bluuebunny/crossref_metadata_2025 huggingface dataset:
A multimetric approach to analysis of genome-wide association by single markers and composite likelihood
Authors: Gibson Jane , Tapper William , Cox David , Zhang Weihua , Pfeufer Arne , Gieger Christian , Wichmann H.-Erich , Kääb Stefan , Collins Andrew R. , Meitinger Thomas , Morton Newton
Published: February 2008

Two case/control studies with different phenotypes, marker densities, and microarrays were examined for the most significant single markers in defined regions. They show a pronounced bias toward exaggerated significance that increases with the number of observed markers and would increase further with imputed markers. This bias is eliminated by Bonferroni adjustment, thereby allowing combination by principal component analysis with a Malecot model composite likelihood evaluated by a permutation procedure to allow for multiple dependent markers. This intermediate value identifies the only demonstrated causal locus as most significant even in the preliminary analysis and clearly recognizes the strongest candidate in the other sample. Because the three metrics (most significant single marker, composite likelihood, and their principal component) are correlated, choice of the
n
smallest
P
values by each test gives <3
n
regions for follow-up in the next stage. In this way, methods with different response to marker selection and density are given approximately equal weight and economically compared, without expressing an untested prejudice or sacrificing the most significant results for any of them. Large numbers of cases, controls, and markers are by themselves insufficient to control type 1 and 2 errors, and so efficient use of multiple metrics with Bonferroni adjustment promises to be valuable in identifying causal variants and optimal design simultaneously.
Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma
Authors: Ratnacaram Chandrahas Koumar , Teletin Marius , Jiang Ming , Meng Xiangjun , Chambon Pierre , Metzger Daniel
Published: February 2008

Studies of prostate cancer pathogenesis and development of new therapies have been hampered by a lack of appropriate mouse models. We have generated PSA-Cre-ER
T2
mice that express the tamoxifen-dependent Cre-ER
T2
recombinase selectively in prostatic epithelium, thus allowing us to target floxed genes selectively in epithelial cells of fully differentiated prostate of adult mice and to modulate the number of genetically altered cells. Our present mouse model, in which prostate carcinogenesis is initiated through Cre-ER
T2
-mediated somatic biallelic ablation of the tumor suppressor gene PTEN after puberty, closely mimics the course of human cancer formation. Indeed, mutant mice developed prostate epithelium hyperplasia within 4 weeks after PTEN ablation and prostatic intraepithelial neoplasia (PIN) in all lobes within 2–3 months, with the highest incidence in the dorsolateral lobe, which is considered to be the most similar to the peripheral zone of the human prostate, in which adenocarcinoma is preferentially localized. Eight to 10 months after PTEN ablation some PINs of the dorsolateral lobe had progressed to adenocarcinoma, but no distant metastases were found up to 20 months after PTEN ablation, indicating that progression to metastasis requires an additional mutation or mutations. Interestingly, monoallelic Cre-ER
T2
-mediated PTEN ablation in epithelial cells of adult prostate also generated focal hyperplasia and PINs, but exclusively in the dorsolateral lobe, and in much lower number and after a longer latency. However, no progression to adenocarcinoma was observed. Because PTEN expression was undetectable in epithelial cells from these PINs, loss of PTEN function appears to act as a permissive event for uncontrolled cell proliferation.
Sterility and absence of histopathological defects in nonreproductive organs of a mouse ERβ-null mutant
Authors: Antal Maria Cristina , Krust Andrée , Chambon Pierre , Mark Manuel
Published: February 2008

Estrogen signaling is mediated by estrogen receptors α (ERα) and β (ERβ). Although a consensus has now been reached concerning many physiological functions of ERα, those of ERβ are still controversial: When housed and examined in two distant laboratories, mice originating from the same initial ERβ mutant exhibited widely different phenotypes, which were themselves different from the phenotype of another ERβ mutant previously generated in our laboratory. Because, in addition to a knockout insertion in exon 3, all these mouse mutants displayed alternative splicing transcripts, we have now constructed a ERβ mouse mutant (ERβ
ST
L−/L−
) in which exon 3 was cleanly deleted by Cre/LoxP-mediated excision and was devoid of any transcript downstream of exon 3. Both females and males were sterile. The histology of the ovary was mildly affected, and no histological defects were detected in other organs, neither in females nor in males. Our present results, which are in contrast with previously published data, suggest that, with the notable exception of male and female reproduction, ERβ is not required in the mouse for the development and homeostasis of the major body systems.
SNAREpin/Munc18 promotes adhesion and fusion of large vesicles to giant membranes
Authors: Tareste David , Shen Jingshi , Melia Thomas J. , Rothman James E.
Published: February 2008

