bluuebunny/crossref_metadata_2025 huggingface dataset:
TimeDelay-ARACNE: Reverse engineering of gene networks from time-course data by an information theoretic approach
Authors: Zoppoli Pietro , Morganella Sandro , Ceccarelli Michele
Published: March 2010

Background

One of main aims of Molecular Biology is the gain of knowledge about how molecular components interact each other and to understand gene function regulations. Using microarray technology, it is possible to extract measurements of thousands of genes into a single analysis step having a picture of the cell gene expression. Several methods have been developed to infer gene networks from steady-state data, much less literature is produced about time-course data, so the development of algorithms to infer gene networks from time-series measurements is a current challenge into bioinformatics research area. In order to detect dependencies between genes at different time delays, we propose an approach to infer gene regulatory networks from time-series measurements starting from a well known algorithm based on information theory.

Results

In this paper we show how the ARACNE (Algorithm for the Reconstruction of Accurate Cellular Networks) algorithm can be used for gene regulatory network inference in the case of time-course expression profiles. The resulting method is called TimeDelay-ARACNE. It just tries to extract dependencies between two genes at different time delays, providing a measure of these dependencies in terms of mutual information. The basic idea of the proposed algorithm is to detect time-delayed dependencies between the expression profiles by assuming as underlying probabilistic model a stationary Markov Random Field. Less informative dependencies are filtered out using an auto calculated threshold, retaining most reliable connections. TimeDelay-ARACNE can infer small local networks of time regulated gene-gene interactions detecting their versus and also discovering cyclic interactions also when only a medium-small number of measurements are available. We test the algorithm both on synthetic networks and on microarray expression profiles. Microarray measurements concernS. cerevisiaecell cycle,E. coliSOS pathways and a recently developed network for in vivo assessment of reverse engineering algorithms. Our results are compared with ARACNE itself and with the ones of two previously published algorithms: Dynamic Bayesian Networks and systems of ODEs, showing that TimeDelay-ARACNE has good accuracy, recall andF-score for the network reconstruction task.

Conclusions

Here we report the adaptation of the ARACNE algorithm to infer gene regulatory networks from time-course data, so that, the resulting network is represented as a directed graph. The proposed algorithm is expected to be useful in reconstruction of small biological directed networks from time course data.
Genome-wide comparative analysis of metacaspases in unicellular and filamentous cyanobacteria
Authors: Jiang Qiao , Qin Song , Wu Qing-yu
Published: March 2010

Background

Cyanobacteria are an ancient group of photoautotrophic prokaryotes with wide variations in genome size and ecological habitat. Metacaspases (MCAs) are cysteine proteinases that have sequence homology to caspases and play essential roles in programmed cell death (PCD). MCAs have been identified in several prokaryotes, fungi and plants; however, knowledge about cyanobacterial metacaspases still remains obscure. With the availability of sequenced genomes of 33 cyanobacteria, we perform a comparative analysis of metacaspases and explore their distribution, domain structure and evolution.

Results

A total of 58 putative MCAs were identified, which are abundant in filamentous diazotrophic cyanobacteria and Acaryochloris marina MBIC 11017 and absent in all Prochlorococcus and marine Synechococcus strains, except Synechococcus sp. PCC 7002. The Cys-His dyad of caspase superfamily is conserved, while mutations (Tyr in place of His and Ser/Asn/Gln/Gly instead of Cys) are also detected in some cyanobacteria. MCAs can be classified into two major families (α and β) based on the additional domain structure. Ten types and a total of 276 additional domains were identified, most of which involves in signal transduction. Apoptotic related NACHT domain was also found in two cyanobacterial MCAs. Phylogenetic tree of MCA catalytic P20 domains coincides well with the domain structure and the phylogenies based on 16s rRNA.

Conclusions

The existence and quantity of MCA genes in unicellular and filamentous cyanobacteria are a function of the genome size and ecological habitat. MCAs of family α and β seem to evolve separately and the recruitment of WD40 additional domain occurs later than the divergence of the two families. In this study, a general framework of sequence-structure-function connections for the metacaspases has been revealed, which may provide new targets for function investigation.
Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGFδ/δ mouse model of amyotrophic lateral sclerosis
Authors: Brockington Alice , Heath Paul R , Holden Hazel , Kasher Paul , Bender Florian LP , Claes Filip , Lambrechts Diether , Sendtner Michael , Carmeliet Peter , Shaw Pamela J
Published: March 2010

Background

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS). Investigating the molecular pathways to neurodegeneration in the VEGFδ/δ mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease.

