bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA‐183 regulates Ezrin expression in lung cancer cells
Authors: Wang Guofu , Mao Weimin , Zheng Shu
Published: October 2008

Lung cancer is the leading cause of cancer death. However, the mechanism of lung cancer relapse and metastasis has been poorly elucidated. Recent researches have addressed the role of MicroRNAs (miRNAs) in mediating tumor metastasis. In the present study, we identified microRNA‐183 (miR‐183) as a potential metastasis‐inhibitor. Expression level of miR‐183 was reversely correlated with the metastatic potential of lung cancer cells. Furthermore, over‐expression of miR‐183 inhibited migration and invasion of lung cancer cells. Mechanistically, we identified VIL2‐coding‐protein Ezrin as a bona fide target of miR‐183. We also found that miR‐183 could regulate the expression of other genes involved in migration and invasion. Taken together, our findings demonstrated a new role and regulatory mechanism of miR‐183 in controlling cancer metastasis.
Selective contribution of Tyk2 to cell activation by lipopolysaccharide
Authors: Schneider Andrea , Reichart Ursula , Gerner Wilhelm , Kolbe Thomas , Saalmüller Armin , Müller Mathias
Published: October 2008

Tyk2 deficient mice show a markedly reduced susceptibility to lipopolysaccharide (LPS) induced shock and a partial impairment of IL‐12 and interferon (IFN) signals. To examine the underlying mechanisms, we analysed the activation of peritoneal macrophages (PMΦs) and spleen cells after LPS challenge. In PMΦs and spleen cells the contribution of Tyk2 to the induction of the T‐cell co‐stimulatory molecules CD86, CD40 and MHC II was small or insignificant. By contrast, induced expression of the early activation marker CD69 on PMΦs and splenic cell populations required type I interferons (IFN‐I) and Tyk2. The data suggest a selective contribution of Tyk2 to the activation of inflammation‐relevant cell types by LPS.
Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells
Authors: Park Juwon , Ayyappan Vasudevan , Bae Eun-Kyung , Lee Chansu , Kim Byung-Su , Kim Byoung Kook , Lee Young-Yiul , Ahn Kwang-Sung , Yoon Sung-Soo
Published: October 2008

Growth of multiple myeloma cells is controlled by various factors derived from host bone marrow microenvironments. Interaction between multiple myeloma cells and bone marrow stromal cells (BMSCs) plays an important role in the expression of adhesive molecules and secretion of growth factors involved in multiple myeloma (MM) cell growth, survival, and resistance to anticancer drugs. Recently, the possibility of developing novel anti‐cancer therapeutic strategies targeting both MM cells and MM cell–BMSC interactions has been discussed. Here we present data showing that curcumin, a major constituent of turmeric compounds extracted from the rhizomes of the plant Curcuma longa, effectively reduced the growth of MM cells and BMSCs. Upon treatment with curcumin, IL‐6/sIL‐6R‐induced STAT3 and Erk phosphorylation was dramatically reduced in the co‐cultured cells. In addition, curcumin inhibited the production of pro‐inflammatory cytokines and VEGF, factors that are associated with the progression of multiple myeloma, from both MM cells and BMSCs. In a combination treatment with curcumin and bortezomib, IL‐6/sIL‐6R‐induced STAT3 and Erk phosphorylation was effectively inhibited. Moreover, this combination treatment synergistically inhibited the growth of MM cells co‐cultured with BMSCs as compared to controls. Taken together, these results indicate that curcumin potentiates the therapeutic efficacy of bortezomib in MM suggesting this combination therapy to be of value in the clinical management of MM.
Aberrations of the MRE11–RAD50–NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer‐predisposing gene
Authors: Bartkova Jirina , Tommiska Johanna , Oplustilova Lenka , Aaltonen Kirsimari , Tamminen Anitta , Heikkinen Tuomas , Mistrik Martin , Aittomäki Kristiina , Blomqvist Carl , Heikkilä Päivi , Lukas Jiri , Nevanlinna Heli , Bartek Jiri
Published: October 2008

The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11–RAD50–NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer‐predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple‐negative and higher‐grade tumours, among familial (especially BRCA1/BRCA2‐associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1‐associated and ER/PR/ERBB2 triple‐negative tumours also showed high incidence of constitutively active DNA damage signalling (γH2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non‐BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN‐complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re‐expression of wild‐type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non‐BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti‐cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.
Feeding, oviposition and survival of Liriomyza trifolii (Diptera: Agromyzidae) on Bt and non-Bt cottons
Authors: Lei Z. , Liu T.-X. , Greenberg S.M.
Published: October 2008