Exocytic vesicle fusion requires both the SNARE family of fusion proteins and a closely associated regulatory subunit of the Sec1/Munc18 (SM) family. In principle, SM proteins could act at an early SNARE assembly step to promote vesicle–plasma membrane adhesion or at a late step to overcome the energetic barrier for fusion. Here, we use the neuronal cognates of each of these protein families to recapitulate, and distinguish, membrane adhesion and fusion on a novel lipidic platform suitable for imaging by fluorescence microscopy. Vesicle SNARE (v-SNARE) proteins reconstituted into giant vesicles (≈10 μm) are fully mobile and functional. Through confocal microscopy, we observe that large vesicles (≈100 nm) carrying target membrane SNAREs (t-SNAREs) both adhere to and freely move on the surface of the v-SNARE giant vesicle. Under conditions where the intrinsic ability of SNAREs to drive fusion is minimized, Munc18 stimulates both SNARE-dependent stable adhesion and fusion. Furthermore, mutation of a critical Munc18-binding residue on the N terminus of the t-SNARE syntaxin uncouples Munc18-stimulated vesicle adhesion from membrane fusion. We expect that the study of SNARE-mediated fusion with giant membranes will find wide applicability in distinguishing adhesion- and fusion-directed SNARE regulatory factors.
Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms
Authors: Zhao Li , Vogt Peter K.
Published: February 2008

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is up-regulated in cancer.
PIK3CA
, the gene coding for the catalytic subunit p110α of PI3K, is mutated in ≈30% of tumors of the prostate, breast, cervix, and endometrium. The most prominent of these mutants, represented by single amino acid substitutions in the helical or kinase domain, show a gain of enzymatic function, activate AKT signaling, and induce oncogenic transformation. We have carried out a genetic and biochemical analysis of these hot-spot mutations in
PIK3CA
. The results of this study suggest that the helical and kinase domain mutations trigger gain of function through different mechanisms. They show different requirements for interaction with the PI3K regulatory subunit p85 and with RAS-GTP. The gain of function induced by helical domain mutations is independent of binding to p85 but requires interaction with RAS-GTP. In contrast, the kinase domain mutation is active in the absence of RAS-GTP binding but is highly dependent on the interaction with p85. We speculate that the contrasting roles of p85 and RAS-GTP in helical and kinase domain mutations reflect two distinct states of mutated p110α. These two states differ in mutation-induced surface charges and also may differ in conformational properties that are controlled by interactions with p85 and RAS-GTP. The two states do not appear mutually exclusive because the helical and kinase domain mutations act synergistically when present in the same p110α molecule. This synergism also supports the conclusion that the helical and kinase domain mutations operate by two different and independent mechanisms.
The marine lipopeptide somocystinamide A triggers apoptosis via caspase 8
Authors: Wrasidlo Wolf , Mielgo Ainhoa , Torres Vicente A. , Barbero Simone , Stoletov Konstantin , Suyama Takashi L. , Klemke Richard L. , Gerwick William H. , Carson Dennis A. , Stupack Dwayne G.
Published: February 2008

Screening for novel anticancer drugs in chemical libraries isolated from marine organisms, we identified the lipopeptide somocystinamide A (ScA) as a pluripotent inhibitor of angiogenesis and tumor cell proliferation. The antiproliferative activity was largely attributable to induction of programmed cell death. Sensitivity to ScA was significantly increased among cells expressing caspase 8, whereas siRNA knockdown of caspase 8 increased survival after exposure to ScA. ScA rapidly and efficiently partitioned into liposomes while retaining full antiproliferative activity. Consistent with the induction of apoptosis via the lipid compartment, we noted accumulation and aggregation of ceramide in treated cells and subsequent colocalization with caspase 8. Angiogenic endothelial cells were extremely sensitive to ScA. Picomolar concentrations of ScA disrupted proliferation and endothelial tubule formation
in vitro
. Systemic treatment of zebrafish or local treatment of the chick chorioallantoic membrane with ScA resulted in dose-dependent inhibition of angiogenesis, whereas topical treatment blocked tumor growth among caspase-8-expressing tumors. Together, the results reveal an unexpected mechanism of action for this unique lipopeptide and suggest future development of this and similar agents as antiangiogenesis and anticancer drugs.
A cell–cell signaling sensor is required for virulence and insect transmission of
Xylella fastidiosa
Authors: Chatterjee Subhadeep , Wistrom Christina , Lindow Steven E.
Published: February 2008