Results

Microarray analysis was used to determine the transcriptional profile of laser captured spinal motor neurones of transgenic and wild-type littermates at 3 time points of disease. 324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGFδ/δ mice, 382 at disease onset, and 689 at late stage disease. Massive transcriptional downregulation occurred with disease progression, associated with downregulation of genes involved in RNA processing at late stage disease. VEGFδ/δ mice showed reduction in expression, from symptom onset, of the cholesterol synthesis pathway, and genes involved in nervous system development, including axonogenesis, synapse formation, growth factor signalling pathways, cell adhesion and microtubule-based processes. These changes may reflect a reduced capacity of VEGFδ/δ mice for maintenance and remodelling of neuronal processes in the face of demands of neural plasticity. The findings are supported by the demonstration that in primary motor neurone cultures from VEGFδ/δ mice, axon outgrowth is significantly reduced compared to wild-type littermates.

Conclusions

Downregulation of these genes involved in axon outgrowth and synapse formation in adult mice suggests a hitherto unrecognized role of VEGF in the maintenance of neuronal circuitry. Dysregulation of VEGF may lead to neurodegeneration through synaptic regression and dying-back axonopathy.
Physical mapping in highly heterozygous genomes: a physical contig map of the Pinot Noir grapevine cultivar
Authors: Scalabrin Simone , Troggio Michela , Moroldo Marco , Pindo Massimo , Felice Nicoletta , Coppola Giuseppina , Prete Giacomo , Malacarne Giulia , Marconi Raffaella , Faes Giorgia , Jurman Irena , Grando Stella , Jesse Taco , Segala Cinzia , Valle Giorgio , Policriti Alberto , Fontana Paolo , Morgante Michele , Velasco Riccardo
Published: March 2010

Background

Most of the grapevine (Vitis vinifera L.) cultivars grown today are those selected centuries ago, even though grapevine is one of the most important fruit crops in the world. Grapevine has therefore not benefited from the advances in modern plant breeding nor more recently from those in molecular genetics and genomics: genes controlling important agronomic traits are practically unknown. A physical map is essential to positionally clone such genes and instrumental in a genome sequencing project.

Results

We report on the first whole genome physical map of grapevine built using high information content fingerprinting of 49,104 BAC clones from the cultivar Pinot Noir. Pinot Noir, as most grape varieties, is highly heterozygous at the sequence level. This resulted in the two allelic haplotypes sometimes assembling into separate contigs that had to be accommodated in the map framework or in local expansions of contig maps. We performed computer simulations to assess the effects of increasing levels of sequence heterozygosity on BAC fingerprint assembly and showed that the experimental assembly results are in full agreement with the theoretical expectations, given the heterozygosity levels reported for grape. The map is anchored to a dense linkage map consisting of 994 markers. 436 contigs are anchored to the genetic map, covering 342 of the 475 Mb that make up the grape haploid genome.

Conclusions

We have developed a resource that makes it possible to access the grapevine genome, opening the way to a new era both in grape genetics and breeding and in wine making. The effects of heterozygosity on the assembly have been analyzed and characterized by using several complementary approaches which could be easily transferred to the study of other genomes which present the same features.
Healthcare workers and health care-associated infections: knowledge, attitudes, and behavior in emergency departments in Italy
Authors: Parmeggiani Cristiana , Abbate Rossella , Marinelli Paolo , Angelillo Italo F
Published: March 2010

Background

This survey assessed knowledge, attitudes, and compliance regarding standard precautions about health care-associated infections (HAIs) and the associated determinants among healthcare workers (HCWs) in emergency departments in Italy.

Methods

An anonymous questionnaire, self-administered by all HCWs in eight randomly selected non-academic acute general public hospitals, comprised questions on demographic and occupational characteristics; knowledge about the risks of acquiring and/or transmitting HAIs from/to a patient and standard precautions; attitudes toward guidelines and risk perceived of acquiring a HAI; practice of standard precautions; and sources of information.

Results

HCWs who know the risk of acquiring Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV) from a patient were in practice from less years, worked fewer hours per week, knew that a HCW can transmit HCV and HIV to a patient, knew that HCV and HIV infections can be serious, and have received information from educational courses and scientific journals. Those who know that gloves, mask, protective eyewear, and hands hygiene after removing gloves are control measures were nurses, provided care to fewer patients, knew that HCWs' hands are vehicle for transmission of nosocomial pathogens, did not know that a HCW can transmit HCV and HIV to a patient, and have received information from educational courses and scientific journals. Being a nurse, knowing that HCWs' hands are vehicle for transmission of nosocomial pathogens, obtaining information from educational courses and scientific journals, and needing information were associated with a higher perceived risk of acquiring a HAI. HCWs who often or always used gloves and performed hands hygiene measures after removing gloves were nurses, provided care to fewer patients, and knew that hands hygiene after removing gloves was a control measure.

