
Authors: Cundiff Nicole L. , Komarraju Meera
Published: July 2008

The relationship between attitudes toward members of ethnic or cultural minority groups and men and women in authority or leadership positions was examined. The Ethnocultural Empathy Scale and Gender Authority Measure were completed by 317 participants. Results yielded a positive relationship among the attitudinal measures, indicating that individuals who express more empathy toward individuals from diverse ethnic or cultural backgrounds are likely to have positive perceptions of women in authority/leadership positions. Furthermore, gender differences in perceptions suggest that, relative to males, females are more likely to report higher levels of ethnic or cultural empathy and also have higher preference for women in leadership and authority positions.
Layoff Agency
Authors: Parker Thomas , McKinley William
Published: July 2008

The current downsizing literature has neglected the cognitions and behaviors of layoff agents. In this article, layoff agents are defined as employees who assist in the implementation of layoffs in their employing organizations. The article develops a theoretical framework that focuses on the cognitions and perceptions of those individuals. This framework suggests that layoff agents have the potential to experience cognitive dissonance as a result of their layoff agency activities, and under some conditions they will seek to reduce that dissonance by altering their perceptions of organizational downsizing. The framework specifies variables that moderate the relationship between layoff agency and cognitive dissonance and also variables that moderate the relationship between layoff agency—induced cognitive dissonance and agent perceptions of organizational downsizing. The moderating effects of these variables are captured in a set of propositions suitable for testing in future empirical research on the psychology of layoff agents.
Can Leaders Step Outside of the Gender Box? An Examination of Leadership and Gender Role Stereotypes
Authors: Embry Andrew , Padgett Margaret Y. , Caldwell Craig B.
Published: July 2008

This study examined gender stereotypes for leaders using a more indirect method than is typical in stereotype research. Rather than reveal the leader's gender, this study used vignettes in which the leader's gender was unknown. Consistent with their hypothesis, the authors found that participants were more likely to infer a male (female) gender identity than a female (male) gender identity when presented with a leader using a masculine (feminine) style. They also hypothesized that a leader using a gender-consistent leadership style would be viewed more positively than a leader using a gender-inconsistent style. Contrary to this hypothesis, results revealed that men using a gender-inconsistent (feminine) style were actually evaluated more positively than men using a gender-consistent style. It is interesting that a perceived female leader who used a gender-inconsistent (masculine) style was evaluated more positively than a perceived male leader who used a masculine style, but only by female participants. Possible explanations for these results are discussed.
High Risk Community—Men’s Perceptions of Black Infant Mortality: A Qualitative Inquiry
Authors: Quinn Gwendolyn P. , August Euna M. , Austin Deborah , Keefe Candace , Bernadotte Christina , Scarborough Kenneth , Jeffers Delores
Published: July 2008

Infant mortality has been identified as a key public health concern in the United States. Although infant mortality rates (IMRs) in the United States have declined during the past 10 years, the rates among Blacks are more than two times higher as compared with other racial and ethnic groups. This study used focus groups to explore Black men’s awareness and perceptions of the rising IMR in their community. Twenty-five men participated in an initial and follow-up focus group, which revealed that men had limited awareness of infant mortality, reduced sense of personal responsibility for pregnancy outcomes, and perceptions that stress, the age of the mother, and the health care system were responsible for poor birth outcomes. The role of the community and possible interventions to involve and educate men were also explored.
Violent Behavior of Men in Their Intimate Relationships, as They Experience It
Authors: Flinck Aune , Paavilainen Eija
Published: July 2008

Violence against women has been extensively studied in various disciplines, whereas less attention has been paid to the experiences of men. Even the violent behavior of men in their intimate relationships has been mostly studied as experienced by women. This study follows Husserlian descriptive phenomenology. Twenty open-ended interviews were conducted with 10 Finnish men with a history of intimate partner violence (IPV). The data were analyzed by the method developed by Colaizzi. Findings suggested that men considered communication and dynamics of the relationship important. Fundamentally, these abusive men had a need to be respected as men, and they sought to experience human dignity. It is necessary to readjust the framework on interpersonal violence, listen to the voice of men, and develop prevention, early identification, and supportive intervention strategies for men, couples, and families. Research on IPV should be expanded to include the experiences of both genders.
Learned Resourcefulness and the Long-Term Benefits of a Chronic Pain Management Program
Authors: Kennett Deborah J. , O'Hagan Fergal T. , Cezer Diego
Published: July 2008