Cell–cell signaling in
Xylella fastidiosa
, a xylem-colonizing plant pathogenic bacterium, mediated by a fatty acid
D
iffusible
S
ignaling
F
actor (DSF), is required to colonize insect vectors and to suppress virulence to grape. Here, we show that a hybrid two-component regulatory protein RpfC is involved in negative regulation of DSF synthesis by RpfF in
X. fastidiosa. X. fastidiosa rpfC
mutants hyperexpress
rpfF
and overproduce DSF and are deficient in virulence and movement in the xylem vessels of grape. The expression of the genes encoding the adhesins FimA, HxfA, and HxfB is much higher in
rpfC
mutants, which also exhibit a hyperattachment phenotype in culture that is associated with their inability to migrate in xylem vessels and cause disease.
rpfF
mutants deficient in DSF production have the opposite phenotypes for all of these traits. RpfC is also involved in the regulation of other signaling components including
rpfG
,
rpfB
, a GGDEF domain protein that may be involved in intracellular signaling by modulating the levels of cyclic-di-GMP, and the virulence factors
tolC
and
pglA
required for disease.
rpfC
mutants are able to colonize the mouthparts of insect vectors and wild-type strains but are not transmitted as efficiently to new host plants, apparently because of their high levels of adhesiveness. Because of the conflicting contributions of adhesiveness and other traits to movement within plants and vectoring to new host plants,
X. fastidiosa
apparently coordinates these traits in a population-size-dependent fashion involving accumulation of DSF.
The influence of the school in the decision to participate in learning post‐16
Authors: Foskett Nick , Dyke Martin , Maringe Felix
Published: February 2008

The primary aim of this study, funded by the Department for Education and Skills, was to identify the nature and influence of school‐based factors in the choices of young people about their post‐16 education, training and career pathways. The study also contributes to the wider understanding of ‘choice’, and identifies implications for the development of careers education and guidance and decision‐making awareness amongst pupils and students in schools. It also further enhances the modelling of pupil decision making in education and training markets, and in labour markets. The research is based on a series of qualitative interviews in 24 schools across nine local education authorities. Focus groups were undertaken with young people in years 10, 11 and 12. Interviews were also conducted with head teachers, heads of year and heads of careers. A postal survey of parents was also undertaken. Four key school‐based factors were found to have a very strong influence in the choices and decisions of young people about their post‐16 education, training and career pathways. These were: whether the school had a sixth form or not; the characteristics of school leadership, ethos and values; the socio‐economic status (SES) of the schools' catchment; and the organisation and delivery of careers education and guidance at the school level. In the main, high SES schools see themselves as developing pupils for academic university careers, while low SES schools maintain a rather stronger commitment to vocational pathways. The academic ethos of schools offers a very powerful influence on post‐16 choices and decisions of pupils. The usual interventions put in place to influence choices and decisions appear to have greater impact in schools with a less robust academic vision.
I liked your course because you taught me well: The influence of grades, workload, expectations and goals on students' evaluations of teaching
Authors: Remedios Richard , Lieberman David A.
Published: February 2008

There has been considerable debate as to whether course evaluations are valid measures of teaching quality, or whether students instead reward tutors who give them high grades and assign low levels of work. To assess the factors that influence course evaluations, we measured university students' achievement goals and expectations at the beginning of the semester and also obtained information on grades and workload. Although grades and course difficulty did have a small influence on end‐of‐semester course ratings, structural modelling revealed that ratings were largely determined by how much students enjoyed or felt stimulated by the course content, which in turn depended on the perceived quality of teaching. Students with a mastery goal were more likely to look forward to the course, and this also contributed to positive course evaluations, but the effect was small. Overall, the results suggested that by far the largest determinant of student evaluation of courses is the quality of the teaching.
The professional voice: Comparing questionnaire and telephone methods in a national survey of teachers' perceptions
Authors: Sturman Linda , Taggart Geoff
Published: February 2008

This article compares the results obtained from using two different methodological approaches to elicit teachers' views on their professional role, the key challenges and their aspirations for the future. One approach used a postal/online questionnaire, while the other used telephone interviews, posing a selection of the same questions. The research was carried out on two statistically comparable samples of teachers in England in spring 2004. Significant differences in responses were observed which seem to be attributable to the methods employed. In particular, more ‘definite’ responses were obtained in the interviews than in response to the questionnaire. This article reviews the comparative outcomes in the context of existing research and explores why the separate methods may have produced significantly different responses to the same questions.
‘Bunking off’: The impact of truancy on pupils and teachers
Authors: Wilson Valerie , Malcolm Heather , Edward Sheila , Davidson Julia
Published: February 2008

There is widespread interest in the impact of unauthorised absence on pupil attainment, links with disaffection, exclusion from school and criminality. However, little is heard about what those who take unauthorised absence from school think that the effect has been on them; nor do we hear the voices of other pupils and their teachers. This article presents evidence from a one‐year study of absence in seven local authorities in England funded by the Department for Education and Skills. It defines ‘truancy’, explores some issues from existing literature on pupil non‐attendance, and presents evidence to show the impact that absence from school has on truants, other pupils and teachers. Finally, it suggests that although the greatest impact is on the academic and socio‐psychological development of persistent absentees, the attitudes and learning of other pupils and the workload and morale of teachers are also affected.
The Japanese Innovation System: University–Industry Linkages, Small Firms and Regional Technology Clusters
1
Authors: Edgington David W.
Published: February 2008