Conclusions

HCWs have high knowledge, positive attitudes, but low compliance concerning standard precautions. Nurses had higher knowledge, perceived risk, and appropriate HAIs' control measures than physicians and HCWs answered correctly and used appropriately control measures if have received information from educational courses and scientific journals.
DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response
Authors: Dejeux Emelyne , Rønneberg Jo Anders , Solvang Hiroko , Bukholm Ida , Geisler Stephanie , Aas Turid , Gut Ivo G. , Børresen-Dale Anne-Lise , Lønning Per Eystein , Kristensen Vessela N. , Tost Jörg
Published: March 2010

Background

Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment.

Results

We investigated quantitatively the methylation patterns in the promoter regions of 14 genes (ABCB1, ATM, BRCA1, CDH3, CDKN2A, CXCR4, ESR1, FBXW7, FOXC 1, GSTP1, IGF2, HMLH1, PPP2R2B, and PTEN) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters.

Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the FOXC1 promoter. Absence of methylation at the ABCB1 promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of GSTP1, FOXC1 and ABCB1 correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis GSTP1 and FOXC1 methylation status proved to be independent prognostic markers associated with survival.

Conclusions

Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the ABCB1 or GSTP1 promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while FOXC1 methylation might be a protective factor against tumour invasiveness. FOXC1 proved to be general prognostic factor, while ABCB1 and GSTP1 might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.
Downregulated expression of HSP27 in human low-grade glioma tissues discovered by a quantitative proteomic analysis
Authors: Shen Guobo , Liang Shufang , Xu Zhizhong , Zhou Liangxue , Xiao Shiyin , Xia Xiangying , Li Ronghui , Liao Ying , You Chao , Wei Yuquan
Published: March 2010

Background

Heat shock proteins (HSPs), including mainly HSP110, HSP90, HSP70, HSP60 and small HSP families, are evolutionary conserved proteins involved in various cellular processes. Abnormal expression of HSPs has been detected in several tumor types, which indicates that specific HSPs have different prognostic significance for different tumors. In the current studies, the expression profiling of HSPs in human low-grade glioma tissues (HGTs) were investigated using a sensitive, accurate SILAC (stable isotope labeling with amino acids in cell culture)-based quantitative proteomic strategy.

Results

The five HSP family members were detected and quantified in both HGTs and autologous para-cancerous brain tissues (PBTs) by the SILAC-based mass spectrometry (MS) simultaneously. HSP90 AB1, HSP A5(70 KDa), and especially HSP27 were significantly downregulated in HGTs, whereas the expression level of HSPA9 (70 KDa) was little higher in HGTs than that in PBTs. It was noted that the downregulation ratio of HSP27 was 0.48-fold in HGTs versus PBTs, which was further validated by results from RT-PCR, western blotting and immunohistochemistry. Furthermore, we detected HSP27 expression changes along with cell growth under heat shock treatment in glioma H4 cells.

Conclusion

The SILAC-MS technique is an applicable and efficient novel method, with a high-throughput manner, to quantitatively compare the relative expression level of HSPs in brain tumors. Different HSP family members have specific protein expression levels in human low-grade glioma discovered by SILAC-MS analysis. HSP27 expression was obviously downregulated in HGTs versus PBTs, and it exhibited temporal and spatial variation under heat shock treatment (43°C/0-3 h) in vitro. HSP27's rapid upregulation was probably correlated with the temporary resistance to heat shock in order to maintain the survival of human glioma cells.
An Improved Behavioural Assay Demonstrates That Ultrasound Vocalizations Constitute a Reliable Indicator of Chronic Cancer Pain and Neuropathic Pain
Authors: Kurejova Martina , Nattenmüller Ulrike , Hildebrandt Ullrich , Selvaraj Deepitha , Stösser Sebastian , Kuner Rohini
Published: March 2010

Background:

On-going pain is one of the most debilitating symptoms associated with a variety of chronic pain disorders. An understanding of mechanisms underlying on-going pain, i.e. stimulus-independent pain has been hampered so far by a lack of behavioural parameters which enable studying it in experimental animals. Ultrasound vocalizations (USVs) have been proposed to correlate with pain evoked by an acute activation of nociceptors. However, literature on the utility of USVs as an indicator of chronic pain is very controversial. A majority of these inconsistencies arise from parameters confounding behavioural experiments, which include novelty, fear and stress due to restrain, amongst others.

Results:

We have developed an improved assay which overcomes these confounding factors and enables studying USVs in freely moving mice repetitively over several weeks. Using this improved assay, we report here that USVs increase significantly in mice with bone metastases-induced cancer pain or neuropathic pain for several weeks, in comparison to sham-treated mice. Importantly, analgesic drugs which are known to alleviate tumour pain or neuropathic pain in human patients significantly reduce USVs as well as mechanical allodynia in corresponding mouse models.