A concurrent mixed methods approach was used to understand how learned resourcefulness empowers individuals. After completing Rosenbaum's Self-Control Schedule (SCS) measuring resourcefulness, 16 past clients of a multimodal pain clinic were interviewed about the kinds of pain-coping strategies they were practicing from the program. Constant comparative analysis of the text-based data revealed striking differences in the type of pain management strategies used by high- and low-resourceful participants. A substantive theory is advanced, whereby introspection and emotion allow for acceptance, which in turn permits the constructive use of social supports and enactment of active, and sometimes creative, pain-coping strategies to engage in meaningful activities.
Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation
Authors: Grech Godfrey , Blázquez-Domingo Montserrat , Kolbus Andrea , Bakker Walbert J. , Müllner Ernst W. , Beug Hartmut , von Lindern Marieke
Published: July 2008

Stem cell factor (SCF)–induced activation of phosphoinositide-3-kinase (PI3K) is required for transient amplification of the erythroblast compartment. PI3K stimulates the activation of mTOR (target of rapamycin) and subsequent release of the cap-binding translation initiation factor 4E (eIF4E) from the 4E-binding protein 4EBP, which controls the recruitment of structured mRNAs to polysomes. Enhanced expression of eIF4E renders proliferation of erythroblasts independent of PI3K. To investigate which mRNAs are selectively recruited to polysomes, we compared SCF-dependent gene expression between total and polysome-bound mRNA. This identified 111 genes primarily subject to translational regulation. For 8 of 9 genes studied in more detail, the SCF-induced polysome recruitment of transcripts exceeded 5-fold regulation and was PI3K-dependent and eIF4E-sensitive, whereas total mRNA was not affected by signal transduction. One of the targets, Immunoglobulin binding protein 1 (Igbp1), is a regulatory subunit of protein phosphatase 2A (Pp2a) sustaining mTOR signaling. Constitutive expression of Igbp1 impaired erythroid differentiation, maintained 4EBP and p70S6k phosphorylation, and enhanced polysome recruitment of multiple eIF4E-sensitive mRNAs. Thus, PI3K-dependent polysome recruitment of Igbp1 acts as a positive feedback mechanism on translation initiation underscoring the important regulatory role of selective mRNA recruitment to polysomes in the balance between proliferation and maturation of erythroblasts.
Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells
Authors: Maës Jerome , Maleszewska Marta , Guillemin Claire , Pflumio Francoise , Six Emmanuelle , André-Schmutz Isabelle , Cavazzana-Calvo Marina , Charron Dominique , Francastel Claire , Goodhardt Michele
Published: July 2008

To address the role of chromatin structure in the establishment of hematopoietic stem cell (HSC) multilineage potential and commitment to the lymphoid lineage, we have analyzed histone modifications at a panel of lymphoid- and myeloid-affiliated genes in multipotent and lineage-committed hematopoietic cells isolated from human cord blood. Our results show that many B- and T-lymphoid genes, although silent in HSCs, are associated with acetylated histones H3 and H4. We also detected histone H3 lysine 4 methylation but not repressive lysine 9 or 27 methylation marks at these loci, indicative of an open chromatin structure. Interestingly, the relative level of H3 lysine 4 dimethylation to trimethylation at B-specific loci was high in multipotent CD34+CD38lo progenitors and decreased as they become actively transcribed in B-lineage cells. In vitro differentiation of CD34+ cells toward the erythroid, granulocyte, and T-cell lineages resulted in a loss of histone acetylation at nonlineage-associated genes. This study provides evidence that histone modifications involved in chromatin decondensation are already in place at lymphoid-specific genes in primary human HSCs, supporting the idea that these genes are “primed” for expression before lineage commitment. This permissive chromatin structure is progressively lost as the stem cell differentiates.
Characterization of megakaryocyte GATA1-interacting proteins: the corepressor ETO2 and GATA1 interact to regulate terminal megakaryocyte maturation
Authors: Hamlett Isla , Draper Julia , Strouboulis John , Iborra Francisco , Porcher Catherine , Vyas Paresh
Published: July 2008

