bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncogenomic analysis of mycosis fungoides reveals major differences with Sézary syndrome
Authors: van Doorn Remco , van Kester Marloes S. , Dijkman Remco , Vermeer Maarten H. , Mulder Aat A. , Szuhai Karoly , Knijnenburg Jeroen , Boer Judith M. , Willemze Rein , Tensen Cornelis P.
Published: October 2008

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a malignancy of mature, skin-homing T cells. Sézary syndrome (Sz) is often considered to represent a leukemic phase of MF. In this study, the pattern of numerical chromosomal alterations in MF tumor samples was defined using array-based comparative genomic hybridization (CGH); simultaneously, gene expression was analyzed using microarrays. Highly recurrent chromosomal alterations in MF include gain of 7q36, 7q21-7q22 and loss of 5q13 and 9p21. The pattern characteristic of MF differs markedly from chromosomal alterations observed in Sz. Integration of data from array-based CGH and gene-expression analysis yielded several candidate genes with potential relevance in the pathogenesis of MF. We confirmed that the FASTK and SKAP1 genes, residing in loci with recurrent gain, demonstrated increased expression. The RB1 and DLEU1 tumor suppressor genes showed diminished expression associated with loss. In addition, it was found that the presence of chromosomal alterations on 9p21, 8q24, and 1q21-1q22 was associated with poor prognosis in patients with MF. This study provides novel insight into genetic alterations underlying MF. Furthermore, our analysis uncovered genomic differences between MF and Sz, which suggest that the molecular pathogenesis and therefore therapeutic requirements of these cutaneous T-cell lymphomas may be distinct.
CD4+CD25+ T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen-specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses
Authors: Verma Nirupama D. , Plain Karren M. , Nomura Masaru , Tran Giang T. , Robinson Catherine , Boyd Rochelle , Hodgkinson Suzanne J. , Hall Bruce M.
Published: October 2008

CD4+CD25+Foxp3+ T cells are regulatory/suppressor cells (Tregs) that include non-antigen (Ag)–specific as well as Ag-specific Tregs. How non–Ag-specific naive CD4+CD25+ Treg develop into specific Tregs is unknown. Here, we generated adaptive Tregs by culture of naive CD4+CD25+Foxp3+ T cells with allo-Ag and either interleukin-2 (IL-2) or IL-4. Within days, IL-2 enhanced interferon-γ receptor (Ifnγr) and Il-5 mRNA and IL-4 induced a reciprocal profile with de novo IL-5Rα and increased IFN-γ mRNA expression. Both IL-2– and IL-4–alloactivated CD4+CD25+ Tregs within 3 to 4 days of culture had enhanced capacity to induce tolerance to specific donor but not to third-party cardiac allografts. These hosts became tolerant as allografts functioned more than 250 days, with a physiologic ratio of less than 10% CD4+CD25+Foxp3+ T cells in the CD4+ population. CD4+CD25+ T cells from tolerant hosts given IL-2–cultured cells had increased Il-5 and Ifnγr mRNA. Those from hosts given IL-4–cultured cells had enhanced IL-5Rα mRNA expression and IL-5 enhanced their proliferation to donor but not third-party allo-Ag. Thus, IL-2 and IL-4 activated allo-Ag–specific Tregs with distinct phenotypes that were retained in vivo. These findings suggested that T-helper 1 (Th1) and Th2 responses activate 2 pathways of adaptive Ag-specific Tregs that mediate tolerance. We propose they be known as T-suppressor 1 (Ts1) and Ts2 cells.
R/parallel – speeding up bioinformatics analysis with R
Authors: Vera Gonzalo , Jansen Ritsert C , Suppi Remo L
Published: October 2008

Background

R is the preferred tool for statistical analysis of many bioinformaticians due in part to the increasing number of freely available analytical methods. Such methods can be quickly reused and adapted to each particular experiment. However, in experiments where large amounts of data are generated, for example using high-throughput screening devices, the processing time required to analyze data is often quite long. A solution to reduce the processing time is the use of parallel computing technologies. Because R does not support parallel computations, several tools have been developed to enable such technologies. However, these tools require multiple modications to the way R programs are usually written or run. Although these tools can finally speed up the calculations, the time, skills and additional resources required to use them are an obstacle for most bioinformaticians.

Results

We have designed and implemented an R add-on package, R/parallel, that extends R by adding user-friendly parallel computing capabilities. With R/parallel any bioinformatician can now easily automate the parallel execution of loops and benefit from the multicore processor power of today's desktop computers. Using a single and simple function, R/parallel can be integrated directly with other existing R packages. With no need to change the implemented algorithms, the processing time can be approximately reducedN-fold,Nbeing the number of available processor cores.

Conclusion

R/parallel saves bioinformaticians time in their daily tasks of analyzing experimental data. It achieves this objective on two fronts: first, by reducing development time of parallel programs by avoiding reimplementation of existing methods and second, by reducing processing time by speeding up computations on current desktop computers. Future work is focused on extending the envelope of R/parallel by interconnecting and aggregating the power of several computers, both existing office computers and computing clusters.
Deaf-1 regulates epithelial cell proliferation and side-branching in the mammary gland
Authors: Barker Holly E , Smyth Gordon K , Wettenhall James , Ward Teresa A , Bath Mary L , Lindeman Geoffrey J , Visvader Jane E
Published: October 2008

Background

The transcription factor DEAF-1 has been identified as a high affinity binding partner of the LIM-only protein LMO4 that plays important roles in mammary gland development and breast cancer. Here we investigated the influence of DEAF-1 on human and mouse mammary epithelial cells bothin vitroandin vivoand identified a potential target gene.