Conclusions:

We show that studying USVs and mechanical allodynia in the same cohort of mice enables comparing the temporal progression of on-going pain (i.e. stimulus-independent pain) and stimulus-evoked pain in these clinically highly-relevant forms of chronic pain.
Diagnostic challenge: bilateral infected lumbar facet cysts - a rare cause of acute lumbar spinal stenosis and back pain
Authors: Freedman Brett A , Bui Tuan L , Yoon S Timothy
Published: March 2010

Symptomatic synovial lumbar facet cysts are a relatively rare cause of radiculopathy and spinal stenosis. This case and brief review of the literature, details a patient who presented with acutely symptomatic bilateral spontaneously infected synovial facet (L4/5) cysts. This report highlights diagnostic clues for identifying infection of a facet cyst.
Genetic variation in the estrogen metabolic pathway and mammographic density as an intermediate phenotype of breast cancer
Authors: Li Jingmei , Eriksson Louise , Humphreys Keith , Czene Kamila , Liu Jianjun , Tamimi Rulla M , Lindström Sara , Hunter David J , Vachon Celine M , Couch Fergus J , Scott Christopher G , Lagiou Pagona , Hall Per
Published: March 2010

Introduction

Several studies have examined the effect of genetic variants in genes involved in the estrogen metabolic pathway on mammographic density, but the number of loci studied and the sample sizes evaluated have been small and pathways have not been evaluated comprehensively. In this study, we evaluate the association between mammographic density and genetic variants of the estrogen metabolic pathway.

Methods

A total of 239 SNPs in 34 estrogen metabolic genes were studied in 1,731 Swedish women who participated in a breast cancer case-control study, of which 891 were cases and 840 were controls. Film mammograms of the medio-lateral oblique view were digitalized and the software Cumulus was used for computer-assisted semi-automated thresholding of mammographic density. Generalized linear models controlling for possible confounders were used to evaluate the effects of SNPs on mammographic density. Results found to be nominally significant were examined in two independent populations. The admixture maximum likelihood-based global test was performed to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three subpathways for androgen synthesis, androgen-to-estrogen conversion and estrogen removal.

Results

Genetic variants of genes involved in estrogen metabolism exhibited no appreciable effect on mammographic density. None of the nominally significant findings were validated. In addition, global analyses on the overall estrogen metabolic pathway and its subpathways did not yield statistically significant results.

Conclusions

Overall, there is no conclusive evidence that genetic variants in genes involved in the estrogen metabolic pathway are associated with mammographic density in postmenopausal women.
Ghrelin and Obestatin Circadian Levels Differentiate Bingeing-Purging from Restrictive Anorexia Nervosa
Authors: Germain Natacha , Galusca Bogdan , Grouselle Dominique , Frere Delphine , Billard Stephane , Epelbaum Jacques , Estour Bruno
Published: March 2010

Context: Anorexia nervosa (AN) patients present with restrictive food behavior (AN-R). Some of them develop episodes of bulimia (AN-BP) without any clear pathophysiological explanation to date. Their clinical differentiation is important but not easily performed. Orexigenic/anorexigenic peptides measurements could provide some clues for that matter.

Objective: The objective of the study was to determine whether the circadian profile of total and acylated ghrelin, obestatin, and peptide YY (PYY) levels is different in AN-R subjects when compared with AN-BP patients.

Design and Settings: This was a cross-sectional study in an endocrinological unit.

Patients and Control Subjects: Four groups of age-matched young women: 22 AN-R, 10 AN-BP, 16 normal-weight bulimia nervosa (BN), and nine controls.

Main Outcome Measures: Twelve-point circadian profiles of plasma total and acylated ghrelin, obestatin, and PYY were measured.

Results: Total and acylated ghrelin and obestatin circadian levels were increased in AN-R when compared with controls but decreased in both AN-BP and BN groups (P < 0.001). PYY was decreased in all groups with eating disorders. Acylated to total ghrelin ratio was decreased in AN-BP and BN (P < 0.001), whereas obestatin to acylated ghrelin and PYY to acylated ghrelin ratios were increased in both groups with bingeing-purging behavior (P < 0.0001).

Conclusions: Patients with AN-associated bingeing-purging behavior present a very different profile of appetite regulatory peptides when compared with the pure restrictive type. The assessment of ghrelin (and eventually obestatin) could be of particular interest for differential diagnosis. Very low ghrelin levels and increased anorexigenic to orexigenic peptide ratios suggest either a lack of adaptation to a starvation state or a higher facility to cope with undernutrition.
The Expression of E-Cadherin in Somatotroph Pituitary Adenomas Is Related to Tumor Size, Invasiveness, and Somatostatin Analog Response
Authors: Fougner Stine Lyngvi , Lekva Tove , Borota Olivera Casar , Hald John K. , Bollerslev Jens , Berg Jens Petter
Published: March 2010

Context: Appropriate cell-to-cell adhesion is fundamental for the epithelial phenotype of pituitary cells. Loss of the adhesion protein E-cadherin has been associated with invasiveness, metastasis, and poor prognosis in cancers of epithelial origin. In somatotroph adenomas, a variable and reduced expression of E-cadherin has been demonstrated. In addition, nuclear translocation of E-cadherin was found to correlate with pituitary tumor invasion.