The transcription factor GATA1 coordinates timely activation and repression of megakaryocyte gene expression. Loss of GATA1 function results in excessive megakaryocyte proliferation and disordered terminal platelet maturation, leading to thrombocytopenia and leukemia in patients. The mechanisms by which GATA1 does this are unclear. We have used in vivo biotinylated GATA1 to isolate megakaryocyte GATA1-partner proteins. Here, several independent approaches show that GATA1 interacts with several proteins in the megakaryocyte cell line L8057 and in primary megakaryocytes. They include FOG1, the NURD complex, the pentameric complex containing SCL/TAL-1, the zinc-finger regulators GFI1B and ZFP143, and the corepressor ETO2. Knockdown of ETO2 expression promotes megakaryocyte differentiation and enhances expression of select genes expressed in terminal megakaryocyte maturation, eg, platelet factor 4 (Pf4). ETO2-dependent direct repression of the Pf4 proximal promoter is mediated by GATA-binding sites and an E-Box motif. Consistent with this, endogenous ETO2, GATA1, and the SCL pentameric complex all specifically bind the promoter in vivo. Finally, as ETO2 expression is restricted to immature megakaryocytes, these data suggest that ETO2 directly represses inappropriate early expression of a subset of terminally expressed megakaryocyte genes by binding to GATA1 and SCL.
The PPARgamma-selective ligand BRL-49653 differentially regulates the fate choices of rat calvaria versus rat bone marrow stromal cell populations
Authors: Hasegawa Takuro , Oizumi Kiyoshi , Yoshiko Yuji , Tanne Kazuo , Maeda Norihiko , Aubin Jane E
Published: July 2008

Background

Osteoblasts and adipocytes are derived from a common mesenchymal progenitor and an inverse relationship between expression of the two lineages is seen with certain experimental manipulations and in certain diseases,i.e., osteoporosis, but the cellular pathway(s) and developmental stages underlying the inverse relationship is still under active investigation. To determine which precursor mesenchymal cell types can differentiate into adipocytes, we compared the effects of BRL-49653 (BRL), a selective ligand for peroxisome proliferators-activated receptor (PPAR)γ, a master transcription factor of adipogenesis, on osteo/adipogeneis in two different osteoblast culture models: the rat bone marrow (RBM) versus the fetal rat calvaria (RC) cell system.

Results

BRL increased the number of adipocytes and corresponding marker expression, such as lipoprotein lipase, fatty acid-binding protein (aP2), and adipsin, in both culture models, but affected osteoblastogenesis only in RBM cultures, where a reciprocal decrease in bone nodule formation and osteoblast markers,e.g., osteopontin, alkaline phosphatase (ALP), bone sialoprotein, and osteocalcin was seen, and not in RC cell cultures. Even though adipocytes were histologically undetectable in RC cultures not treated with BRL, RC cells expressed PPAR and CCAAT/enhancer binding protein (C/EBP) mRNAs throughout osteoblast development and their expression was increased by BRL. Some single cell-derived BRL-treated osteogenic RC colonies were stained not only with ALP/von Kossa but also with oil red O and co-expressed the mature adipocyte marker adipsin and the mature osteoblast marker OCN, as well as PPAR and C/EBP mRNAs.

Conclusion

The data show that there are clear differences in the capacity of BRL to alter the fate choices of precursor cells in stromal (RBM) versus calvarial (RC) cell populations and that recruitment of adipocytes can occur from multiple precursor cell pools (committed preadipocyte pool, multi-/bipotential osteo-adipoprogenitor pool and conversion of osteoprogenitor cells or osteoblasts into adipocytes (transdifferentiation or plasticity)). They also show that mechanisms beyond activation of PPARγ by its ligand are required for changing the fate of committed osteoprogenitor cells and/or osteoblasts into adipocytes.
Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases
Authors: Martínez Alfonso , Santiago Jose Luis , Varadé Jezabel , Márquez Ana , Lamas José Ramón , Mendoza Juan Luis , de la Calle Hermenegildo , Díaz-Rubio Manuel , de la Concha Emilio G , Fernández-Gutiérrez Benjamín , Urcelay Elena
Published: July 2008

Background

Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component.