This essay introduces the articles in a special edition on advances made in the Japanese innovation system. It sets the papers against a broad overview of traditional Japanese approaches to innovation and recent calls for change. An analysis is made of the geography of high‐technology factories and recent job losses in the manufacturing sector. The new policies and their impact on Japan’s national and regional innovation systems are then outlined and a synopsis given of the other papers in this special edition. The essay makes a number of concluding remarks on the appropriateness of Japan following the US‐model of innovation.
Putting Innovation in Place: Policy Strategies for Industrial Services, Regional Clusters, and Manufacturing SMEs in Japan and the United States
1
Authors: Shapira Philip
Published: February 2008

This paper examines the evolving situation of mature manufacturing small and midsize enterprises (SMEs) in Japan and the United States and considers some of the key challenges they now face in an era of globalization and rapid technological change. The rationale and justification for policy intervention to support mature SMEs is considered. A review is offered of illustrative policy initiatives in three areas: framework policies, industrial services, and regional industrial cluster policies. The convergence of manufacturing and regional policies is noted. The relative strengths and weaknesses of Japanese and US strategies are assessed. The paper concludes with a comparison of Japanese and US approaches to retaining manufacturing SMEs, interpreted through the various and at times interactive ways through which each country’s innovation system develops and evolves technology and business support policies.
Knowledge Clusters and the Revitalization of Regional Economies in Japan: A Case Study of the Biomedical Industry in Kobe
Authors: Collins Steven W.
Published: February 2008

On a cold January morning in 1995, a powerful earthquake rocked Kobe, Japan, killing thousands and shattering the economy of one of Japan’s most vibrant cities. Three years later, a small group of local leaders, realizing that much of the lost industrial output would never return, hatched a plan to develop the city as an international hub for biomedical research and innovation. Out of this was born the Kobe Medical Industry Development Project. Housed on part of an artificial island, the project integrates basic, applied, clinical, and translational research in regenerative medicine and biomedical equipment, providing a comprehensive platform for research, development, and commercialization of new medical therapies and technologies. This article reviews and assesses the achievements of this initiative in the context of the broader effort by central and regional governments to harness localized knowledge and resources as catalysts of sustainable economic development.
Targeted inactivation of the COP9 signalosome impairs multiple stagesof T cell development
Authors: Panattoni Martina , Sanvito Francesca , Basso Veronica , Doglioni Claudio , Casorati Giulia , Montini Eugenio , Bender Jeffrey R. , Mondino Anna , Pardi Ruggero
Published: February 2008

Genetic programs promoting cell cycle progression, DNA repair, and survival are coordinately induced in developing T cells and require rapid turnover of effector molecules. As the COP9 signalosome (CSN) has been placed at the crossroads of these programs in lower organisms, we addressed its role by conditionally deleting CSN5/JAB1, its catalytic subunit, in developing thymocytes. CSN5/JAB1del/del thymocytes show defective S phase progression and massive apoptosis at the double-negative (DN) 4–double-positive (DP) transition stage, which is paralleled by altered turnover of selected CSN-controlled substrates, including p53, IκB-α, and β-catenin. Combined dysregulation of the p53 and NF-κB pathways affects thymocyte survival by altering the mRNA and protein levels of selected Bcl-2 family members. Genetic complementation analysis performed on p53−/−, Bcl-xL/Bcl-2A1, or T cell receptor transgenic backgrounds indicates that CSN5/JAB1 acts at distinct developmental stages to coordinate proliferation, survival, and positive selection of thymocytes by controlling the induction of defined genetic programs acting downstream of CSN-regulated transcription factors.
Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20
Authors: Turer Emre E. , Tavares Rita M. , Mortier Erwan , Hitotsumatsu Osamu , Advincula Rommel , Lee Bettina , Shifrin Nataliya , Malynn Barbara A. , Ma Averil
Published: February 2008

Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor–associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain–containing adaptor inducing interferon (IFN) β–dependent nuclear factor κB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated.
Altered development of the brain after focal herpesvirus infection of the central nervous system
Authors: Koontz Thad , Bralic Marina , Tomac Jelena , Pernjak-Pugel Ester , Bantug Glen , Jonjic Stipan , Britt William J.
Published: February 2008

Human cytomegalovirus infection of the developing central nervous system (CNS) is a major cause of neurological damage in newborn infants and children. To investigate the pathogenesis of this human infection, we developed a mouse model of infection in the developing CNS. Intraperitoneal inoculation of newborn animals with murine cytomegalovirus resulted in virus replication in the liver followed by virus spread to the brain. Virus infection of the CNS was associated with the induction of inflammatory responses, including the induction of a large number of interferon-stimulated genes and histological evidence of focal encephalitis with recruitment of mononuclear cells to foci containing virus-infected cells. The morphogenesis of the cerebellum was delayed in infected animals. The defects in cerebellar development in infected animals were generalized and, although correlated temporally with virus replication and CNS inflammation, spatially unrelated to foci of virus-infected cells. Specific defects included decreased granular neuron proliferation and migration, expression of differentiation markers, and activation of neurotrophin receptors. These findings suggested that in the developing CNS, focal virus infection and induction of inflammatory responses in resident and infiltrating mononuclear cells resulted in delayed cerebellar morphogenesis.
Forward genetic analysis of Toll-like receptor responses in wild-derived mice reveals a novel antiinflammatory role for IRAK1BP1
Authors: Conner James R. , Smirnova Irina I. , Poltorak Alexander
Published: February 2008