Objective: The objective was to examine the protein expression of E-cadherin in somatotroph pituitary adenomas in relation to adenoma size, invasiveness, and somatostatin analog (SMS) efficacy.

Patients and Methods: Eighty-three patients were included, and 29 were treated preoperatively with SMS. Adenoma E-cadherin protein expression was analyzed by Western blot (61 patients) and immunohistochemistry (IHC) (80 patients) with antibodies directed against both extracellular and intracellular domains (IHC). The acute (direct surgery group) and long-term (preoperatively treated group) SMS responses were evaluated. Baseline tumor volume and invasiveness were measured on magnetic resonance imaging scans.

Results: Membranous E-cadherin was lost in several adenomas. Nine of these were nuclear E-cadherin positive. The E-cadherin protein expression correlated negatively to tumor size and positively to acute SMS response. Low E-cadherin levels (preoperatively treated group only) and loss of membranous E-cadherin correlated to tumor invasiveness. The E-cadherin level correlated positively to tumor reduction after SMS treatment, and adenomas with nuclear E-cadherin staining had lower IGF-I reduction and tumor shrinkage. Preoperatively treated adenomas had reduced E-cadherin protein levels, but the IHC expression was unaltered.

Conclusion: Reduced E-cadherin expression may correlate to a dedifferentiated phenotype in the somatotroph pituitary adenomas.
Stochastic Monotonicity and Continuity Properties of the Extinction Time of Bellman-Harris Branching Processes: An Application to Epidemic Modelling
Authors: González M. , Martínez R. , Slavtchova-Bojkova M.
Published: March 2010

The aim of this paper is to study the stochastic monotonicity and continuity properties of the extinction time of Bellman-Harris branching processes depending on their reproduction laws. Moreover, we show their applications in an epidemiological context, obtaining an optimal criterion to establish the proportion of susceptible individuals in a given population that must be vaccinated in order to eliminate an infectious disease. First the spread of infection is modelled by a Bellman-Harris branching process. Finally, we provide a simulation-based method to determine the optimal vaccination policies.
Transient Asymptotics of Lévy-Driven Queues
Authors: Dębicki Krzysztof , Es-Saghouani Abdelghafour , Mandjes Michel
Published: March 2010

With (Qt)t denoting the stationary workload process in a queue fed by a Lévy input process (Xt)t, this paper focuses on the asymptotics of rare event probabilities of the type P(Q0 > pB, QTB > qB) for given positive numbers p and q, and a positive deterministic function TB. We first identify conditions under which the probability of interest is dominated by the ‘most demanding event’, in the sense that it is asymptotically equivalent to P(Q > max{p, q}B) for large B, where Q denotes the steady-state workload. These conditions essentially reduce to TB being sublinear (i.e.
TB/B → 0 as B → ∞). A second condition is derived under which the probability of interest essentially ‘decouples’, in that it is asymptotically equivalent to P(Q > pB)P(Q > qB) for large B. For various models considered in the literature, this ‘decoupling condition’ reduces to requiring that TB is superlinear (i.e. TB / B → ∞ as B → ∞). This is not true for certain ‘heavy-tailed’ cases, for instance, the situations in which the Lévy input process corresponds to an α-stable process, or to a compound Poisson process with regularly varying job sizes, in which the ‘decoupling condition’ reduces to TB / B2 → ∞. For these input processes, we also establish the asymptotics of the probability under consideration for TB increasing superlinearly but subquadratically. We pay special attention to the case TB = RB for some R > 0; for light-tailed input, we derive intuitively appealing asymptotics, intensively relying on sample path large deviations results. The regimes obtained can be interpreted in terms of the most likely paths to overflow.
RBPjκ-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development
Authors: Dong Yufeng , Jesse Alana M. , Kohn Anat , Gunnell Lea M. , Honjo Tasuku , Zuscik Michael J. , O'Keefe Regis J. , Hilton Matthew J.
Published: March 2010