The effects of Bt transgenic cottons (Bt-I expressing cry1Ac and Bt-II expressing cry1Ab and cry2Ab or cry1Ab and cry1Fa) and non-Bt cottons on feeding, oviposition and longevity of adults, and development and survival of Liriomyza trifolii larvae were studied under laboratory conditions; and infestation on four Bt and two non-Bt cotton traits were investigated under field conditions. Laboratory choice and no-choice tests showed that L. trifolii adults were capable of distinguishing between Bt cottons and non-Bt cottons. In a choice test on younger plants (4–5 leaves), the adults were found more often and made more feeding punctures (FP) on non-Bt cottons than on Bt cottons. On older plants (8–9 leaves), adults made the most FP on non-Bt cotton followed by those on Bt-II cottons and the least on Bt-I cotton. The females oviposited more eggs (6.7 eggs per leaf) on non-Bt cotton than on Bt-I (1.7 eggs per leaf) and Bt-II (0.8 eggs per leaf) cottons on younger plants and oviposited similar numbers of eggs (0.7–1.3 eggs per leaf) on non-Bt and Bt cottons on older plants. In a no-choice test, the females also fed more FP on non-Bt cottons than on Bt cottons on both younger and older plants. The females oviposited more eggs (15.6 eggs per leaf) on non-Bt cotton than on Bt-I (8.2 eggs per leaf) and Bt-II (6.5 eggs per leaf) cottons on younger plants and similar numbers of eggs (2.5–3.3 eggs per leaf) on non-Bt and Bt cottons on older plants. Larval and puparial survivals were not different among Bt and non-Bt cottons. The occurrence and damage of leafminers on cottons in the field showed that L. trifolii infested more plants and leaves and had more mines on non-Bt cotton than on Bt cottons.
Detecting dominant QTL with variance component analysis in simulated pedigrees
Authors: ROWE SUZANNE J. , RICARDO PONG-WONG , HALEY CHRISTOPHER S. , KNOTT SARA A. , KONING DIRK-JAN DE
Published: October 2008

Dominance is an important source of variation in complex traits. Here, we have carried out the first thorough investigation of quantitative trait locus (QTL) detection using variance component (VC) models extended to incorporate both additive and dominant QTL effects. Simulation results showed that the empirical distribution of the test statistic when testing for dominant QTL effects did not behave in accordance with existing theoretical expectations and varied with pedigree structure. Extensive simulations were carried out to assess accuracy of estimates, type 1 error and statistical power in two-generation human-, poultry- and pig-type pedigrees each with 1900 progeny in small-, medium- and large-sized families, respectively. The distribution of the likelihood-ratio test statistic was heavily dependent on family structure, with empirical thresholds lower for human pedigrees. Power to detect QTL was high (0·84–1·0) in pig and poultry scenarios for dominance effects accounting for >7% of phenotypic variance but much lower (0·42) in human-type pedigrees. Maternal or common environment effects can be partially confounded with dominance and must be fitted in the QTL model. Including dominance in the QTL model did not affect power to detect additive QTL effects. Also, detection of spurious dominance QTL effects only occurred when maternal effects were not included in the QTL model. When dominance effects were present in the data but not in the analysis model, this resulted in spurious detection of additive QTL or inflated estimates of additive QTL effects. The study demonstrates that dominance can be included routinely in QTL analysis of general pedigrees; however, optimal power is dependent on selection of the appropriate thresholds for pedigree structure.
Effect of genetic background on acoustic startle response in fragile X knockout mice
Authors: ERRIJGERS VANESSA , FRANSEN ERIK , D'HOOGE RUDI , DE DEYN PETER P. , FRANK KOOY R.
Published: October 2008

To study the effect of genetic background on theFmr1knockout mutation in mice, we compared the acoustic startle response (ASR) of male fragile X knockout mice bred in three different genetic backgrounds, including C57BL/6J (C57BL/6J×129P2/OlaHsd) F1 and F2 intercross. ASR is used as a behavioural tool to assess the neuronal basis of behavioural plasticity. For each background studied, fragile X knockouts clearly differed in ASR from their control littermates. C57BL/6J knockouts showed an increase in ASR in response to the lowest stimulus of 90 dB and a decrease in ASR in response to the highest stimulus of 110 dB when compared with control mice, whereas knockouts of the F1 generation showed significantly lower ASRs for all the three stimulus intensities used when compared with control littermates. These data demonstrate that the expression of the fragile X phenotype in ASR of fragile X knockout mice may be influenced by the presence of 129 genes in the genetic background and that modifier genes may influence the fragile X phenotype. Surprisingly, and in contrast with knockouts of the F1 generation that showed a decreased ASR, knockouts of the F2 generation showed a significantly increased ASR compared with their control littermates. This is especially remarkable as both F1 and F2 mice consist of 50% of the genetic material from each of the parental strains C57BL/6J and 129P2/OlaHsd strain. Thus, the different distribution of the genetic background seems to be responsible for the difference in ASR between F1 and F2. This opposite ASR in the F1 and F2 generations is unique in behavioural studies and has, to our knowledge, not been previously reported.
Extreme value theory in analysis of differential expression in microarrays where either only up- or down-regulated genes are relevant or expected
Authors: IVANEK RENATA , GRÖHN YRJÖ T. , WELLS MARTIN T. , RAENGPRADUB SARITA , KAZMIERCZAK MARK J. , WIEDMANN MARTIN
Published: October 2008