Results

Overexpression of DEAF-1 in human breast epithelial MCF10A cells enhanced cell proliferation in the mammary acini that develop in 3D cultures. To investigate the effects of Deaf-1 on mammary gland development and oncogenesis, we generatedMMTV-Deaf-1transgenic mice. Increased ductal side-branching was observed in young virgin mammary glands, accompanied by augmented cell proliferation. In addition, the ratio of the progesterone receptor isoforms PRA and PRB, previously implicated in regulating ductal side-branching, was altered. Affymetrix gene profiling studies revealedRac3as a potential target gene and quantitative RT-PCR analysis confirmed thatRac3was upregulated by Deaf-1 in immortalized mouse mammary epithelial cells. Furthermore,MMTV-Deaf-1transgenic mammary glands were found to have elevated levels ofRac3mRNA, suggesting that it is abona fidetarget.

Conclusion

We have demonstrated that overexpression ofDeaf-1enhances the proliferation of human breast epithelial cellsin vitroand mouse epithelial cellsin vivo. Transgenic mammary glands overexpressing Deaf-1 exhibited a modest side-branching phenotype, accompanied by an increase in the number of BrdU-positive cells and a decrease in the proportion of PRA-expressing cells. Although proliferation was enhanced in Deaf-1 transgenic mice, overexpression of this gene was not sufficient to induce the formation of mammary tumors. In addition, our studies identifiedRac3, encoding a small Rho-like GTPase, as a potential target of Deaf-1 in mouse mammary epithelial cells.
Prebiotic replicase evolution in a surface-bound metabolic system: parasites as a source of adaptive evolution
Authors: Könnyű Balázs , Czárán Tamás , Szathmáry Eörs
Published: October 2008

Background

The remarkable potential of recent forms of life for reliably passing on genetic information through many generations now depends on the coordinated action of thousands of specialized biochemical "machines" (enzymes) that were obviously absent in prebiotic times. Thus the question how a complicated system like the living cell could have assembled on Earth seems puzzling. In seeking for a scientific explanation one has to search for step-by-step evolutionary changes from prebiotic chemistry to the emergence of the first proto-cell.

Results

We try to sketch a plausible scenario for the first steps of prebiotic evolution by exploring the ecological feasibility of a mineral surface-bound replicator system that facilitates a primitive metabolism. Metabolism is a hypothetical network of simple chemical reactions producing monomers for the template-copying of RNA-like replicators, which in turn catalyse metabolic reactions. Using stochastic cellular automata (SCA) simulations we show that the surface-bound metabolic replicator system is viable despite internal competition among the genes and that it also maintains a set of mild "parasitic" sequences which occasionally evolve functions such as that of a replicase.

Conclusion

Replicase activity is shown to increase even at the expense of slowing down the replication of the evolving ribozyme itself, due to indirect mutualistic benefits in a diffuse form of group selection among neighbouring replicators. We suggest possible paths for further evolutionary changes in the metabolic replicator system leading to increased metabolic efficiency, improved replicase functionality, and membrane production.
Linkage disequilibrium compared between five populations of domestic sheep
Authors: Meadows Jennifer RS , Chan Eva KF , Kijas James W
Published: October 2008

Background

The success of genome-wide scans depends on the strength and magnitude of linkage disequilibrium (LD) present within the populations under investigation. High density SNP arrays are currently in development for the sheep genome, however little is known about the behaviour of LD in this livestock species. This study examined the behaviour of LD within five sheep populations using two LD metrics, D' and x2'. Four economically important Australian sheep flocks, three pure breeds (White Faced Suffolk, Poll Dorset, Merino) and a crossbred population (Merino × Border Leicester), along with an inbred Australian Merino museum flock were analysed.

Results

Short range LD (0 – 5 cM) was observed in all five populations, however the persistence with increasing distance and magnitude of LD varied considerably between populations. Average LD (x2') for markers spaced up to 20 cM exceeded the non-syntenic average within the White Faced Suffolk, Poll Dorset and Macarthur Merino. LD decayed faster within the Merino and Merino × Border Leicester, with LD below or consistent with observed background levels. Using marker-marker LD as a guide to the behaviour of marker-QTL LD, estimates of minimum marker spacing were made. For a 95% probability of detecting QTL, a microsatellite marker would be required every 0.1 – 2.5 centimorgans, depending on the population used.

Conclusion

Sheep populations were selected which were inbred (Macarthur Merino), highly heterogeneous (Merino) or intermediate between these two extremes. This facilitated analysis and comparison of LD (x2') between populations. The strength and magnitude of LD was found to differ markedly between breeds and aligned closely with both observed levels of genetic diversity and expectations based on breed history. This confirmed that breed specific information is likely to be important for genome wide selection and during the design of successful genome scans where tens of thousands of markers will be required.
The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains
Authors: Ren Siyuan , Yang Guang , He Youyu , Wang Yiguo , Li Yixue , Chen Zhengjun
Published: October 2008

Background

Many well-represented domains recognize primary sequences usually less than 10 amino acids in length, called Short Linear Motifs (SLiMs). Accurate prediction of SLiMs has been difficult because they are short (often < 10 amino acids) and highly degenerate. In this study, we combined scoring matrixes derived from peptide library and conservation analysis to identify protein classes enriched of functional SLiMs recognized by SH2, SH3, PDZ and S/T kinase domains.

