bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in the Systemic Management of Metastatic Breast Cancer
Authors: Michaud Laura Boehnke , Jones Kellie L.
Published: April 2009

Although improvements in breast cancer management have been made, many women are diagnosed with metastatic breast cancer, an incurable stage of the disease. Several new therapies have become available over the past years that have changed the way we manage metastatic breast cancer. The new aromatase inhibitors, anastrozole, letrozole, and exemestane, are potent agents in this fight. Anastrozole and letrozole have been shown to produce superior efficacy and tolerability compared with tamoxifen as first-line endocrine therapy for metastatic breast cancer. Exemestane is being compared with tamoxifen in a similar manner, but results are pending. Trastuzumab is a monoclonal antibody directed against the HER2 oncogene with intrinsic antitumor activity and synergistic activity with traditional chemotherapy. Newer combinations with trastuzumab are also changing the way we administer other chemotherapy agents in patients who overexpress this oncogene. Traditional chemotherapy has also changed over the recent past and now includes an oral agent, capecitabine, for the treatment of metastatic breast cancer. Epirubicin, an anthracycline new to the United States, appears to have similar efficacy and toxicity to doxorubicin, with dosing issues being quite important. With all of these new agents within our grasp, there is hope for all patients with metastatic breast cancer.
Ubiquitin‐mediated control of oncogene and tumor suppressor gene products
Authors: Kitagawa Kyoko , Kotake Yojiro , Kitagawa Masatoshi
Published: April 2009

Cellular levels of products from both oncogenes and tumor suppressor genes in normal cells need to be critically regulated to avoid malignant transformation. These products are often controlled by the ubiquitin proteasome pathway, the specific degradation mechanism in the cell. E3 ubiquitin ligases polyubiquitylate their specific substrates by collaborating with E1 and E2, and then the modified substrates are degraded in the proteasome. Mdm2 targets p53 and retinoblastoma protein, two major tumor suppressor gene products, for ubiquitin‐dependent degradation. SCFSkp2 targets other tumor suppressor gene products and CDK inhibitors such as p130, Tob1, p27Kip1, p57Kip2, and p21Cip1. Therefore, both E3 ligases act like oncogene products. In contrast, degradation of several oncogene products, such as Cyclin E, Notch, c‐Myc, c‐Jun, and c‐Myb, are mediated by SCFFbw7. Fbw7 is often deleted or mutated in human cancers and acts like a tumor suppressor. As well as growth factor receptors and signal transduction regulators, DNA repair‐related proteins are also regulated via the ubiquitin–proteasome pathway mediated by their specific E3 ligases. The stabilization of oncogene products and enhanced degradation of tumor suppressor gene products or DNA repair proteins might be associated with carcinogenesis and malignant progression, due to defects or the abnormal expression of their E3 ligases. (Cancer Sci 2009)
Ergot: from witchcraft to biotechnology
Authors: HAARMANN THOMAS , ROLKE YVONNE , GIESBERT SABINE , TUDZYNSKI PAUL
Published: April 2009

The ergot diseases of grasses, caused by members of the genus Claviceps, have had a severe impact on human history and agriculture, causing devastating epidemics. However, ergot alkaloids, the toxic components of Claviceps sclerotia, have been used intensively (and misused) as pharmaceutical drugs, and efficient biotechnological processes have been developed for their in vitro production. Molecular genetics has provided detailed insight into the genetic basis of ergot alkaloid biosynthesis and opened up perspectives for the design of new alkaloids and the improvement of production strains; it has also revealed the refined infection strategy of this biotrophic pathogen, opening up the way for better control. Nevertheless, Claviceps remains an important pathogen worldwide, and a source for potential new drugs for central nervous system diseases.
Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD‐subgroup analyses across four randomized trials
Authors: LICHTENSTEIN G. R. , DIAMOND R. H. , WAGNER C. L. , FASANMADE A. A. , OLSON A. D. , MARANO C. W. , JOHANNS J. , LANG Y. , SANDBORN W. J.
Published: April 2009

Background  Benefits and risks of concomitant immunomodulators and maintenance infliximab in inflammatory bowel disease (IBD) patients have not been adequately evaluated.

Aim  To assess the effect of concomitant immunomodulator and infliximab maintenance therapy using data from four prospective, randomized Phase 3 trials in IBD patients.