We propose an empirical Bayes method based on the extreme value theory (EVT) (BE) for the analysis of data from spotted microarrays where the interest of the investigator (e.g. to identify up-regulated gene markers of a disease) or the design of the experiment (e.g. in certain ‘wild-type versus mutant’ experiments) limits identification of differentially expressed genes to those regulated in a single direction (either up or down). In such experiments, unlike in genome-wide microarrays, analysis is restricted to the tail of the distribution (extremes) of all the genes in the genome. The EVT provides a platform to account for this extreme behaviour, and is therefore a natural candidate for inference about differential expression. We compared the performance of the developed BE method with two other empirical Bayes methods on two real ‘wild-type versus mutant’ datasets where a single direction of regulation was expected due to experimental design, and in a simulation study. The BE method appears to have a better fit to the real data. In the analysis of simulated data, the BE method showed better accuracy and precision while being robust to different characteristics of microarray experiments. The BE method, therefore, seems promising and useful for inference about differential expression in microarrays where either only up- or down-regulated genes are relevant or expected.
Introduction
Authors: GILMARTIN DAVID
Published: October 2008

These papers were originally presented at the retirement conference for Prof. John F. Richards, which was held at Duke University on September 29–30, 2006. The conference, entitled ‘Expanding Frontiers in South Asian and World History’, brought together students, colleagues and associates of Prof. Richards to discuss themes that have marked Richards's work as a historian in an academic career of almost 40 years. These themes focused on ‘frontiers’ in multiple contexts, all relating to Richards's work: frontiers and state building; frontiers and environmental change; cultural frontiers; frontiers, trade and drugs; and frontiers and world history.
At Empire's End: The Nizam, Hyderabad and Eighteenth-Century India
Authors: FARUQUI MUNIS D.
Published: October 2008

Nizam-ul-Mulk (d. 1748) was a Mughal nobleman who founded the post-Mughal successor state of Hyderabad. Engaging the Nizam's long and varied career, this essay re-evaluates the Nizam's decision to abandon the Mughal imperial system. In so doing, it highlights the ways in which the Nizam's story contrasts with that of founders of other post-Mughal successor states. This essay also seeks to explore Hyderabad's early history, the unique challenges faced by the new state, and the inventive ways in which it sought to overcome them. Ultimately, this essay aims to broaden and complicate our understanding of India's political history in the late-seventeenth and early-eighteenth century.
The Political Economy of Opium Smuggling in Early Nineteenth Century India: Leakage or Resistance?
Authors: MARKOVITS CLAUDE
Published: October 2008

This article looks at the political economy of opium smuggling in India in the first decades of the nineteenth century, in particular in relation to Sindh, one of the last independent polities in the subcontinent. After a description of the smuggling of ‘Malwa’ opium (grown in the princely states of Central India) into China—in defiance of the monopoly of the East India Company over ‘Bengal’ or ‘Patna’ opium, grown in Bihar—it considers the role of Indian merchants and capitalists in its emergence and development, and critiques the argument put forward in a recent book by Amar Farooqi that it represented both a form of ‘subversion’ and that it contributed decisively to capital accumulation in Western India. This article concludes by analysing the role of the opium trade in integrating Sindh into the British imperial trading system, arguing that it was more effective in boosting Empire than in nurturing indigenous capitalism in India.
Chinese Revenue Farms and Borders in Southeast Asia
Authors: TROCKI CARL A.
Published: October 2008

This article examines the role of Chinese revenue farmers in defining the borders of the various colonial territories and the states of Southeast Asia during the nineteenth century. Their significance has largely been neglected in writing on the formation of state boundaries. Nicholas Tarling notes, ‘Between the late eighteenth and the early twentieth almost all southeast Asia was divided into colonies or protectorates held by the Western powers, and new boundaries were drawn with the object of avoiding conflict among them’ (Tarling, 2001:44). This paper argues that Chinese revenue farmers were of considerable significance in giving substance to the formalistic pronouncements of remote diplomats and statesmen.
Mappings of finite distortion: a new proof for discreteness and openness
Authors: Onninen Jani , Zhong Xiao
Published: October 2008

We give a new and elementary proof of the known result: a non-constant mapping of finite distortion f : Ω ⊂ ℝn → ℝn is discrete and open, provided that its distortion function if n = 2 and that for some p > n − 1 if n ≥ 3.
Γ-limit of the Ginzburg–Landau energy in a thin domain with a large magnetic field
Authors: Shieh Tien-Tsan
Published: October 2008

A one-dimensional Ginzburg–Landau model that describes a superconducting closed thin wire with an arbitrary cross-section subject to a large applied magnetic field is derived from the three-dimensional Ginzburg–Landau energy in the spirit of Γ-convergence. Our result proves the validity of the formal result of Richardson and Rubinstein, which reveals the double limit of a large field and a thin domain. An additional magnetic potential related to the applied field is found in the limiting functional, which yields a parabolic background for the oscillatory phase transition curve between the normal and superconducting states.
Solutions to a model for interface motion by interface diffusion
Authors: Alber Hans-Dieter , Zhu Peicheng
Published: October 2008