Results

Our combined approach revealed that SLiMs are highly conserved in proteins from functional classes that are known to interact with a specific domain, but that they are not conserved in most other protein groups. We found that SLiMs recognized by SH2 domains were highly conserved in receptor kinases/phosphatases, adaptor molecules, and tyrosine kinases/phosphatases, that SLiMs recognized by SH3 domains were highly conserved in cytoskeletal and cytoskeletal-associated proteins, that SLiMs recognized by PDZ domains were highly conserved in membrane proteins such as channels and receptors, and that SLiMs recognized by S/T kinase domains were highly conserved in adaptor molecules, S/T kinases/phosphatases, and proteins involved in transcription or cell cycle control. We studied Tyr-SLiMs recognized by SH2 domains in more detail, and found that SH2-recognized Tyr-SLiMs on the cytoplasmic side of membrane proteins are more highly conserved than those on the extra-cellular side. Also, we found that SH2-recognized Tyr-SLiMs that are associated with SH3 motifs and a tyrosine kinase phosphorylation motif are more highly conserved.

Conclusion

The interactome of protein domains is reflected by the evolutionary conservation of SLiMs recognized by these domains. Combining scoring matrixes derived from peptide libraries and conservation analysis, we would be able to find those protein groups that are more likely to interact with specific domains.
An efficient method for visualization and growth of fluorescent Xanthomonas oryzae pv. oryzae in planta
Authors: Han Sang-Wook , Park Chang-Jin , Lee Sang-Won , Ronald Pamela C
Published: October 2008

Background

Xanthomonas oryzae pv. oryzae, the causal agent of bacterial blight disease, is a serious pathogen of rice. Here we describe a fluorescent marker system to study virulence and pathogenicity of X. oryzae pv. oryzae.

Results

A fluorescent X. oryzae pv. oryzae Philippine race 6 strain expressing green fluorescent protein (GFP) (PXO99GFP) was generated using the gfp gene under the control of the neomycin promoter in the vector, pPneo-gfp. The PXO99GFPstrain displayed identical virulence and avirulence properties as the wild type control strain, PXO99. Using fluorescent microscopy, bacterial multiplication and colonization were directly observed in rice xylem vessels. Accurate and rapid determination of bacterial growth was assessed using fluoremetry and an Enzyme-Linked ImmunoSorbant Assay (ELISA).

Conclusion

Our results indicate that the fluorescent marker system is useful for assessing bacterial infection and monitoring bacterial multiplication in planta.
Rhythm generation by the pre-Bötzinger Complex in medullary slice and island preparations: Effects of adenosine A1receptor activation
Authors: VanDam Richard J , Shields Edward J , Kelty Jonathan D
Published: October 2008

Background

The pre-Bötzinger complex (preBötC) is a central pattern generator within the ventrolateral medulla oblongata's ventral respiratory group that is important for the generation of respiratory rhythm. Activation of adenosine A1 receptors (A1R) depresses preBötC rhythmogenesis. Although it remains unclear whether A1R activation is important for organisms in a normal metabolic state, A1R activation is important to the response of the preBötC to metabolic stress, such as hypoxia. This study examined mechanisms linking A1R activation to depression of preBötC rhythmogenesis in medullary slice and island preparations from neonatal mice.

Results

Converting medullary slices to islands by cutting away much of the medullary tissue adjacent to the preBötC decreased the amplitude of action potential bursts generated by a population of neurons within the preBötC (recorded with an extracellular electrode, and integrated using a hardware integrator), without noticeably affecting burst frequency. The A1R agonist N6-Cyclopentyladenosine (NCPA) reduced population burst frequency in slices by ca. 33% and in islands by ca. 30%. As in normal (drug-free) artificial cerebrospinal fluid (aCSF), NCPA decreased burst frequency in slices when GABAAergic or GABAAergic and glycinergic transmission were blocked, and in islands when GABAAergic transmission was antagonized. Converting slices to island preparations decreased synaptic input to inspiratory neurons. NCPA further decreased the frequency of synaptic inputs to neurons in island preparations and lowered the input resistance of inspiratory neurons, even when chemical communication between neurons and other cells was impeded.

Conclusion

Together these data support the suggestion that depression of preBötC activity by A1R activation involves both decreased neuronal excitability and diminished inter-neuronal communication.
Musashi1 modulates cell proliferation genes in the medulloblastoma cell line Daoy
Authors: Sanchez-Diaz Patricia C , Burton Tarea L , Burns Suzanne C , Hung Jaclyn Y , Penalva Luiz OF
Published: October 2008

Background

Musashi1 (Msi1) is an RNA binding protein with a central role during nervous system development and stem cell maintenance. High levels of Msi1 have been reported in several malignancies including brain tumors thereby associating Msi1 and cancer.