Although inflammatory cytokines produced by activation of Toll-like receptors (TLRs) are essential for early host defense against infection, they also mediate a vast array of pathologies, including autoimmune disease, hypersensitivity reactions, and sepsis. Thus, numerous regulatory mechanisms exist in parallel with proinflammatory pathways to prevent excessive release of these potent effector molecules. We report elucidation of a novel regulatory function for interleukin receptor–associated kinase (IRAK)-1 binding protein 1 (IRAK1BP1, also known as SIMPL) through quantitative trait locus mapping of the TLR response in wild-derived mouse strains. This gene emerged as a negative regulator of TLR2-mediated interleukin (IL)-6 production in MOLF/Ei mice, which expressed IRAK1BP1 mRNA in an allele-specific manner when crossed with the C57BL/6J strain. Human peripheral blood mononuclear cells and primary macrophages from two other wild-derived mouse strains also induced IRAK1BP1 mRNA by 4 hours after stimulation with agonists of various TLRs. Examination of its effects on IL-6 and other cytokines demonstrated that IRAK1BP1 regulates transcription of a specific subset of TLR-responsive genes, producing an overall antiinflammatory profile. Our results reveal that IRAK1BP1 is a critical factor in preventing dangerous overproduction of proinflammatory cytokines by the innate immune system and in influencing the specificity of TLR responses. Furthermore, these results show that the genetic diversity of wild-derived mouse strains makes them a valuable model of important human gene functions that have been lost in some laboratory-inbred strains.
IL-33 reduces the development of atherosclerosis
Authors: Miller Ashley M. , Xu Damo , Asquith Darren L. , Denby Laura , Li Yubin , Sattar Naveed , Baker Andrew H. , McInnes Iain B. , Liew Foo Y.
Published: February 2008

Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1–like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE−/− mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33–treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNγ in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG1, but decreased IgG2a, which is consistent with a Th1-to-Th2 switch. IL-33–treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE−/− mice compared with control IgG-treated mice. Furthermore, coadministration of an anti–IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.
Vaccine protection againstStaphylococcus aureuspneumonia
Authors: Wardenburg Juliane Bubeck , Schneewind Olaf
Published: February 2008

Staphylococcus aureus pneumonia causes significant mortality in hospitalized or healthy individuals, and recent increases in morbidity are attributed to the rapid spread of methicillin-resistant S. aureus (MRSA) strains, which are often not susceptible to antibiotic therapy. α-Hemolysin (Hla), a secreted pore-forming toxin, is an essential virulence factor of MRSA in a mouse model of S. aureus pneumonia. We show that the level of Hla expression by independent S. aureus strains directly correlates with their virulence. Active immunization with a mutant form of Hla (HlaH35L), which cannot form pores, generates antigen-specific immunoglobulin G responses and affords protection against staphylococcal pneumonia. Moreover, transfer of Hla-specific antibodies protects naive animals against S. aureus challenge and prevents the injury of human lung epithelial cells during infection. Thus, Hla vaccination or immunotherapy may prevent S. aureus pneumonia in humans.
Glucose-6-Phosphate Dehydrogenase Deficiency Enhances Human Coronavirus 229E Infection
Authors: Wu Yi-Hsuan , Tseng Ching-Ping , Cheng Mei-Ling , Ho Hung-Yao , Shih Shin-Ru , Chiu Daniel Tsun-Yee
Published: February 2008

The host cellular environment is a key determinant of pathogen infectivity. Viral gene expression and viral particle production of glucose-6-phosphate dehydrogenase (G6PD)–deficient and G6PD-knockdown cells were much higher than their counterparts when human coronavirus (HCoV) 229E was applied at 0.1 multiplicity of infection. These phenomena were correlated with increased oxidant production. Accordingly, ectopic expression of G6PD in G6PD-deficient cells or addition of antioxidant (such as α-lipoic acid) to G6PD-knockdown cells attenuated the increased susceptibility to HCoV 229E infection. All experimental data indicated that oxidative stress in host cells is an important factor in HCoV 229E infectivity
Genodiversity of ResistantPseudomonas aeruginosaIsolates in Relation to Antimicrobial Usage Density and Resistance Rates in Intensive Care Units
Authors: Jonas Daniel , Meyer Elisabeth , Schwab Frank , Grundmann Hajo
Published: February 2008

Objective.

To evaluate the assumption that resistance rates in intensive care units (ICUs) are markedly influenced by cross-transmission events in addition to high rates of antimicrobial usage.