Existence of weak solutions is proved for a phase field model describing an interface in an elastically deformable solid, which moves by diffusion of atoms along the interface. The volume of the different regions separated by the interface is conserved, since no exchange of atoms across the interface occurs. The diffusion is driven only by reduction of the bulk free energy. The evolution of the order parameter in this model is governed by a degenerate parabolic fourth-order equation. If a regularizing parameter in this equation tends to zero, then solutions tend to solutions of a sharp interface model for interface diffusion. The existence proof is valid only for a 1½-dimensional situation.
The isoperimetric problem in complete annuli of revolution with increasing Gauss curvature
Authors: Cañete Antonio , Ritoré Manuel
Published: October 2008

In this work we describe the isoperimetric regions in complete symmetric annuli of revolution with Gauss curvature non-decreasing from the shortest parallel. This description allows us to complete the classification of isoperimetric regions in quadrics of revolution.
Associations between infectious mononucleosis and cancer: record-linkage studies
Authors: GOLDACRE M. J. , WOTTON C. J. , YEATES D. G. R.
Published: October 2008

Infection with Epstein–Barr virus (EBV) followed by infectious mononucleosis (IM) is now considered to be a risk factor for Hodgkin's disease (HD). It is less clear whether EBV infection and IM are associated with an increased risk of cancer generally. We used a longstanding record-linkage dataset in Oxford (years 1963–1998), and a more recent record-linkage dataset covering England (1999–2005), to compare rate ratios for cancer between people admitted to hospital for IM and a reference cohort. In the Oxford cohort, there was an increased risk of subsequent HD [rate ratio (RR) 6·0, 95% confidence interval (CI) 2·4–12·5] but not of other cancers combined (RR 0·85, 95% CI 0·57–1·23). In the England cohort, there were increased risks of HD (RR 3·2, 95% CI 1·2–7·0), non-Hodgkin's lymphoma (RR 5·6, 95% CI 2·9–9·8), and oropharyngeal cancer (RR 5·4, 95% CI 1·1–16·2), but no significant overall risk of cancer when lymphomas were excluded (RR 1·01, 95% CI 0·71–1·41). We confirm an association between IM and lymphoma; but the risk, if any, of cancer more generally is likely to be small.
Outbreak of meningococcal disease in and around New Delhi, India, 2005–2006: a report from a tertiary care hospital
Authors: NAIR D. , DAWAR R. , DEB M. , CAPOOR M. R. , SINGAL S. , UPADHAYAY D. J. , AGGARWAL P. , DAS B. , SAMANTARAY J. C.
Published: October 2008

The first of several cases of meningococcal meningitis was reported in April 2005, in New Delhi, India. Subsequent to this the Government declared an outbreak, which persisted for two periods, from April–July 2005 and January–March 2006. The National Institute of Communicable Diseases (NICD) recommended using WHO criteria for diagnosis of disease. During the outbreak 380 clinically suspected cases were investigated. Of 55 cases diagnosed as confirmed/probable the mortality rate was 14·6%. Meningitis was reported in 60% of cases and meningococcaemia in 40%. Microscopy of petechial rash was positive in 87·5%, CSF Gram stain positive in 68·3%, and latex agglutination test of CSF positive in 64·9% of samples.Neisseria meningitidis(serogroup A) was isolated from 37·7% of cases, 57·7% from CSF. Blood culture was positive in 10·4% of cases. CrgA polymerase chain reaction forN.meningitidisconfirmed the isolates. All isolates were susceptible to third-generation cephalosporins, azithromycin and rifampicin, with increasing resistance to ceftriaxone. Penicillin resistance was encountered in 15·4% of strains. Resistance to quinolones was very high at 100% for levofloxacin, 84·6% for ofloxacin and 65·4% for ciprofloxacin. All patients with penicillin-resistant organisms (4) or intermediate sensitivity (4) succumbed to the disease. These patients also had a higher minimum inhibitory concentration to ceftriaxone.
Ovine-associated Q fever
Authors: WEBSTER D. , HAASE D. , MARRIE T. J. , CAMPBELL N. , PETTIPAS J. , DAVIDSON R. , HATCHETTE T. F.
Published: October 2008

In Atlantic Canada, the traditional risk factor for acquisition of Q fever infection has been exposure to infected parturient cats or newborn kittens. In this study we describe the first case of Q fever in Nova Scotia acquired as a result of direct exposure to sheep. A serosurvey of the associated flock was undertaken using an indirect immunofluorescence assay (IFA) testing for antibodies to phase I and phase IICoxiella burnetiiantigens. This serosurvey revealed that 23 of 46 sheep (50%) were seropositive for the phase II antibody. Four of these sheep had titres of 1:64 including three nursing ewes, one of which had delivered two lambs that died shortly after delivery. Only one ewe had phase I antibodies but had the study's highest phase II antibody titre (1:128). Molecular studies using polymerase chain reaction (PCR) failed to detectC. burnetiiDNA in any of the milk specimens.
The incidence of pneumonia using data from a computerized general practice database
Authors: MYLES P. R. , McKEEVER T. M. , POGSON Z. , SMITH C. J. P. , HUBBARD R. B.
Published: October 2008