Methods

We used the human medulloblastoma cell line Daoy as model system in this study to knock down the expression of Msi1 and determine the effects upon soft agar growth and neurophere formation. Quantitative RT-PCR was conducted to evaluate the expression of cell proliferation, differentiation and survival genes in Msi1 depleted Daoy cells.

Results

We observed that MSI1 expression was elevated in Daoy cells cultured as neurospheres compared to those grown as monolayer. These data indicated that Msi1 might be involved in regulating proliferation in cancer cells. Here we show that shRNA mediated Msi1 depletion in Daoy cells notably impaired their ability to form colonies in soft agar and to grow as neurospheres in culture. Moreover, differential expression of a group of Notch, Hedgehog and Wnt pathway related genes including MYCN, FOS, NOTCH2, SMO, CDKN1A, CCND2, CCND1, and DKK1, was also found in the Msi1 knockdown, demonstrating that Msi1 modulated the expression of a subset of cell proliferation, differentiation and survival genes in Daoy.

Conclusion

Our data suggested that Msi1 may promote cancer cell proliferation and survival as its loss seems to have a detrimental effect in the maintenance of medulloblastoma cancer cells. In this regard, Msi1 might be a positive regulator of tumor progression and a potential target for therapy.
Development of a food allergy education resource for primary care physicians
Authors: Yu Joyce E , Kumar Arvind , Bruhn Christine , Teuber Suzanne S , Sicherer Scott H
Published: October 2008

Background

Food allergy is estimated to affect 3–4% of adults in the US, but there are limited educational resources for primary care physicians. The goal of this study was to develop and pilot a food allergy educational resource based upon a needs survey of non-allergist healthcare providers.

Methods

A survey was undertaken to identify educational needs and preferences for providers, with a focus on physicians caring for adults and teenagers, including emergency medicine providers. The results of the survey were used to develop a teaching program that was subsequently piloted on primary care and emergency medicine physicians. Knowledge base tests and satisfaction surveys were administered to determine the effectiveness of the educational program.

Results

Eighty-two physicians (response rate, 65%) completed the needs assessment survey. Areas of deficiency and educational needs identified included: identification of potentially life-threatening food allergies, food allergy diagnosis, and education of patients about treatment (food avoidance and epinephrine use). Small group, on-site training was the most requested mode of education. A slide set and narrative were developed to address the identified needs. Twenty-six separately enrolled participants were administered the teaching set. Pre-post knowledge base scores increased from a mean of 38% correct to 64% correct (p < 0.001). Ability to correctly demonstrate the use of epinephrine self injectors increased significantly. Nearly all participants (>95%) indicated that the teaching module increased their comfort with recognition and management of food allergy.

Conclusion

Our pilot food allergy program, developed based upon needs assessments, showed strong participant satisfaction and educational value.
Molecular and macromolecular alterations of recombinant adenoviral vectors do not resolve changes in hepatic drug metabolism during infection
Authors: Callahan Shellie M , Wonganan Piyanuch , Croyle Maria A
Published: October 2008

In this report we test the hypothesis that long-term virus-induced alterations in CYP occur from changes initiated by the virus that may not be related to the immune response. Enzyme activity, protein expression and mRNA of CYP3A2, a correlate of human CYP3A4, and CYP2C11, responsive to inflammatory mediators, were assessed 0.25, 1, 4, and 14 days after administration of several different recombinant adenoviruses at a dose of 5.7 × 1012 virus particles (vp)/kg to male Sprague Dawley rats. Wild type adenovirus, containing all viral genes, suppressed CYP3A2 and 2C11 activity by 37% and 39%, respectively within six hours. Levels fell to 67% (CYP3A2) and 79% (CYP2C11) of control by 14 days (p ≤ 0.01). Helper-dependent adenovirus, with all viral genes removed, suppressed CYP3A2 (43%) and CYP2C11 (55%) within six hours. CYP3A2 remained significantly suppressed (47%, 14 days, p ≤ 0.01) while CYP2C11 returned to baseline at this time. CYP3A2 and 2C11 were reduced by 45 and 42% respectively 6 hours after treatment with PEGylated adenovirus, which has a low immunological profile (p ≤ 0.05). CYP3A2 remained suppressed (34%, p ≤ 0.05) for 14 days while CYP2C11 recovered. Inactivated virus suppressed CYP3A2 activity by 25–50% for 14 days (p ≤ 0.05). CYP2C11 was affected similar manner but recovered by day 14. Microarray and in vitro studies suggest that changes in cellular signaling pathways initiated early in virus infection contribute to changes in CYP.
Characterization of Mouse Orofacial Pain and the Effects of Lesioning TRPV1-Expressing Neurons on Operant Behavior
Authors: Neubert John K , King Christopher , Malphurs Wendi , Wong Fong , Weaver James P , Jenkins Alan C , Rossi Heather L , Caudle Robert M
Published: October 2008

Background:

Rodent models of orofacial pain typically use methods adapted from manipulations to hind paw; however, limitations of these models include animal restraint and subjective assessments of behavior by the experimenter. In contrast to these methods, assessment of operant responses to painful stimuli has been shown to overcome these limitations and expand the breadth of interpretation of the behavioral responses. In the current study, we used an operant model based on a reward-conflict paradigm to assess nociceptive responses in three strains of mice (SKH1-Hrhr, C57BL/6J, TRPV1 knockout). We previously validated this operant model in rats and hypothesized in this study that wildtype mice would demonstrate a similar thermal stimulus-dependent response and similar operant pain behaviors. Additionally, we evaluated the effects on operant behaviors of mice manipulated genetically (e.g., TRPV1 k.o.) or pharmacologically with resiniferatoxin (RTX), a lesioning agent for TRPV1-expressing neurons. During the reward-conflict task, mice accessed a sweetened milk reward solution by voluntarily position their face against a neutral or heated thermode (37–55°C).