Results

Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study.

Conclusion

Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.
Structure and properties of transcriptional networks driving selenite stress response in yeasts
Authors: Salin Hélène , Fardeau Vivienne , Piccini Eugenia , Lelandais Gaelle , Tanty Véronique , Lemoine Sophie , Jacq Claude , Devaux Frédéric
Published: July 2008

Background

Stress responses provide valuable models for deciphering the transcriptional networks controlling the adaptation of the cell to its environment. We analyzed the transcriptome response of yeast to toxic concentrations of selenite. We used gene network mapping tools to identify functional pathways and transcription factors involved in this response. We then used chromatin immunoprecipitation and knock-out experiments to investigate the role of some of these regulators and the regulatory connections between them.

Results

Selenite rapidly activates a battery of transcriptional circuits, including iron deprivation, oxidative stress and protein degradation responses. The mRNA levels of several transcriptional regulators are themselves regulated. We demonstrate the existence of a positive transcriptional loop connecting the regulator of proteasome expression, Rpn4p, to the pleiotropic drug response factor, Pdr1p. We also provide evidence for the involvement of this regulatory module in the oxidative stress response controlled by the Yap1p transcription factor and its conservation in the pathogenic yeast C. glabrata. In addition, we show that the drug resistance regulator gene YRR1 and the iron homeostasis regulator gene AFT2 are both directly regulated by Yap1p.

Conclusion

This work depicted a highly interconnected and complex transcriptional network involved in the adaptation of yeast genome expression to the presence of selenite in its chemical environment. It revealed the transcriptional regulation of PDR1 by Rpn4p, proposed a new role for the pleiotropic drug resistance network in stress response and demonstrated a direct regulatory connection between oxidative stress response and iron homeostasis.
Transcriptional profiling in C. elegans suggests DNA damage dependent apoptosis as an ancient function of the p53 family
Authors: Greiss Sebastian , Schumacher Björn , Grandien Kaj , Rothblatt Jonathan , Gartner Anton
Published: July 2008

Background

In contrast to the three mammalian p53 family members, p53, which is generally involved in DNA damage responses, and p63 and p73 which are primarily needed for developmental regulation,cep-1encodes for the singleC.elegansp53-like gene.cep-1acts as a transcription activator in a primordial p53 pathway that involves CEP-1 activation and the CEP-1 dependent transcriptional induction of the worm BH3 only domain encoding genesegl-1andced-13to induce germ cell apoptosis. EGL-1 and CED-13 proteins inactivate Bcl-2 like CED-9 to trigger CED-4 and CED-3 caspase dependent germ cell apoptosis. To address the function of p53 in global transcriptional regulation we investigate genome-wide transcriptional responses upon DNA damage andcep-1deficiency.

Results

ExaminingC. elegansexpression profiles using whole genome Affymetrix GeneChip arrays, we found that 83 genes were induced more than two fold upon ionizing radiation (IR). None of these genes, with exception of an ATP ribosylase homolog, encode for known DNA repair genes. Using two independentcep-1loss of function alleles we did not find genes regulated bycep-1in the absence of IR. Among the IR-induced genes only three are dependent oncep-1, namelyegl-1,ced-13and a novelC. elegansspecific gene. The majority of IR-induced genes appear to be involved in general stress responses, and qRT-PCR experiments indicate that they are mainly expressed in somatic tissues. Interestingly, we reveal an extensive overlap of gene expression changes occurring in response to DNA damage and in response to bacterial infection. Furthermore, many genes induced by IR are also transcriptionally regulated in longevity mutants suggesting that DNA damage and aging induce an overlapping stress response.