Despite being widely recognized as a significant public health problem there are surprisingly few contemporary data available on the incidence of pneumonia in the UK. We conducted a general population-based cohort study to determine the incidence of pneumonia in general practice in the United Kingdom. Data were obtained from The Health Improvement Network (THIN) – a computerized, longitudinal, general practice database. Recorded diagnoses of pneumonia between 1991 and 2003 were used to calculate the incidence of pneumonia stratified by year, sex, age group and deprivation score. The overall incidence of pneumonia was 233/100 000 person-years [95% confidence interval (CI) 231–235] and this rate was stable between 1991 and 2003. The incidence of pneumonia was slightly lower in females compared to males [age-adjusted incidence rate ratio (IRR) 0·88, 95% CI 0·86–0·89]. Pneumonia was most common in children aged <4 years and adults aged >65 years. There was an increased incidence of pneumonia with higher levels of socioeconomic disadvantage such that people living in the most deprived areas of the United Kingdom were 28% more likely to get pneumonia than those in the least deprived areas (age- and gender-adjusted IRR 1·28, 95% CI 1·24–1·32). In conclusion, pneumonia is an important public health problem and the incidence of pneumonia is higher in people at the extremes of age, men and people living in socially deprived areas.
Aligning the top-level of SNOMED-CT with Basic Formal Ontology
Authors: Hogan William
Published: October 2008

Effective translational research requires automated analysis of large datasets collected by multiple researchers working at multiple locations. Reliable, machine interpretation of-—and reasoning with—-large datasets assembled at different times and places by different researchers requires standard representations of data. These representations are controlled, structured vocabularies also known as ontologies. By far, the most successful ontology is the Gene Ontology (GO), used by bioinformatics researchers to annotate genomics data. However, to address the phenotype side of translational research will require annotation of electronic medical record data and clinical research data with a clinical-phenotype ontology analogous to GO. One leading candidate for this ontology is SNOMED-CT (SNCT). However, GO and SNCT are incompatible representations. GO is based on an upper level ontology called Basic Formal Ontology (BFO). In this work, we aligned the upper level of SNCT with BFO to enhance its suitability for translational research. Most (14/19 or 74%) of the top-level concepts of SNCT can be fitted into the framework of BFO, but only after significant reorganization. An important concept that does not align is Clinical Finding, which is intended to comprehend diseases and signs and symptoms of disease. However, a finding of disease (epistemology) is not the same thing as a disease (ontology). This discrepancy between SNCT and BFO is important to consider further. Another key result is that children of the top-level concepts do not necessarily follow their parents into BFO, and thus one must align each SNCT concept independently. Future work is to align the next level of SNCT (345 concepts) with BFO.
Indirect recruitment of the signalling adaptor Shc to the fibroblast growth factor receptor 2 (FGFR2)
Authors: Schüller Annika C. , Ahmed Zamal , Levitt James A. , Suen Kin M. , Suhling Klaus , Ladbury John E.
Published: October 2008

The adaptor protein Shc (Src homology and collagen-containing protein) plays an important role in the activation of signalling pathways downstream of RTKs (receptor tyrosine kinases) regulating diverse cellular functions, such as differentiation, adhesion, migration and mitogenesis. Despite being phosphorylated downstream of members of the FGFR (fibroblast growth factor receptor) family, a direct interaction of Shc with this receptor family has not been described to date. Various studies have suggested potential binding sites for the Shc PTB domain (phosphotyrosine-binding domain) and/or the SH2 (Src homology 2) domain on FGFR1, but no interaction of full-length Shc with these sites has been reported in vivo. In the present study, we investigated the importance of the SH2 domain and the PTB domain in recruitment of Shc to FGFR2(IIIc) to characterize the interaction of these two proteins. Confocal microscopy revealed extensive co-localization of Shc with FGFR2. The PTB domain was identified as the critical component of Shc which mediates membrane localization. Results from FLIM (fluorescence lifetime imaging microscopy) revealed that the interaction between Shc and FGFR2 is indirect, suggesting that the adaptor protein forms part of a signalling complex containing the receptor. We identified the non-RTK Src as a protein which potentially mediates the formation of such a ternary complex. Although an interaction between Src and Shc has been described previously, in the present study we implicate the Shc SH2 domain as a novel mediator of this association. The recruitment of Shc to FGFR2 via an indirect mechanism provides new insight into the regulation of protein assembly and activation of various signalling pathways downstream of this RTK.
Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway
Authors: Gjymishka Altin , Su Nan , Kilberg Michael S.
Published: October 2008