Results:

As the temperature of the thermal stimulus became noxiously hot, reward licking events in SKH1-Hrhr and C57BL/6J mice declined while licking events in TRPV1 k.o. mice were insensitive to noxious heat within the activation range of TRPV1 (37–52°C). All three strains displayed nocifensive behaviors at 55°C, as indicated by a significant decrease in reward licking events. Induction of neurogenic inflammation by topical application of capsaicin reduced licking events in SKH1-Hrhr mice, and morphine rescued this response. Again, these results parallel what we previously documented using rats in this operant system. Following intracisternal treatment with RTX, C57BL/6J mice demonstrated a block of noxious heat at both 48 and 55°C. RTX-treated TRPV1 k.o. mice and all vehicle-treated mice displayed similar reward licking events as compared to the pre-treatment baseline levels. Both TRPV1 k.o. and RTX-treated C57BL/6J had complete abolishment of eye-wipe responses following corneal application of capsaicin.

Conclusion:

Taken together, these results indicate the benefits of using the operant test system to investigate pain sensitivity in mice. This ability provides an essential step in the development of new treatments for patients suffering from orofacial pain disorders.
Rapid identification of PAX2/5/8 direct downstream targets in the otic vesicle by combinatorial use of bioinformatics tools
Authors: Ramialison Mirana , Bajoghli Baubak , Aghaallaei Narges , Ettwiller Laurence , Gaudan Sylvain , Wittbrodt Beate , Czerny Thomas , Wittbrodt Joachim
Published: October 2008

Background

The pax2/5/8 genes belonging to the PAX family of transcription factors are key developmental regulators that are involved in the patterning of various embryonic tissues. More particularly, their function in inner ear specification has been widely described. However, little is known about the direct downstream targets and, so far, no global approaches have been performed to identify these target genes in this particular tissue.

Results

Here we present an original bioinformatics pipeline composed of comparative genomics, database querying and text mining tools, which is designed to rapidly and specifically discover PAX2/5/8 direct downstream targets involved in inner ear development. We provide evidence supported by experimental validation in medaka fish that brain 2 (POU domain, class 3, transcription factor 2), claudin-7, secretory pathway component sec31-like and meteorin-like precursor are novel direct downstream targets of PAX2/5/8.

Conclusions

This study illustrates the power of extensive mining of public data repositories using bioinformatics methods to provide answers for a specific biological question. It furthermore demonstrates how the usage of such a combinatorial approach is advantageous for the biologist in terms of experimentation time and costs.
A genome wide analysis of the response to uncapped telomeres in budding yeast reveals a novel role for the NAD+ biosynthetic gene BNA2in chromosome end protection
Authors: Greenall Amanda , Lei Guiyuan , Swan Daniel C , James Katherine , Wang Liming , Peters Heiko , Wipat Anil , Wilkinson Darren J , Lydall David
Published: October 2008

Background

Telomeres prevent the ends of eukaryotic chromosomes from being recognized as damaged DNA and protect against cancer and ageing. When telomere structure is perturbed, a co-ordinated series of events promote arrest of the cell cycle so that cells carrying damaged telomeres do not divide. In order to better understand the eukaryotic response to telomere damage, budding yeast strains harboring a temperature sensitive allele of an essential telomere capping gene (cdc13-1) were subjected to a transcriptomic study.

Results

The genome-wide response to uncapped telomeres in yeast cdc13-1 strains, which have telomere capping defects at temperatures above approximately 27°C, was determined. Telomere uncapping in cdc13-1 strains is associated with the differential expression of over 600 transcripts. Transcripts affecting responses to DNA damage and diverse environmental stresses were statistically over-represented. BNA2, required for the biosynthesis of NAD+, is highly and significantly up-regulated upon telomere uncapping in cdc13-1 strains. We find that deletion of BNA2 and NPT1, which is also involved in NAD+ synthesis, suppresses the temperature sensitivity of cdc13-1 strains, indicating that NAD+ metabolism may be linked to telomere end protection.

Conclusions

Our data support the hypothesis that the response to telomere uncapping is related to, but distinct from, the response to non-telomeric double-strand breaks. The induction of environmental stress responses may be a conserved feature of the eukaryotic response to telomere damage. BNA2, which is involved in NAD+ synthesis, plays previously unidentified roles in the cellular response to telomere uncapping.
Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1
Authors: Pęczkowska Mariola , Erlic Zoran , Hoffmann Michael M. , Furmanek Mariusz , Ćwikła Jarosław , Kubaszek Agata , Prejbisz Aleksander , Szutkowski Zbigniew , Kawecki Andrzej , Chojnowski Krzysztof , Lewczuk Anna , Litwin Mieczysław , Szyfter Witold , Walter Martin A. , Sullivan Maren , Eng Charis , Januszewicz Andrzej , Neumann Hartmut P. H.
Published: October 2008

Context and Objective: Germline mutations of the genes SDHB, SDHC, and SDHD predispose to paraganglioma syndromes. Mutation-specific counseling, risk assessment, and management recommendations ideally should be performed. Here, we provide data for a single common mutation of the SDHD gene.