Conclusion

We performed genome-wide gene expression analyses which indicate that only a surprisingly small number of genes are regulated by CEP-1 and that DNA damage induced apoptosis via the transcriptional induction of BH3 domain proteins is likely to be an ancient DNA damage response function of the p53 family. Interestingly, although the apoptotic response to DNA damage is regulated through the transcriptional activity of CEP-1, other DNA damage responses do not appear to be regulated on the transcriptional level and do not require the p53 like genecep-1.
Genetic interaction network of the Saccharomyces cerevisiae type 1 phosphatase Glc7
Authors: Logan Michael R , Nguyen Thao , Szapiel Nicolas , Knockleby James , Por Hanting , Zadworny Megan , Neszt Michael , Harrison Paul , Bussey Howard , Mandato Craig A , Vogel Jackie , Lesage Guillaume
Published: July 2008

Background

Protein kinases and phosphatases regulate protein phosphorylation, a critical means of modulating protein function, stability and localization. The identification of functional networks for protein phosphatases has been slow due to their redundant nature and the lack of large-scale analyses. We hypothesized that a genome-scale analysis of genetic interactions using the Synthetic Genetic Array could reveal protein phosphatase functional networks. We apply this approach to the conserved type 1 protein phosphatase Glc7, which regulates numerous cellular processes in budding yeast.

Results

We created a novel glc7 catalytic mutant (glc7-E101Q). Phenotypic analysis indicates that this novel allele exhibits slow growth and defects in glucose metabolism but normal cell cycle progression and chromosome segregation. This suggests that glc7-E101Q is a hypomorphic glc7 mutant. Synthetic Genetic Array analysis of glc7-E101Q revealed a broad network of 245 synthetic sick/lethal interactions reflecting that many processes are required when Glc7 function is compromised such as histone modification, chromosome segregation and cytokinesis, nutrient sensing and DNA damage. In addition, mitochondrial activity and inheritance and lipid metabolism were identified as new processes involved in buffering Glc7 function. An interaction network among 95 genes genetically interacting with GLC7 was constructed by integration of genetic and physical interaction data. The obtained network has a modular architecture, and the interconnection among the modules reflects the cooperation of the processes buffering Glc7 function.

Conclusion

We found 245 genes required for the normal growth of the glc7-E101Q mutant. Functional grouping of these genes and analysis of their physical and genetic interaction patterns bring new information on Glc7-regulated processes.
CpG oligodeoxynucleotide stimulates production of anti-neutrophil cytoplasmic antibodies in ANCA associated vasculitis
Authors: Hurtado Plinio R , Jeffs Lisa , Nitschke Jodie , Patel Mittal , Sarvestani Ghafar , Cassidy John , Hissaria Pravin , Gillis David , Au Peh Chen
Published: July 2008

Background

Wegener's Granulomatosis and Microscopic Polyangiitis are life-threatening systemic necrotizing vasculitides of unknown aetiology. The appearance of circulating antibodies to neutrophil cytoplasmic antigens (ANCA) is strongly associated with the development of the disease. A link between infection and disease has long been suspected, and the appearance of ANCA antibodies has been reported following bacterial and viral infections. The depletion of circulating B cells with monoclonal antibody therapy can induce remission, and this observation suggests a pathogenic role for B cells in this disease. As bacterial DNA is known to induce B cell proliferation and antibody production via TLR-9 stimulation, we have explored the possibility that unmethylated CpG oligodeoxynucleotide, as found in bacterial and viral DNA, may play a role in stimulating circulating autoreactive B cells to produce ANCA in patients with vasculitis.

Results

We have confirmed that unmethylated CpG oligonucleotide is a potent stimulator of antibody production by PBMC in vitro. The stimulation of PBMC with CpG oligonucleutides resulted in the production of similar amounts of IgG in both ANCA+ patients and normal controls. In spite of this, PR3 ANCA+ patients synthesised significantly higher amount of IgG ANCA than normal controls. In MPO ANCA+ patients, there was a tendency for patients to produce higher amount of ANCA than controls, however, the difference did not reach significance. Furthermore, we were able to detect circulating MPO-reactive B cells by ELISpot assay from the peripheral blood of 2 MPO+ ANCA vasculitis patients. Together, this indicates that circulating anti-neutrophil autoreactive B cells are present in ANCA+ vasculitis patients, and they are capable of producing antibodies in response to CpG stimulation. Of note, CpG also induced the production of the relevant autoantibodies in patients with other types of autoimmune diseases.