Methods.

This was a prospective ICU- and laboratory-based surveillance study involving 35 German ICUs from 1999 through 2004. A total of 585 ciprofloxacin- or imipenem-resistant isolates ofPseudomonas aeruginosawere investigated together with resistance rate and unit-based antimicrobial usage density. Antimicrobial use was reported in terms of defined daily doses per 1,000 patient-days. All the strains were assigned to ICU-based genotypes. Genodiversity was calculated as the numbers of indistinguishable ICU-based genotypes found per isolates tested. Reduced ICU-based genodiversity was taken as an indirect measure of frequently occurring cross-transmission events.

Results.

The genodiversity of ciprofloxacin- and imipenem-resistant P.aeruginosaisolates was significantly lower (P≤ .05, by Fisher exact test) in ICUs with high resistance rate and low antimicrobial usage density (genodiversity, 0.50 and 0.50, respectively) than in ICUs that featured low resistance rate in the presence of high antimicrobial usage density (genodiversity, 0.90 and 0.95, respectively). In ICUs with low genodiversity, there was a greater rise in resistance rate with increasing antimicrobial usage density, compared with that in ICUs with high diversity.

Conclusions.

This study on resistant P.aeruginosaisolates supports the assumption that high resistance rate in the presence of low antimicrobial usage density results from more-frequent cross-transmission events. A greater rise in resistance rate with increasing antimicrobial usage density in ICUs with low genodiversity indicates that resistance rate in ICUs might be markedly determined by cross-transmission events other than antimicrobial usage.
A Latin-cross-shaped integrated resonant cantilever with second torsion-mode resonance for ultra-resoluble bio-mass sensing
Authors: Xia Xiaoyuan , Zhang Zhixiang , Li Xinxin
Published: February 2008

Second torsion-mode resonance is proposed for microcantilever biosensors for ultra-high mass-weighing sensitivity and resolution. By increasing both the resonant frequency andQ-factor, the higher mode torsional resonance is favorable for improving the mass-sensing performance. For the first time, a Latin-cross-shaped second-mode resonant cantilever is constructed and optimally designed for both signal-readout and resonance-exciting elements. The cantilever sensor is fabricated by using silicon micromachining techniques. The transverse piezoresistive sensing element and the specific-shaped resonance-exciting loop are successfully integrated in the cantilever. Alpha-fetoprotein (AFP) antibody–antigen specific binding is implemented for the sensing experiment. The proposed cantilever sensor is designed with significantly superior sensitivity to the previously reported first torsion-mode one. After analysis with an Allan variance algorithm, which can be easily embedded in the sensing system, the Latin-cross-shaped second torsion-mode resonant cantilever is evaluated with ultra-high mass resolution. Therefore, the high-performance integrated micro-sensor is promising for on-the-spot bio-molecule detection.
The rational Schur algebra
Authors: Dipper Richard , Doty Stephen
Published: February 2008

We extend the family of classical Schur algebras in typeAA, which determine the polynomial representation theory of general linear groups over an infinite field, to a larger family, the rational Schur algebras, which determine the rational representation theory of general linear groups over an infinite field. This makes it possible to study the rational representation theory of such general linear groups directly through finite dimensional algebras. We show that rational Schur algebras are quasihereditary over any field, and thus have finite global dimension.

We obtain explicit cellular bases of a rational Schur algebra by a descent from a certain ordinary Schur algebra. We also obtain a description, by generators and relations, of the rational Schur algebras in characteristic zero.
Complexity reduction of biochemical rate expressions
Authors: Schmidt Henning , Madsen Mads F. , Danø Sune , Cedersund Gunnar
Published: February 2008

Motivation: The current trend in dynamical modelling of biochemical systems is to construct more and more mechanistically detailed and thus complex models. The complexity is reflected in the number of dynamic state variables and parameters, as well as in the complexity of the kinetic rate expressions. However, a greater level of complexity, or level of detail, does not necessarily imply better models, or a better understanding of the underlying processes. Data often does not contain enough information to discriminate between different model hypotheses, and such overparameterization makes it hard to establish the validity of the various parts of the model. Consequently, there is an increasing demand for model reduction methods.

Results: We present a new reduction method that reduces complex rational rate expressions, such as those often used to describe enzymatic reactions. The method is a novel term-based identifiability analysis, which is easy to use and allows for user-specified reductions of individual rate expressions in complete models. The method is one of the first methods to meet the classical engineering objective of improved parameter identifiability without losing the systems biology demand of preserved biochemical interpretation.

Availability: The method has been implemented in the Systems Biology Toolbox 2 for MATLAB, which is freely available from http://www.sbtoolbox2.org. The Supplementary Material contains scripts that show how to use it by applying the method to the example models, discussed in this article.