Methods  Overall, 1383 patients from ACCENT I and ACCENT II [luminal and fistulizing Crohn’s disease trials] and ACT 1 and ACT 2 [ulcerative colitis trials] were analysed. Patients were treated with placebo or infliximab 5 or 10 mg/kg at weeks 0, 2 and 6 followed by every‐8‐week maintenance therapy. Clinical response, clinical remission, fistula response, complete fistula response, infection and infusion reaction rates; serum infliximab concentrations and immunogenicity were summarized by baseline concomitant immunomodulator subgroup (use or non‐use).

Results  Overall, almost 40% of evaluated IBD patients received concomitant immunomodulators. Efficacy, infection, and serious infection rates were generally similar in patients who received maintenance therapy with or without concomitant immunomodulators. There were no consistent differences in serum infliximab concentrations with or without immunomodulators in patients who received scheduled maintenance therapy. Concomitant immunomodulators reduced infusion reactions and immunogenicity.

Conclusion  Concomitant immunomodulators did not improve efficacy or pharmacokinetics in IBD patients who received maintenance infliximab.
Systematic review: the epidemiology and clinical features of travellers’ diarrhoea
Authors: DUPONT H. L.
Published: April 2009

Background  Travellers’ diarrhoea is the most common medical complaint among persons venturing into developing areas from industrialized regions.

Aim  To review recent developments dealing with microbiological, clinical, pathophysiological and therapeutic aspects of travellers’ diarrhoea.

Methods  The author’s extensive file plus a review of publications listed in PubMed on January 22, 2009 on the topic of travellers’ diarrhoea were reviewed.

Results  Travellers’ diarrhoea is largely caused by detectable and undetected bacterial enteropathogens, explaining the remarkable effectiveness of antibacterial agents in prophylaxis and therapy of the illness. A number of host genetic polymorphisms have been recently linked with susceptibility to travellers’ diarrhoea. Novel antisecretory agents are being developed for treatment considering their physiological effects in acute diarrhoea. All travellers should be armed with one of three antibacterial drugs, ciprofloxacin, rifaximin or azithromycin, before their trips to use in self therapy should diarrhoea occur during travel. Loperamide may treat milder forms of travellers’ diarrhoea and can be employed with antibacterial drugs.

Conclusions  Diarrhoea will continue to plague international travellers to high‐risk regions. More studies of the incidence rate, relative important of the various pathogens by geographical region of the world, host risk factors and optimal therapeutic approach are needed.
Fine mapping of quantitative trait loci for mastitis resistance on bovine chromosome 11
Authors: Schulman N. F. , Sahana G. , Iso‐Touru T. , Lund M. S. , Andersson‐Eklund L. , Viitala S. M. , Värv S. , Viinalass H. , Vilkki J. H.
Published: April 2009

Quantitative trait loci (QTL) affecting clinical mastitis (CM) and somatic cell score (SCS) were mapped on bovine chromosome 11. The mapping population consisted of 14 grandsire families belonging to three Nordic red cattle breeds: Finnish Ayrshire (FA), Swedish Red and White (SRB) and Danish Red. The families had previously been shown to segregate for udder health QTL. A total of 524 progeny tested bulls were included in the analysis. A linkage map including 33 microsatellite and five SNP markers was constructed. We performed combined linkage disequilibrium and linkage analysis (LDLA) using the whole data set. Further analyses were performed for FA and SRB separately to study the origin of the identified QTL/haplotype and to examine if it was common in both populations. Finally, different two‐trait models were fitted. These postulated either a pleiotropic QTL affecting both traits; two linked QTL, each affecting one trait; or one QTL affecting a single trait. A QTL affecting CM was fine‐mapped. In FA, a haplotype having a strong association with a high negative effect on mastitis resistance was identified. The mapping precision of an earlier detected SCS‐QTL was not improved by the LDLA analysis because of lack of linkage disequilibrium between the markers used and the QTL in the region.
Detection of QTL affecting harvest traits in a commercial Atlantic salmon population
Authors: Houston R. D. , Bishop S. C. , Hamilton A. , Guy D. R. , Tinch A. E. , Taggart J. B. , Derayat A. , McAndrew B. J. , Haley C. S.
Published: April 2009