Conclusion

Circulating ANCA autoreactive B cells are present in patients with ANCA+ vasculitis. The production of ANCA from these cells in response to unmethylated CpG stimulation lead us to propose that stimulation of these cells by immunostimulatory DNA sequences such as CpG oligodeoxynucleotide during infection may provide a link between infection and ANCA associated vasculitis. This phenomenon may also apply to other antibody mediated autoimmune diseases.
Processing of predicted substrates of fungal Kex2 proteinases from Candida albicans, C. glabrata, Saccharomyces cerevisiae and Pichia pastoris
Authors: Bader Oliver , Krauke Yannick , Hube Bernhard
Published: July 2008

Background

Kexin-like proteinases are a subfamily of the subtilisin-like serine proteinases with multiple regulatory functions in eukaryotes. In the yeast Saccharomyces cerevisiae the Kex2 protein is biochemically well investigated, however, with the exception of a few well known proteins such as the α-pheromone precursors, killer toxin precursors and aspartic proteinase propeptides, very few substrates are known. Fungal kex2 deletion mutants display pleiotropic phenotypes that are thought to result from the failure to proteolytically activate such substrates.

Results

In this study we have aimed at providing an improved assembly of Kex2 target proteins to explain the phenotypes observed in fungal kex2 deletion mutants by in vitro digestion of recombinant substrates from Candida albicans and C. glabrata. We identified CaEce1, CA0365, one member of the Pry protein family and CaOps4-homolog proteins as novel Kex2 substrates.

Conclusion

Statistical analysis of the cleavage sites revealed extended subsite recognition of negatively charged residues in the P1', P2' and P4' positions, which is also reflected in construction of the respective binding pockets in the ScKex2 enzyme. Additionally, we provide evidence for the existence of structural constrains in potential substrates prohibiting proteolysis. Furthermore, by using purified Kex2 proteinases from S. cerevisiae, P. pastoris, C. albicans and C. glabrata, we show that while the substrate specificity is generally conserved between organisms, the proteinases are still distinct from each other and are likely to have additional unique substrate recognition.
Presence of Helicobacter pylori in a Mexican Pre-Columbian Mummy
Authors: Castillo-Rojas Gonzalo , Cerbón Marco A , López-Vidal Yolanda
Published: July 2008

Background

Recent studies showed that Helicobacter pylori existed in the New World prior to the arrival of Columbus. The purpose of the present study was to detect the presence of Helicobacter pylori in pre-Columbian mummies from Northern Mexico.

Methods

Six samples were studied (four samples of gastric remains, tongue-soft palate, and brain remained as negative controls) from two of the six naturally mummified corpses studied (adult male and infant male). Samples were taken from tissues suitable for DNA amplification by Polymerase chain reaction (PCR). DNA was extracted and H. pylori detection was carried out by PCR and hybridized with the pHp probe from 16S rRNA gene. The purified PCR products were cloned and sequenced in both directions. DNA sequences were analyzed with ALIGN and BLAST software. A second amplification was performed using ureB gene by real-time PCR.

Results

From four samples of gastric remnant, only two were H. pylori-positive for amplification of a 109 bp DNA fragment; the remaining two were negative, as were the tongue-soft palate and the brain biopsies as well. These PCR products were hybridized with a pHp probe. Nucleotide sequence analysis showed homology with H. pylori in 98 of 99% when compared with the gene bank nucleotide sequence. Only one sample of gastric remnant H. pylori-positive with 16S rRNA gene was also positive for ureB gene from H. pylori.