Methods: The European-American Pheochromocytoma-Paraganglioma Registry served as the source for unrelated index cases affected by pheochromocytoma or paraganglioma. Patients with the SDHD c.33 C→A (p.Cys11X) germline mutations were reinvestigated by whole-body magnetic resonance imaging and 24-h urinary catecholamine assay. First-degree relatives underwent genetic testing and those testing positive had same clinical investigations. Microsatellite analyses were used to test the hypothesis that all index cases were related and the mutation is a founding one.

Results: Sixteen index cases with the mutation SDHD p.Cys11X are registered. After testing their relatives, there were a total of 25 mutation carriers. We excluded seven subjects who inherited the mutation from the mother because of maternal imprinting. Thus, 18 mutation carriers were clinically affected. Among these 16 (89%) had head and neck paragangliomas, six (33%) thoracic tumors, six (33%) extraadrenal retroperitoneal, and five (28%) intraadrenal. Of note, 16 (89%) had multiple tumors at first diagnosis, and one (5%) had signs of malignancy during follow-up. Overall penetrance was 100% at age 54. Haplotype analyses revealed evidence for a founder effect.

Conclusions: The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.
Lévy-based Cox point processes
Authors: Hellmund Gunnar , Prokešová Michaela , Vedel Jensen Eva B.
Published: October 2008

In this paper we introduce Lévy-driven Cox point processes (LCPs) as Cox point processes with driving intensity function Λ defined by a kernel smoothing of a Lévy basis (an independently scattered, infinitely divisible random measure). We also consider log Lévy-driven Cox point processes (LLCPs) with Λ equal to the exponential of such a kernel smoothing. Special cases are shot noise Cox processes, log Gaussian Cox processes, and log shot noise Cox processes. We study the theoretical properties of Lévy-based Cox processes, including moment properties described bynth-order product densities, mixing properties, specification of inhomogeneity, and spatio-temporal extensions.
Random Laguerre tessellations
Authors: Lautensack Claudia , Zuyev Sergei
Published: October 2008

A systematic study of random Laguerre tessellations, weighted generalisations of the well-known Voronoi tessellations, is presented. We prove that every normal tessellation with convex cells in dimension three and higher is a Laguerre tessellation. Tessellations generated by stationary marked Poisson processes are then studied in detail. For these tessellations, we obtain integral formulae for geometric characteristics and densities of the typical k-faces. We present a formula for the linear contact distribution function and prove various limit results for convergence of Laguerre to Poisson-Voronoi tessellations. The obtained integral formulae are subsequently evaluated numerically for the planar case, demonstrating their applicability for practical purposes.
A new metric between distributions of point processes
Authors: Schuhmacher Dominic , Xia Aihua
Published: October 2008

Most metrics between finite point measures currently used in the literature have the flaw that they do not treat differing total masses in an adequate manner for applications. This paper introduces a new metricd̅1that combines positional differences of points under a closest match with the relative difference in total mass in a way that fixes this flaw. A comprehensive collection of theoretical results aboutd̅1and its induced Wasserstein metricd̅2for point process distributions are given, including examples of usefuld̅1-Lipschitz continuous functions,d̅2upper bounds for the Poisson process approximation, andd̅2upper and lower bounds between distributions of point processes of independent and identically distributed points. Furthermore, we present a statistical test for multiple point pattern data that demonstrates the potential ofd̅1in applications.
Maximization of the long-term growth rate for a portfolio with fixed and proportional transaction costs
Authors: Tamura Takashi
Published: October 2008

We study the problem of maximizing the long-run average growth of total wealth for a logarithmic utility function under the existence of fixed and proportional transaction costs. The market model consists of one riskless asset and d risky assets. Impulsive control theory is applied to this problem. We derive a quasivariational inequality (QVI) of ‘ergodic’ type and obtain a weak solution for the inequality. Using this solution, we obtain an optimal investment strategy to achieve the optimal growth.
Moment and MGF convergence of overshoots and undershoots for Lévy insurance risk processes
Authors: Park Hyun Suk , Maller Ross
Published: October 2008

This paper is concerned with the finiteness and large-time behaviour of moments of the overshoot and undershoot of a high level, and of their moment generating functions (MGFs), for a Lévy process which drifts to -∞ almost surely. This provides information relevant to quantities associated with the ruin of an insurance risk process. Results of Klüppelberg, Kyprianou, and Maller (2004) and Doney and Kyprianou (2006) for asymptotic overshoot and undershoot distributions in the class of Lévy processes with convolution equivalent canonical measures are shown to have moment and MGF convergence extensions.
Asymptotic behavior of a Feller evolution family involved in the Fisher-Wright model
Authors: Bobrowski Adam
Published: October 2008