Contact:  henning.schmidt@uni-rostock.de

Supplementary information: Supplementary data are available at Bioinformatics online.
Performance of Transgenic Potato Containing the Late Blight Resistance Gene RB
Authors: Halterman Dennis A. , Kramer Lara Colton , Wielgus Susan , Jiang Jiming
Published: February 2008

Late blight of potato, caused by Phytophthora infestans, is one of the most devastating diseases of potato. A major late blight resistance gene, called RB, previously was identified in the wild potato species Solanum bulbocastanum through map-based cloning. The full-length gene coding sequence, including the open reading frame and promoter, has been integrated into cultivated potato (S. tuberosum) using Agrobacterium-mediated transformation. RB-containing transgenic plants were challenged with P. infestans under optimal late blight conditions in greenhouse experiments. All transgenic lines containing RB exhibited strong foliar resistance. Field-grown transgenic tubers also were tested for resistance to P. infestans. In contrast to the foliar resistance phenotype, RB-containing tubers did not exhibit increased resistance. Two years of field trials were used to ascertain whether the presence of RB had any effect on tuber yield. We were unable to detect any significant effect on tuber size or yield after addition of the resistance gene to several S. tuberosum cultivars.
Distribution and Recovery of Tilletia indica Teliospores from Regulated Wheat Fields in Texas
Authors: Allen T. W. , Maples H. W. , Workneh F. , Stein J. M. , Rush C. M.
Published: February 2008

Eight wheat fields from the Karnal bunt-regulated regions within Texas were grid sampled to gain a better understanding of the ecology and epidemiology of teliospores produced by the causal agent, Tilletia indica. Teliospores from 25-g aliquots of soil from each grid point were extracted using a size-selective sieving sucrose-centrifugation procedure. Teliospores were recovered from all eight fields and, in some cases, from every grid point within a field. Total teliospore numbers ranged from 0 to 1,305 per 25 g of soil. Over 70% of the total grid sampled points contained one or more teliospores. The relation between soil chemical and physical characteristics and teliospore numbers from each field was evaluated. In general, no consistent, significant trend could be made between soil factors and teliospore numbers. Geostatistics were used to analyze data from grid points and create contour maps. Teliospore distribution was aggregated in four of the fields, random in three of the fields, and discontinuous (neither random nor aggregated) in a single field. This is the first report of widespread distribution and high teliospore numbers from wheat field soils in the United States.
Bacteria and Yeast Associated with Sugar Beet Root Rot at Harvest in the Intermountain West
Authors: Strausbaugh Carl A. , Gillen Anne M.
Published: February 2008

An undescribed wet rot of roots was observed in surveys of recently harvested sugar beet roots in Idaho and eastern Oregon in 2004 and 2005. Microorganisms isolated from 287 roots fell into the following groups: A (41% of strains), B (29%), C (17%), D (11%), E (2%), and F (1%). Groups A, B, C, and F were composed of bacteria while groups D and E were yeasts. Subgroup A1 (80% of group A strains) included Leuconostoc mesenteroides subsp. dextranicum strains and subgroup A2 (20%) contained Lactobacillus strains. Group B was dominated by subgroup B1 (92% of strains), which included Gluconobacter strains. When only one organism was isolated from rotted roots, strains from subgroup A1 were isolated most frequently. Group C was composed of enteric bacteria. Strain B322 of L. mesenteroides subsp. dextranicum caused the most severe rot on root slices and produced symptoms similar to those in harvested roots. Results suggest that L. mesenteroides subsp. dextranicum is among the first bacterial species to enter sugar beet roots, closely following fungal infections or entering directly through openings such as growth cracks. The bacterial rot leads to yield loss in the field but likely also leads to storage and factory-processing problems.
Epidemiology of Xiphinema americanum and Tomato ringspot virus on Red Raspberry, Rubus idaeus
Authors: Pinkerton J. N. , Kraus J. , Martin R. R. , Schreiner R. P.
Published: February 2008

Population dynamics of Xiphinema americanum and transmission of Tomato ringspot virus (ToRSV) were studied in a red raspberry field in Washington State. Population densities of X. americanum were highest in the winter, lowest in the summer, and were correlated with precipitation (R2 = 0.42). All nematode stages were present throughout the year. Gravid females were observed only in the spring, indicating one generation per year. The sequence of the coat protein of the ToRSV from this field was similar to those of other raspberry isolates from the Pacific Northwest. Cucumber seedlings were planted in soil collected monthly from the field and were evaluated for nematode transmission of ToRSV by enzyme-linked immunosorbent assay (ELISA). The proportion of assay plants infected with ToRSV was negatively correlated with nematode densities (R2 = 0.31). In another study, ToRSV was detected by ELISA in fine roots of raspberry plants 5 months after planting in field soil infested with viruliferous nematodes, in all subterranean portions of plants after 12 months, and in all aerial portions the second year. The rate of spread of ToRSV in a raspberry field was 70 cm per year. These results suggest that the rate of ToRSV spread is limited by systemic spread of virus in plants when nematode-infested soil is not transported in the field.
Virulence Frequencies in Oat Crown Rust in the United States from 2001 Through 2005
Authors: Carson M. L.
Published: February 2008