Conclusion

This data supported infection with H. pylori in Mexican pre-Columbian mummies dating from approximately 1,350 AC.
The Arabidopsis thaliana response regulator ARR22 is a putative AHP phospho-histidine phosphatase expressed in the chalaza of developing seeds
Authors: Horák Jakub , Grefen Christopher , Berendzen Kenneth W , Hahn Achim , Stierhof York-Dieter , Stadelhofer Bettina , Stahl Mark , Koncz Csaba , Harter Klaus
Published: July 2008

Background

The Arabidopsis response regulator 22 (ARR22) is one of two members of a recently defined novel group of two-component system (TCS) elements. TCSs are stimulus perception and response modules of prokaryotic origin, which signal by a His-to-Asp phosphorelay mechanism. In plants, TCS regulators are involved in hormone response pathways, such as those for cytokinin and ethylene. While the functions of the other TCS elements in Arabidopsis, such as histidine kinases (AHKs), histidine-containing phosphotransfer proteins (AHPs) and A-type and B-type ARRs are becoming evident, the role of ARR22 is poorly understood.

Results

We present evidence that ARR22 is a preferentially cytoplasmic protein, exclusively expressed in the chalaza of developing seeds. ARR22 specifically interacts with AHP2, AHP3 and AHP5 in yeast and living plant cells. Two new loss-of-function alleles, arr22-2 and arr22-3, were isolated and characterized. With respect to their morphology and metabolite status, no significant difference in the developing seeds of the arr22 mutants was observed compared to wild type. The genetic complementation of the arr22 mutants with a genomic ARR22 fragment resulted in plants (arr22/gARR22) with a pleiotropic phenotype of different penetrance. This phenotype was not observed when the phosphorylatable Asp74 of ARR22 was changed to either a dominant-active Glu or a dominant-inactive Asn. The phenotype of the arr22/gARR22 plants was comparable to that of multiple ahk, ahp and B-type arr mutants.

Conclusion

Our results favor the model that ARR22 acts as a phospho-histidine phosphatase on specific AHPs in the cytoplasm of Arabidopsis chalaza cells. The lack of any aberrant morphological and metabolite phenotype in the seeds of the arr22 mutants indicates that ARR22 is probably primarily responsible for the fine tuning of specific branches of chalaza-based TCS signalling. Even when slightly mis-expressed, ARR22 interferes with hormone homeostasis in non-chalaza tissues. Our data indicate that the chromatin status might play a crucial role in maintaining the chalaza-restricted expression of ARR22.
Nicotinic acetylcholine receptor subunit variants are associated with blood pressure; findings in the Old Order Amish and replication in the Framingham Heart Study
Authors: McArdle Patrick F , Rutherford Sue , Mitchell Braxton D , Damcott Coleen M , Wang Ying , Ramachandran Vasan , Ott Sandy , Chang Yen-Pei C , Levy Daniel , Steinle Nanette
Published: July 2008

Background

Systemic blood pressure, influenced by both genetic and environmental factors, is regulated via sympathetic nerve activity. We assessed the role of genetic variation in three subunits of the neuromuscular nicotinic acetylcholine receptor positioned on chromosome 2q, a region showing replicated evidence of linkage to blood pressure.

Methods

We sequencedCHRNA1,CHRNDandCHRNGin 24 Amish subjects from the Amish Family Diabetes Study (AFDS) and identified 20 variants. We then performed association analysis of non-redundant variants (n = 12) in the complete AFDS cohort of 1,189 individuals, and followed by genotyping blood pressure-associated variants (n = 5) in a replication sample of 1,759 individuals from the Framingham Heart Study (FHS).

Results

The minor allele of a synonymous coding SNP, rs2099489 inCHRNG, was associated with higher systolic blood pressure in both the Amish (p = 0.0009) and FHS populations (p = 0.009) (minor allele frequency = 0.20 in both populations).

Conclusion

CHRNGis currently thought to be expressed only during fetal development. These findings support the Barker hypothesis, that fetal genotype and intra-uterine environment influence susceptibility to chronic diseases later in life. Additional studies of this variant in other populations, as well as the effect of this variant on acetylcholine receptor expression and function, are needed to further elucidate its potential role in the regulation of blood pressure. This study suggests for the first time in humans, a possible role for genetic variation in the neuromuscular nicotinic acetylcholine receptor, particularly the gamma subunit, in systolic blood pressure regulation.