The Notch pathway has recently been implicated in mesenchymal progenitor cell (MPC) differentiation from bone marrow-derived progenitors. However, whether Notch regulates MPC differentiation in an RBPjκ-dependent manner, specifies a particular MPC cell fate, regulates MPC proliferation and differentiation during early skeletal development or controls specific Notch target genes to regulate these processes remains unclear. To determine the exact role and mode of action for the Notch pathway in MPCs during skeletal development, we analyzed tissue-specific loss-of-function (Prx1Cre; Rbpjkf/f), gain-of-function (Prx1Cre; Rosa-NICDf/+) and RBPjκ-independent Notch gain-of-function (Prx1Cre; Rosa-NICDf/+; Rbpjkf/f) mice for defects in MPC proliferation and differentiation. These data demonstrate for the first time that the RBPjκ-dependent Notch signaling pathway is a crucial regulator of MPC proliferation and differentiation during skeletal development. Our study also implicates the Notch pathway as a general suppressor of MPC differentiation that does not bias lineage allocation. Finally, Hes1 was identified as an RBPjκ-dependent Notch target gene important for MPC maintenance and the suppression of in vitro chondrogenesis.
The FoxF/FoxC factor LET-381 directly regulates both cell fate specification and cell differentiation inC. elegansmesoderm development
Authors: Amin Nirav M. , Shi Herong , Liu Jun
Published: March 2010

Forkhead transcription factors play crucial and diverse roles in mesoderm development. In particular, FoxF and FoxC genes are, respectively, involved in the development of visceral/splanchnic mesoderm and non-visceral mesoderm in coelomate animals. Here, we show at single-cell resolution that, in the pseudocoelomate nematode C. elegans, the single FoxF/FoxC transcription factor LET-381 functions in a feed-forward mechanism in the specification and differentiation of the non-muscle mesodermal cells, the coelomocytes (CCs). LET-381/FoxF directly activates the CC specification factor, the Six2 homeodomain protein CEH-34, and functions cooperatively with CEH-34/Six2 to directly activate genes required for CC differentiation. Our results unify a diverse set of studies on the functions of FoxF/FoxC factors and provide a model for how FoxF/FoxC factors function during mesoderm development.
Recombineering Hunchback identifies two conserved domains required to maintain neuroblast competence and specify early-born neuronal identity
Authors: Tran Khoa D. , Miller Michael R. , Doe Chris Q.
Published: March 2010

The Hunchback/Ikaros family of zinc-finger transcription factors is essential for specifying the anterior/posterior body axis in insects, the fate of early-born pioneer neurons in Drosophila, and for retinal and immune development in mammals. Hunchback/Ikaros proteins can directly activate or repress target gene transcription during early insect development, but their mode of action during neural development is unknown. Here, we use recombineering to generate a series of Hunchback domain deletion variants and assay their function during neurogenesis in the absence of endogenous Hunchback. Previous studies have shown that Hunchback can specify early-born neuronal identity and maintain ‘young’ neural progenitor (neuroblast) competence. We identify two conserved domains required for Hunchback-mediated transcriptional repression, and show that transcriptional repression is necessary and sufficient to induce early-born neuronal identity and maintain neuroblast competence. We identify pdm2 as a direct target gene that must be repressed to maintain competence, but show that additional genes must also be repressed. We propose that Hunchback maintains early neuroblast competence by silencing a suite of late-expressed genes.
The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation
Authors: Mangos Steve , Lam Pui-ying , Zhao Angela , Liu Yan , Mudumana Sudha , Vasilyev Aleksandr , Liu Aiping , Drummond Iain A.
Published: March 2010

Mutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10–15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b- and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.
Ontogenetic scaling of locomotor kinetics and kinematics of the ostrich (Struthio camelus)
Authors: Smith Nicola C. , Jespers Karin J. , Wilson Alan M.
Published: March 2010

Kinematic and kinetic parameters of running gait were investigated through growth in the ostrich, from two weeks up to 10 months of age, in order to investigate the effects of increasing body size. Ontogenetic scaling relationships were compared with published scaling relationships found to exist with increasing body size between species to determine whether dynamic similarity is maintained during growth. During the study, ostrich mass (Mb) ranged from 0.7 kg to 108.8 kg. Morphological measurements showed that lengths scaled with positive allometry during growth (hip height ∝Mb0.40; foot segment length ∝Mb0.40; tarsometatarsus length ∝Mb0.41; tibiotarsus length ∝Mb0.38; femur length ∝Mb0.37), significantly exceeding the close to geometric scaling observed between mammalian and avian species of increasing body size. Scaling of kinematic variables largely agreed with predicted scaling for increasing size and demonstrated relationships close to dynamic similarity and, as such, ontogenetic scaling of locomotor parameters was similar to that observed with increasing body mass between species. However, the ways in which these scaling trends were achieved were very different, with ontogenetic scaling of locomotor mechanics largely resulting from simple scaling of the limb segments rather than postural changes, likely to be due to developmental constraints. Small deviations from dynamic similarity of kinematic parameters and a reduction in the predicted scaling of limb stiffness (∝Mb0.59) were found to be accounted for by the positive allometric scaling of the limb during growth.
Life in acid: interactive effects of pH and natural organic acids on growth, development and locomotor performance of larval striped marsh frogs (Limnodynastes peronii)
Authors: Barth B. J. , Wilson R. S.
Published: March 2010