In all, 680 single-pustule isolates of the oat crown rust pathogen, Puccinia coronata f. sp. avenae, were collected from cultivated and wild oat (Avena sativa and A. fatua, respectively) in the major oat-production areas of the United States from 2001 through 2005. They were tested for virulence on seedlings of differential oat lines in the greenhouse. In all, 171 races were found among the 357 isolates from the winter oat region of the United States, whereas 212 races were found among 323 isolates from the spring oat region. The crown rust population derived from winter oat in the southern United States was distinct from the spring oat population in the upper Midwest, although there was no virulence unique to either population. Virulence to Pc48 and Pc52 increased significantly in both regions during 2001 to 2005. Virulence to Pc59 increased and virulence to Pc53 decreased in the winter oat region during the same period. Many of the virulence associations previously reported in the U.S. oat crown rust population in the early 1990s also were found in both regions in this survey. Associations between virulence to the Pc genes were predominately positive in both regions; however, both positive and negative associations occurred more frequently in the winter oat region. Much of the virulence diversity in the oat crown rust population in the United States can be related to the deployment of resistance genes in commercial oat cultivars and virulence associations existing in the oat crown rust population. The mean virulence of the U.S. populations of crown rust continued to increase from 2001 to 2005. Genes for crown rust resistance derived from A. sterilis appear to be rapidly defeated, as has happened to Pc genes from A. sativa.
Evaluation of Weather-Based Spray Advisories for Improved Control of Peanut Stem Rot
Authors: Rideout S. L. , Brenneman T. B. , Culbreath A. K. , Langston D. B.
Published: February 2008

Stem rot of peanut, caused by the soilborne fungus Sclerotium rolfsii, is greatly influenced by environmental conditions. Disease management programs rely heavily on fungicides, which are applied on a calendar-based program. To determine whether improved control of stem rot could result from weather-based spray advisories, models were constructed using what is currently known about the biology of S. rolfsii and etiology of stem rot epidemics in peanut. Spray advisories based on soil temperature, precipitation, and host parameters were tested, along with advisories focusing on soil temperature and precipitation or precipitation alone. The advisories were evaluated and compared with the currently used calendar-based program over four locations annually for 3 years. Fungicide application timing had a significant effect on both stem rot control and resulting pod yields. In general, stem rot control following the advisories considering soil temperature, precipitation, and canopy growth was similar or better than that offered by the calendar-based program, but yields generally were comparable. The AU-Pnut advisory for foliar diseases also was effective for scheduling azoxystrobin applications for stem rot.
Virulence Diversity of the Common Bean Rust Pathogen Within and Among Individual Bean Fields and Development of Sampling Strategies
Authors: Jochua C. , Amane M. I. V. , Steadman J. R. , Xue X. , Eskridge K. M.
Published: February 2008

There is a dearth of information on pathogen variation within an individual field. In this study, virulence diversity of Uromyces appendiculatus, cause of bean rust, within individual fields was investigated. From six bean fields in the United States, Honduras, Dominican Republic, and South Africa, 380 U. appendiculatus isolates were differentiated into 65 virulence phenotypes on bean lines containing Andean- and Middle American-derived rust resistance genes. Race variation among bean rust isolates from different geographic regions was found, and virulence phenotypes found in fields from tropical and subtropical regions were more virulent and diverse than those found in fields from temperate regions. The variance components between fields was greater than the variance within a field based on mean disease score on 12 differentials but the variance components within a field were greater than the variances between fields based on number of virulence phenotypes. This is the first report that multiple site samples are needed to represent the fungal virulence diversity in a diseased field. In developing sampling plans, the entire cost of sampling one field is higher than the cost of taking more samples; therefore, to estimate virulence diversity variation, we recommend selecting fewer fields and collecting more samples per field.
Evaluation of Tobacco Germplasm for Seedling Resistance to Stem Rot and Target Spot Caused by Thanatephorus cucumeris
Authors: Elliott P. E. , Lewis R. S. , Shew H. D. , Gutierrez W. A. , Nicholson J. S.
Published: February 2008

Stem rot and target spot of tobacco, caused by Rhizoctonia solani and its teleomorph Thanatephorus cucumeris, respectively, can cause serious problems in production of tobacco (Nicotiana tabacum) seedlings. Previous screens for genetic resistance in tobacco have been limited. The objective of this study was to evaluate 97 genotypes composing several classes of tobacco and related Nicotiana spp. for seedling resistance to stem rot and target spot. Significant differences in disease incidence initially were observed among the genotypes for both stem rot and target spot; however, resistance to target spot was not observed when disease pressure was high. Partial resistance to stem rot was observed in several genotypes in repeated tests. These accessions may be useful as a source of resistance to R. solani in future breeding efforts.