The UPR (unfolded protein response) pathway comprises three signalling cascades mediated by the ER (endoplasmic reticulum) stress-sensor proteins PERK [PKR (double-stranded RNA-activated protein kinase)-like ER kinase], IRE1 (inositol-requiring kinase 1) and ATF6 (activating transcription factor 6). The present study shows that ASNS (asparagine synthetase) transcription activity was up-regulated in HepG2 cells treated with the UPR activators thapsigargin and tunicamycin. ChIP (chromatin immunoprecipitation) analysis demonstrated that during ER stress, ATF4, ATF3 and C/EBPβ (CCAAT/enhancer-binding protein β) bind to the ASNS proximal promoter region that includes the genomic sequences NSRE (nutrient-sensing response element)-1 and NSRE-2, previously implicated by mutagenesis in UPR activation. Consistent with increased ASNS transcription, ChIP analysis also demonstrated that UPR signalling resulted in enhanced recruitment of general transcription factors, including RNA Pol II (polymerase II), to the ASNS promoter. The ASNS gene is also activated by the AAR (amino acid response) pathway following amino acid deprivation of tissue or cells. Immunoblot analysis of HepG2 cells demonstrated that simultaneous activation of the AAR and UPR pathways did not further increase the ASNS or ATF4 protein abundance when compared with triggering either pathway alone. In addition, siRNA (small interfering RNA)-mediated knockdown of XBP1 (X-box-binding protein 1), ATF6α or ATF6β expression did not affect ASNS transcription, whereas siRNA against ATF4 suppressed ASNS transcription during UPR activation. Collectively, these results indicate that the PERK/p-eIF2α (phosphorylated eukaryotic initiation factor 2α)/ATF4 signalling cascade is the only arm of the UPR that is responsible for ASNS transcriptional induction during ER stress. Consequently, ASNS NSRE-1 and NSRE-2, in addition to ERSE (ER stress response element)-I, ERSE-II and the mUPRE (mammalian UPR element), function as mammalian ER-stress-responsive sequences.
The copper-responsive repressor CopR of Lactococcus lactis is a ‘winged helix’ protein
Authors: Cantini Francesca , Banci Lucia , Solioz Marc
Published: October 2008

CopR of Lactococcus lactis is a copper-responsive repressor involved in copper homoeostasis. It controls the expression of a total of 11 genes, the CopR regulon, in a copper-dependent manner. In the absence of copper, CopR binds to the promoters of the CopR regulon. Copper releases CopR from the promoters, allowing transcription of the downstream genes to proceed. CopR binds through its N-terminal domain to a ‘cop box’ of consensus TACANNTGTA, which is conserved in Firmicutes. We have solved the NMR solution structure of the N-terminal DNA-binding domain of CopR. The protein fold has a winged helix structure resembling that of the BlaI repressor which regulates antibiotic resistance in Bacillus licheniformis. CopR differs from other copper-responsive repressors, and the present structure represents a novel family of copper regulators, which we propose to call the CopY family.
Ethical Considerations for Clinical Research Collaborations
Authors: Jones Sherri M. , Figueroa Christina M.
Published: October 2008

The definition of clinical research adopted by the National Institutes of Health (NIH) includes three areas, 1. patient-oriented research, 2. epidemiologic and behavioral studies, and 3. outcomes and health services research (DHHS, 2003). Extensive research training is not a core component of many clinical-degree programs, and clinicians may not have the requisite knowledge and skills to initiate a research program independently. However, clinicians and the clinical sites where they practice can play an integral part in collaborative research. This review discusses five areas for clinical supervisors to consider prior to initiating a research project, which include formal approvals, determining which aspects of the study to be involved in, subject recruitment and informed consent, data collection and storage, and dissemination of results. These are not the only areas that might be considered; however, mutual agreement on these issues before the project begins will facilitate successful collaboration and foster responsible conduct of research. The ethical conduct of research is paramount for the scientific base of our professions. Additionally, the information and guidelines presented are intended to facilitate discussion and offer resources for further study.
Multidisciplinary Evidence to Treat Bilingual Individuals with Aphasia
Authors: Centeno José G.
Published: October 2008

The steady increase in linguistic and cultural diversity in the country, including the number of bilingual speakers, has been predicted to continue. Minorities are expected to be the majority by 2042. Strokes, the third leading cause of death and the leading cause of long-term disability in the U.S., are quite prevalent in racial and ethnic minorities, so population estimates underscore the imperative need to develop valid clinical procedures to serve the predicted increase in linguistically and culturally diverse bilingual adults with aphasia in post-stroke rehabilitation. Bilingualism is a complex phenomenon that interconnects culture, cognition, and language; thus, as aphasia is a social phenomenon, treatment of bilingual aphasic persons would benefit from conceptual frameworks that exploit the culture-cognition-language interaction in ways that maximize both linguistic and communicative improvement leading to social re-adaptation. This paper discusses a multidisciplinary evidence-based approach to develop ecologically-valid treatment strategies for bilingual aphasic individuals. Content aims to spark practitioners' interest to explore conceptually broad intervention strategies beyond strictly linguistic domains that would facilitate linguistic gains, communicative interactions, and social functioning. This paper largely emphasizes Spanish-English individuals in the United States. Practitioners, however, are advised to adapt the proposed principles to the unique backgrounds of other bilingual aphasic clients.
Concurrent Validity of a Parent Survey Measuring Communication Skills of Spanish Speaking Preschoolers with and without Delayed Language
Authors: Guiberson Mark
Published: October 2008

Purpose: The primary objective of the current study was to examine the concurrent validity of a pilot version the Inventario-III (Pilot INV-III) involving parents of Spanish speaking preschoolers with and without delayed language (DL).