The low pH of naturally acidic aquatic environments is the result of soft-water with low buffering capacity and high concentrations of natural organic acids. Our current understanding of the influence of pH on aquatic organisms is largely limited to laboratory studies conducted under controlled conditions with little incorporation of these organic acids. Recent studies suggest natural organic acids may influence the physiology of aquatic species independent of low pH. We examined the effects of pH and varying concentrations of natural wallum water, which is high in organic acids on the hatching success, growth and locomotor performance of larval striped marsh frogs (Limnodynastes peronii). Based on previous studies, we predicted that the detrimental effects of low pH would be further exacerbated by higher concentrations of naturally occurring organic acids (high concentrations of wallum water). In artificial soft-water, embryos experienced both reduced growth and reduced survival when exposed to low pH. However, greater concentrations of natural organic acids did not exacerbate these effects of low pH on growth and development. Instead, we found some evidence that the natural organic acids within wallum water improved growth and swimming performance across all pH treatments. Using path analyses to investigate the effects of pH and natural organic acid concentration on burst swimming performance, we found performance was directly affected by both body length and organic acid concentration. Our data further highlight our limited understanding of the importance of natural organic acids for aquatic organisms and the need to incorporate greater ecological relevance into these studies.
Activity, abundance, distribution and expression of Na+/K+-ATPase in the salt glands ofCrocodylus porosusfollowing chronic saltwater acclimation
Authors: Cramp Rebecca L. , Hudson Nicholas J. , Franklin Craig E.
Published: March 2010

Saltwater crocodiles, Crocodylus porosus, possess lingual salt glands which function to remove excess Na+ and Cl− accumulated as a consequence of living in salt water. Little is known about the nature of ion transport systems in C. porosus salt glands and how these systems respond to an osmotic challenge. In the present study, we examined the distribution and regulation of the Na+/K+-ATPase (NKA) pump, specifically the α-(catalytic) subunit in the salt glands of C. porosus chronically acclimated (6 months) to freshwater (FW) or 70% seawater (SW). We hypothesised that in the SW-acclimated C. porosus there would be an up-regulation of the abundance, activity and gene expression of the NKA transporter. NKA was immunolocalised to the lateral and basal membrane of secretory cells. As predicted, the NKA α-subunit was 2-fold more abundant in SW-acclimated C. porosus salt glands. NKA gene expression was also elevated in the salt glands of SW- vs FW-acclimated crocodiles. There was no increase in the specific activity of NKA in SW-acclimated animals and the in vitro rate of oxygen consumption by salt gland slices from SW-acclimated animals was not significantly different from that of FW-acclimated animals. The proportion of tissue oxygen consumption rate attributable to NKA activity was not different between SW- and FW-acclimated animals (approximately 50%). These data suggest that either chronic SW acclimation does not affect NKA in crocodile salt glands in the same manner as seen in other models or crocodiles possess the capacity to moderate NKA activity following prolonged exposure to SW.
Assessing the Lifetime Performance Index of Gamma Lifetime Products in the Manufacturing Industry
Authors: Lee W-C
Published: March 2010

In the manufacturing (or service) industry, process capability indices (PCIs) are utilized to assess whether product quality meets a required level. The lifetime performance index (or the larger-the-better PCI) CL is frequently used as a means of measuring product performance, where L is the lower specification limit. This study constructs the uniformly minimum variance unbiased estimator (UMVUE) of CL based on a complete sample from a gamma distribution where the shape parameter α is given (or known) and the scale parameter λ is unknown. The UMVUE of CL is then utilized to develop a novel hypothesis testing procedure in the condition of known L. Two practical examples illustrate the use of the testing procedure under a given significance level.
Effect of die aperture offset on flow behaviour in an extrusion process with aluminium alloy
Authors: Li F , Chu G N , Feng S L
Published: March 2010

In order to reveal the mechanism of die aperture offset on metal flow behaviour, numerical simulation was conducted to analyse the different processes. The stress field characteristics were used to create the deformation division. The results show that the shunt section at the bottom of the container moves towards the axis as the die aperture offset increases, and the complexity of metal deformation flow increases significantly. The distribution of the plastic zone gradually becomes non-symmetrical, and the dead zone at the bottom of the die cavity enlarges significantly, while the other side disappears completely. It can be observed that the velocity uniformity of metal flow towards the die pocket can be changed by using different die aperture offsets, and thus can effectively control the degree of bending of the extruded products. The simulation results are consistent with the experiment.
A new study and model for the mechanism of process reciprocating compressors and pumps
Authors: Almasi A
Published: March 2010