We study the evolution in time of the joint distribution of a pair of Feller processes, related by the fact that some random time ago they were identical, evolving as a single Feller process; from that time on, they began to evolve independently, conditional on a state at the time of split, according to the same Feller transition probabilities. Such processes are involved in the Fisher-Wright model: the distribution of the time counted backwards from the present to the time of split in the past is a function of deterministic but time-varying effective size 2Nof the population from which the two processes are sampled. In terms of a corresponding family of Feller operators, assuming asymptotic stability or ergodicity of the process of mutation, we find the limit form of the distribution of such pairs of processes sampled from decaying, asymptotically constant, and growing populations. In the case where mutation is not asymptotically stable or ergodic, limit distributions are found for the distribution of relative differences.
A functional central limit theorem for spatial birth and death processes
Authors: Qi Xin
Published: October 2008

We give a functional central limit theorem for spatial birth and death processes based on the representation of such processes as solutions of stochastic equations. For any bounded and integrable function in Euclidean space, we define a family of processes which is obtained by integrals of this function with respect to the centered and scaled spatial birth and death process with constant death rate. We prove that this family converges weakly to a Gaussian process as the scale parameter goes to infinity. We do not need the birth rates to have a finite range of interaction. Instead, we require that the birth rates have a range of interaction that decays polynomially. In order to show the convergence of the finite-dimensional distributions of the above processes, we extend Penrose's multivariate spatial central limit theorem. An example of the asymptotic normalities of the time-invariance estimators for the birth rates of spatial point processes is given.
On level crossings for a general class of piecewise-deterministic Markov processes
Authors: Borovkov K. , Last G.
Published: October 2008

We consider a piecewise-deterministic Markov process (Xt) governed by a jump intensity function, a rate function that determines the behaviour between jumps, and a stochastic kernel describing the conditional distribution of jump sizes. The paper deals with the point process of upcrossings of some level b by (Xt). We prove a version of Rice's formula relating the stationary density of (Xt) to level crossing intensities and show that, for a wide class of processes (Xt), as b → ∞, the scaled point process where ν+(b) denotes the intensity of upcrossings of b, converges weakly to a geometrically compound Poisson process.
The distribution of wasted spaces in the M/M/∞ queue with ranked servers
Authors: Sohn Eunju , Knessl Charles
Published: October 2008

We consider the M/M/∞ queue with m primary servers and infinitely many secondary servers. All the servers are numbered and ordered. An arriving customer takes the lowest available server. We define the wasted spaces as the difference between the highest numbered occupied server and the total number of occupied servers. Letting ρ = λ0/μ be the ratio of arrival to service rates, we study the probability distribution of the wasted spaces asymptotically for ρ → ∞. We also give some numerical results and the tail behavior for ρ = O(1).
Asymptotic analysis of a fluid model modulated by an M/M/1 queue
Authors: Knessl Charles , Dominici Diego Ernesto
Published: October 2008

We analyze asymptotically a differential-difference equation that arises in a Markov-modulated fluid model. We use singular perturbation methods to analyze the problem with appropriate scalings of the two state variables. In particular, the ray method and asymptotic matching are used.
Perfect sampling methods for random forests
Authors: Dai Hongsheng
Published: October 2008

A weighted graphGis a pair (V, ℰ) containing vertex setVand edge set ℰ, where each edgee∈ ℰ is associated with a weightWe. A subgraph ofGis a forest if it has no cycles. All forests on the graphGform a probability space, where the probability of each forest is proportional to the product of the weights of its edges. This paper aims to simulate forests exactly from the target distribution. Methods based on coupling from the past (CFTP) and rejection sampling are presented. Comparisons of these methods are given theoretically and via simulation.
Reduced tumorigenesis in mouse mammary cancer cells following inhibition of Pea3- or Erm-dependent transcription
Authors: Firlej Virginie , Ladam Franck , Brysbaert Guillaume , Dumont Patrick , Fuks François , de Launoit Yvan , Benecke Arndt , Chotteau-Lelievre Anne
Published: October 2008

Pea3 and Erm are transcription factors expressed in normal developing branching organs such as the mammary gland. Deregulation of their expression is generally associated with tumorigenesis and particularly breast cancer. By using RNA interference (RNAi) to downregulate the expression of Pea3 and/or Erm in a mammary cancer cell line, we present evidence for a role of these factors in proliferation, migration and invasion capacity of cancer cells. We have used different small interfering RNAs (siRNAs) targeting pea3 and erm transcripts in transiently or stably transfected cells, and assessed the physiological behavior of these cells in in vitro assays. We also identified an in vivo alteration of tumor progression after injection of cells that overexpress pea3 and/or erm short hairpin RNAs (shRNAs) in immunodeficient mice. Using transcriptome profiling in Pea3- or Erm-targeted cells, two largely independent gene expression programs were identified on the basis of their shared phenotypic modifications. A statistically highly significant part of both sets of target genes had previously been already associated with the cellular signaling pathways of the `proliferation, migration, invasion' class.