Method: Fifteen parents of 3 year old children participated. Twelve children were typically developing (TD), while three had DL. All of the children attended Head Start programs. Parents completed two surveys, the Pilot INV-III and the Spanish Ages and Stages Questionnaire (Spanish ASQ) shortly after their child's third birthday.

Results: The results indicated that the scores from the Spanish ASQ and the Pilot INV-III were significantly correlated, suggesting that these tools seem to be measuring comparable language skills. Furthermore, the DL group's scores on the Pilot INV-III subscales were much lower than the TD group. These results suggest that the Pilot INV-III may be useful clinically for screening purposes when the only area of concern is communication development.

Conclusions: Limitations and implications for practice and research are presented.
A Clinical Hypothesis for Intermittent Unintelligibility in Two English Language Learners
Authors: Rhein Deborah
Published: October 2008

Purpose: This article reports an unusual speech pattern produced by two English Language Learners (ELLs), who developed intermittent unintelligibility shortly after placement in English-only academic settings.

Method: In order to determine if this speech pattern had been observed by other speech-language pathologists (SLPs), 123 school-based speech language pathologists (SLPs) were surveyed as to their experience with the pattern in both monolingual English-speaking and bilingual (languages unspecified) students aged 3-21 years.

Results: The majority (76%) of SLPs reported having observed the pattern in school-age monolingual and bilingual children.

Conclusions: A theoretical framework to explain the sudden development of intermittent unintelligibility in the two children in the case study as well as other children who produce the speech pattern as reported by the survey respondents is presented. Different clinical implications are suggested for different clinical populations and areas in need of further study are also discussed.
Milieu Communication Training for Late Talkers
Authors: Gilbert Kimberly
Published: October 2008

Milieu communication training (MCT), an intervention designed to elicit early communication and language behaviors in young children with a variety of developmental disabilities, has a large empirical evidence base supporting its efficacy. This article discusses components of MTC, as well as reviews research supporting this intervention approach for children identified as late talkers.
Early Language Delay and Risk for Language Impairment
Authors: Ellis Erica M. , Thal Donna J.
Published: October 2008

Clinicians are often faced with the difficult task of deciding whether a late talker shows normal variability or has a clinically significant language disorder. This article provides an overview of research investigating identification, characteristics, outcomes, and predictors of late talkers. Clinical implications for speech-language pathologists in the identification and treatment of children who are late talkers are discussed.
The Application of Relaxation Training Approaches to Patients With Neurogenic Disorders and Their Caregivers
Authors: Murray Laura L.
Published: October 2008

Purpose:
Because relaxation therapy remains a popular complementary and alternative medicine approach, this review paper was written to (a) introduce speech-language clinicians to relaxation therapy procedures, (b) summarize research regarding outcomes associated with relaxation therapy in healthy and patient populations, including those with neurogenic cognitive and communicative disorders, and (c) identify future research needs and clinical applications regarding the use of relaxation therapy within speech-language management protocols.

Method:
A review of the literature pertaining to relaxation therapy among healthy adults, individuals with non-neurogenic disorders, and individuals with neurogenic cognitive-communicative disorders was conducted and critically summarized.

Results and Conclusions:
Preliminary data suggest that relaxation therapy, when applied alone or in concert with conventional speech-language therapy protocols, may be used to address a variety of neurogenic cognitive and communicative problems ranging from dysarthria in Parkinson's disease to high-level cognitive deficits in traumatic brain injury. Further research is needed, however, given the paucity of studies involving individuals with neurogenic cognitive or communicative disorders and that much of the extant literature regarding relaxation therapy has lacked the methodological rigor necessary to evoke confidence in the reported findings. Suggestions regarding how to broaden the scope of research regarding relaxation training are provided.
Benefits of Physical Fitness Training in Healthy Aging and Neurogenic Patient Populations
Authors: Lorenzen Bonnie , Murray Laura L.
Published: October 2008

Purpose:
In recent years, research has identified a positive connection between physical fitness and exercise, and cognitive performance in healthy aging (e.g., Colcombe & Kramer, 2003) as well as a number of patient populations (e.g., Mostert & Kesselring, 2002). To increase awareness of the benefits of exercise on cognitive and communicative health, this paper reviews the literature pertaining to the cognitive effects of exercise in healthy individuals, as well as preliminary findings regarding the role of exercise in disordered populations including those with stroke, dementia, traumatic brain injury, and multiple sclerosis. It presents a treatment program combining low-intensity fitness training with speech-language therapy that was developed for an individual with traumatic brain injury, stroke, multiple sclerosis, and poor physical fitness.

Method:
A review of the literature was conducted to summarize and synthesize previously published research in the area of exercise and cognition in healthy and patient populations.