Dynamic forces in the mechanism of special-purpose process reciprocating compressors and pumps can cause excessive vibration and noise. A comprehensive model and practical recommendations are presented for design and reliability improvements. Factors such as power per cylinder, rod load, speed range, crosshead pin location, and crosshead clearance have strong effects on mechanism-related vibration and noise.
Ignition delay time correlations for a diesel fuel with application to engine combustion modelling
Authors: Hernández J J , Sanz-Argent J , Carot J M , Jabaloyes J M
Published: March 2010

New diesel engine combustion concepts, such as the homogeneous charge compression ignition (HCCI), have encouraged the development of ignition delay correlations allowing the reliable prediction of the chemical auto-ignition time of the fuel, which depends on its oxidation kinetics. These correlations permit one to design and optimize the most adequate control strategies leading to both low emission levels of pollutants and proper engine performance. Although some diesel ignition correlations can be found in the literature, most of them consider the physical delay time and have been obtained only for high temperature values, which are usual at the end of the compression stroke in traditional diesel engines. However, there is still a significant lack of information regarding the complex three-stage oxidation (low-, intermediate-, and high-temperature range) of a diesel fuel under HCCI conditions. Thus the proposal of delay time correlations for the three temperature ranges is the objective of the present work. The correlations have been assumed as Arrhenius-type equations and consider the effect of the main parameters affecting the auto-ignition time, i.e. pressure, temperature, and equivalence fuel/air ratio. The adjustment coefficients have been calculated by using multiple linear regression and least-squares techniques, and a very good fit between modelling-predicted and correlation-predicted delay values has been obtained ( R2 higher than 0.95 in all cases).
The treatment of varicose veins: an investigation of patient preferences and expectations
Authors: Shepherd A C , Gohel M S , Lim C S , Hamish M , Davies A H
Published: March 2010

Objectives

A number of modalities are now available for the treatment of varicose veins. The aim of the study was to investigate the factors considered important by patients when contemplating treatment of their varicose veins.

Methods

Consecutive new patients referred to a vascular surgery service were invited to complete a short anonymous questionnaire prior to their consultation. The questionnaire consisted of 13 multiple choice questions relating to symptoms, potential varicose vein treatments and patient knowledge of existing therapies.

Results

Of 111 patients, there were 83 complete responses (75%). Symptoms of pain or aching were reported as moderate or severe by 77/103 (75%) of patients and significantly limited the activities of 47/101 (47%). Although the majority (89/103 [86%]) of patients were aware of surgery, only 52/103 (51%) knew of the existence of endothermal ablation (either laser or radiofrequency) and only 23/103 (22%) were aware of foam sclerotherapy. Some 58/92 (63%) were in favour of local anaesthetic treatment. Most patients (74/103, 72%) felt inadequately informed to express a preference regarding treatment type prior to their consultation, although 24/103 (23%) expressed a preference for endovenous treatment. Interestingly, 74/92 (80%) stated that the opinion of their vascular surgeon would be likely to or definitely influence their treatment decision and the majority of patients stated that what they had read in magazines (54/80, 64%) or on the Internet (51/85, 60%) would have no influence on their decision regarding treatment, respectively.

Conclusion

Only a minority of patients referred with varicose veins were aware of endovenous treatments or felt adequately informed to express a treatment preference prior to consultation. Over half of patients expressed a preference for local anaesthetic therapy and a preference for a single visit treatment, although most would be strongly influenced by the opinion of their vascular surgeon and not influenced by media advertising.
Preferences for Consumption Streams: Scale Invariance, Correlation Aversion, and Delay Aversion Under Mortality Risk
Authors: Lichtendahl Kenneth C. , Bodily Samuel E.
Published: March 2010

Lifetime financial decisions often require a decision analyst to elicit a decision maker's preferences for consumption streams. In assessing such preferences, the analyst might look for a set of reasonable conditions to check when selecting a utility form. We provide such a set of conditions and show that they lead to the multiplicative-expo-power (MEP) utility form. Some of our conditions involve trade-offs under certainty and others relate to choices under uncertainty. In the deterministic setting, we invoke increasingness, continuous differentiability, mutual preferential independence, and preferential scale invariance. In the uncertainty setting, we invoke componentwise risk aversion, a utility independence condition, and correlation aversion. We apply the MEP utility in a life-cycle consumption-planning problem under mortality risk. In this context, we find that the correlation-averse MEP utility is more realistic than, and as tractable as, the popular correlation-neutral additive-power and additive-exponential utilities. We show that the correlation-averse decision maker prefers to consume more in life and leave less behind in death. In addition, we demonstrate that the correlation-averse decision maker is more averse to delaying consumption in the face of mortality risk.