These data provide the first evidence, by using endogenous knockdown, for pivotal and complementary roles of Pea3 and Erm transcription factors in events crucial to mammary tumorigenesis, and identify sets of downstream target genes whose expression during tumorigenesis is regulated by these transcription factors.
G-actin regulates rapid induction of actin nucleation by mDia1 to restore cellular actin polymers
Authors: Higashida Chiharu , Suetsugu Shiro , Tsuji Takahiro , Monypenny James , Narumiya Shuh , Watanabe Naoki
Published: October 2008

mDia1 belongs to the formin family of proteins that share FH1 and FH2 domains. Although formins play a critical role in the formation of many actin-based cellular structures, the physiological regulation of formin-mediated actin assembly within the cell is still unknown. Here we show that cells possess an acute actin polymer restoration mechanism involving mDia1. By using single-molecule live-cell imaging, we found that several treatments including low-dose G-actin-sequestering drugs and unpolymerizable actin mutants activate mDia1 to initiate fast directional movement. The FH2 region, the core domain for actin nucleation, is sufficient to respond to latrunculin B (LatB) to increase its actin nucleation frequency. Simulation analysis revealed an unexpected paradoxical effect of LatB that leads to a several fold increase in free G-actin along with an increase in total G-actin. These results indicate that in cells, the actin nucleation frequency of mDia1 is enhanced not only by Rho, but also strongly through increased catalytic efficiency of the FH2 domain. Consistently, frequent actin nucleation by mDia1 was found around sites of vigorous actin disassembly. Another major actin nucleator, the Arp2/3 complex, was not affected by the G-actin increase induced by LatB. Taken together, we propose that transient accumulation of G-actin works as a cue to promote mDia1-catalyzed actin nucleation to execute rapid reassembly of actin filaments.
Sorting of EGF and transferrin at the plasma membrane and by cargo-specific signaling to EEA1-enriched endosomes
Authors: Leonard Deborah , Hayakawa Akira , Lawe Deirdre , Lambright David , Bellve Karl D. , Standley Clive , Lifshitz Lawrence M. , Fogarty Kevin E. , Corvera Silvia
Published: October 2008

The biological function of receptors is determined by their appropriate trafficking through the endosomal pathway. Following internalization, the transferrin (Tf) receptor quantitatively recycles to the plasma membrane, whereas the epidermal growth factor (EGF) receptor undergoes degradation. To determine how Tf and EGF engage these two different pathways we imaged their binding and early endocytic pathway in live cells using total internal reflection fluorescence microscopy (TIRF-M). We find that EGF and Tf bind to distinct plasma membrane regions and are incorporated into different endocytic vesicles. After internalization, both EGF-enriched and Tf-enriched vesicles interact with endosomes containing early endosome antigen 1 (EEA1). EGF is incorporated and retained in these endosomes, while Tf-containing vesicles rapidly dissociate and move to a juxtanuclear compartment. Endocytic vesicles carrying EGF recruit more Rab5 GTPase than those carrying Tf, which, by strengthening their association with EEA1-enriched endosomes, may provide a mechanism for the observed cargo-specific sorting. These results reveal pre-endocytic sorting of Tf and EGF, a specialized role for EEA1-enriched endosomes in EGF trafficking, and a potential mechanism for cargo-specified sorting of endocytic vesicles by these endosomes.
Murine CENPF interacts with syntaxin 4 in the regulation of vesicular transport
Authors: Pooley Ryan D. , Moynihan Katherine L. , Soukoulis Victor , Reddy Samyukta , Francis Richard , Lo Cecilia , Ma Li-Jun , Bader David M.
Published: October 2008

Syntaxin 4 is a component of the SNARE complex that regulates membrane docking and fusion. Using a yeast two-hybrid screen, we identify a novel interaction between syntaxin 4 and cytoplasmic murine CENPF, a protein previously demonstrated to associate with the microtubule network and SNAP-25. The binding domain for syntaxin 4 in CENPF was defined by yeast two-hybrid assay and co-immunoprecipitation. Confocal analyses in cell culture reveal a high degree of colocalization between endogenously expressed proteins in interphase cells. Additionally, the endogenous SNARE proteins can be isolated as a complex with CENPF in immunoprecipitation experiments. Further analyses demonstrate that murine CENPF and syntaxin 4 colocalize with components of plasma membrane recycling: SNAP-25 and VAMP2. Depletion of endogenous CENPF disrupts GLUT4 trafficking whereas expression of a dominant-negative form of CENPF inhibits cell coupling. Taken together, these studies demonstrate that CENPF provides a direct link between proteins of the SNARE system and the microtubule network and indicate a diverse role for murine CENPF in vesicular transport.
CED-9 and mitochondrial homeostasis inC. elegansmuscle
Authors: Tan Frederick J. , Husain Michelle , Manlandro Cara Marie , Koppenol Marijke , Fire Andrew Z. , Hill R. Blake
Published: October 2008

Mitochondrial homeostasis reflects a dynamic balance between membrane fission and fusion events thought essential for mitochondrial function. We report here that altered expression of the C. elegans BCL2 homolog CED-9 affects both mitochondrial fission and fusion. Although striated muscle cells lacking CED-9 have no alteration in mitochondrial size or ultrastructure, these cells appear more sensitive to mitochondrial fragmentation. By contrast, increased CED-9 expression in these cells produces highly interconnected mitochondria. This mitochondrial phenotype is partially suppressed by increased expression of the dynamin-related GTPase DRP-1, with suppression dependent on the BH3 binding pocket of CED-9. This suppression suggests that CED-9 directly regulates DRP-1, a model supported by our finding that CED-9 activates the GTPase activity of human DRP1. Thus, CED-9 is capable of regulating the mitochondrial fission-fusion cycle but is not essential for either fission or fusion.