Results and Conclusions:
There is a growing understanding of the relationship between exercise and cognition in both healthy and aging patient populations. Research with various patient populations reveals positive outcomes and suggests the need to further this line of research in individuals with neurogenic cognitive-communicative disorders.
Food for Thought on Pediatric Feeding and Swallowing
Authors: Arvedson Joan C.
Published: October 2008

“Food for Thought” provides an opportunity for review of pertinent topics to add to updates in areas of concern for professionals involved with feeding and swallowing issues in infants and children. Given the frequency with which speech-language pathologists (SLPs) make decisions to alter feedings when young infants demonstrate silent aspiration on videofluoroscopic swallow studies (VFSS), the need for increased understanding about cough and its development/maturation is a high priority. In addition, understanding of the role(s) of laryngeal chemoreflexes (LCRs), relationships (or lack of relationships) between cough and esophagitis, gastroesophageal reflux (GER), and chronic salivary aspiration is critical. Decision making regarding management must take into account multiple systems and their interactions in order to provide safe feeding for all children to meet nutrition and hydration needs without being at risk for pulmonary problems. The responsibility is huge and should encourage all to search the literature so that clinical practice is as evidence-based as possible; this often requires adequate understanding of developmentally appropriate neurophysiology and function.
Development of Swallowing Function Along the Prenatal to Postnatal Continuum
Authors: Scarborough Donna , Miller Jeri , Fletcher Kara
Published: October 2008

Developmental information is the cornerstone of diagnosis and intervention in pediatric dysphagia. Ongoing research has refined specific parameters of growth and development of the swallow from the prenatal through the postnatal period. The intent of this article is to review the latest findings regarding normal development of feeding/swallowing from the time the fetus is in utero through the postnatal period. This information may provide clinicians valuable tools to make adaptations within the clinical decision making process.
Individualized Developmental Care in the Neonatal Intensive Care Nursery
Authors: VandenBerg Kathleen A. , Ross Erin Sundseth
Published: October 2008

Advances in medical care have improved the success of medical interventions in treating high-risk and premature infants, but long-term developmental outcomes are less positive. The neonatal intensive care unit (NICU) setting influences infant brain development and organization, as well as the parent-infant relationship. One advanced-practice role for a speech-language pathologist (SLP) is that of a newborn developmental specialist (NDS). The NDS working in the NICU understands the influence of medical, environmental, and caregiving interactions on the neurologic and neurobehavioral organization of the infant. The NICU setting advanced practice skills are grounded in an individualized, developmentally supportive care model, such as the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). Neurodevelopmental assessment focuses on the competence of the infant. The developmental assessment and intervention strategies are individualized to support the infant's own goal strivings. In this framework, interactions with infants become modified to increase competence and organization. The SLP working in the NICU is in a unique position to facilitate communication between the infant and the parent, as well as between the infant and professional caregivers. The SLP can help the parent interpret and respond appropriately to the infant's communication by focusing on non-verbal stress and stability cues, and by planning all interactions with a goal of co-regulation. Interactions with infants and families in this Model in the NICU have beneficial lifelong implications.
Feeding in the NICU and Issues That Influence Success
Authors: Ross Erin Sundseth
Published: October 2008

Premature infants are both medically fragile and immature; both of these factors influence their ability to safely feed. Speech-language pathologists (SLPs) working with these infants must recognize normal development of feeding skills as well as diagnose feeding problems and develop individualized treatment plans. Assessments should include all three phases of swallowing (oral, pharyngeal, and esophageal) in the context of overall stability, and interventions need to be individualized to the unique needs of each infant. Decreasing the flow rate of fluid and providing pacing are frequently used strategies to support the medically fragile infant. Therapeutic programs that do not appreciate the role of both individual developmental progression and medical comorbidities are not appropriate, given that volume is not the only goal of feeding. Rather, SLPs must focus on skill acquisition for long-term success within the larger context of parental nurturing. Medical comorbidities significantly influence both the initiation and the progression of oral feeding in this population. The individual variation in development, as well as the medical fragility in this population, challenges the neonatal intensive care unit (NICU) therapist to appreciate the complexity of feeding and to work in collaboration with the other members of the team.
Response to Intervention and Current Implementation
Authors: Proly Janet L.
Published: October 2008

Response to Intervention (RTI) implementation is becoming more widespread due to the references of RTI components in the Federal Regulations. But everyone is not at the same level of understanding about RTI and its implementation. This article will answer several questions. What is RTI? Why are we hearing more and more about RTI? How are states implementing RTI components? How can the speech-language pathologist help in RTI implementation in the presence or absence of a specific RTI infrastructure? How is Florida Proceeding with RTI implementation? Are there any new resources available for principals and other educators who might want to learn more about RTI?
Sensorimotor Elements of the Orofacial System:Reviewing the Basics
Authors: Andreatta Richard D.
Published: October 2008

The functional ability of the central nervous system (CNS) to transduce and process sensory information directly associated with voluntary action is believed to be an important element in sensorimotor learning and skill acquisition for the orofacial system. Muscles of the lower face insert directly into the facial skin, allowing for sensory endings to encode both the static and dynamic consequences of force and movement related to orofacial behavior. These task-related inputs are subsequently made available to sensorimotor cortices whose functions are known to be highly responsive to the consequences underlying precise adjustments in force during skilled motor control. The purpose of this article is to provide a basic review of the fundamental muscular and sensory elements contributing to orofacial sensorimotor control. In addition, select research on sensorimotor integration in the orofacial system will be summarized with a discussion on the importance of these findings in the context of orofacial rehabilitation.