Genetic variation in performance and quality traits measured at harvest has previously been demonstrated in Atlantic salmon aquaculture populations. To map major loci underlying this variation, we utilized data from 10 families from a commercial breeding programme. Significant QTL were detected affecting harvest weight and length traits on linkage group 1, and affecting waste weight on linkage group 5. In total, 11 of the 29 linkage groups examined showed at least suggestive evidence for a QTL. These data suggest that major loci affecting economically important harvest characteristics are segregating in commercial salmon populations.
Human CD80/IL2 lentivirus‐transduced acute myeloid leukaemia (AML) cells promote natural killer (NK) cell activation and cytolytic activity: implications for a phase I clinical study
Authors: Ingram Wendy , Chan Lucas , Guven Hayrettin , Darling David , Kordasti Shahram , Hardwick Nicola , Barber Linda , Mufti Ghulam J. , Farzaneh Farzin
Published: April 2009

Immunotherapeutic strategies may promote T and/or natural killer (NK) cell cytotoxicity. NK cells have the potential to exert a powerful anti‐leukaemia effect, as demonstrated by studies of allogeneic transplantation. We have previously shown that CD80/interleukin 2 (IL2) lentivirus (LV)‐transduced AML cells stimulate in‐vitro T cell activation. The present study demonstrated that allogeneic and autologous culture of peripheral blood mononuclear cells with CD80/IL2‐expressing AML cells also promoted NK cell cytotoxicity. Expression of the activation receptors NKp30, NKp44, CD244, CD25, CD69 and HLA‐DR significantly increased following allogeneic culture and a consistent increased expression of NKp30, NKp44, NKp46, NKG2D, NKG2C and CD69, and up‐regulation of the cytolytic marker CD107a was detected following autologous culture with LV‐CD80/IL2 AML cells. Furthermore, increased NK cell lysis of K562 and primary AML blasts was detected. The lytic activity increased by twofold against K562 (from 46·6% to 90·4%) and allogeneic AML cells (from 11·8% to 20·1%) following in‐vitro stimulation by CD80/IL2‐expressing AML cells. More importantly for potential therapeutic applications, lysis of primary AML cells by autologous NK cells increased by more than 40‐fold (from 0·4% to 22·5%). These studies demonstrated that vaccination of patients with CD80/IL2‐transduced AML cells could provide a powerful strategy for T/NK cell‐mediated stimulation of anti‐leukaemic immunological responses.
The protein kinase C agonist PEP005 increases NF‐κB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells
Authors: Olsnes Astrid Marta , Ersvær Elisabeth , Ryningen Anita , Paulsen Kristin , Hampson Peter , Lord Janet M. , Gjertsen Bjørn Tore , Kristoffersen Einar Klæboe , Bruserud Øystein
Published: April 2009

Acute myeloid leukaemia (AML) cells show constitutive release of several chemokines that occurs in three major clusters: (I) chemokine (C‐C motif) ligand (CCL)2–4/chemokine (C‐X‐C motif) ligand (CXCL)1/8, (II) CCL5/CXCL9–11 and (III) CCL13/17/22/24/CXCL5. Ingenol‐3‐angelate (PEP005) is an activator of protein kinase C and has antileukaemic and immunostimulatory effects in AML. We investigated primary AML cells derived from 35 unselected patients and determined that PEP005 caused a dose‐dependent increase in the release of chemokines from clusters I and II, including several T cell chemotactic chemokines. The release of granulocyte‐macrophage colony‐stimulating factor and hepatocyte growth factor was also increased. CCL2–4/CXCL1/8 release correlated with nuclear factor (NF)‐κB expression in untreated AML cells, and PEP005‐induced chemokine production was associated with further increases in the expression of the NF‐κB subunits p50, p52 and p65. Increased DNA binding of NF‐κB was observed during exposure to PEP005, and the specific NF‐κB inhibitor BMS‐345541 reduced constitutive chemokine release even in the presence of PEP005. Finally, PEP005 decreased expression of stem cell markers (CD117, CXCR4) and increased lineage‐associated CD11b and CD14 expression. To conclude, PEP005 has a unique functional pharmacological profile in human AML. Previous studies have described proapoptotic and T cell stimulatory effects and the present study describes additional T cell chemotactic and differentiation‐inducing effects.
Engineering of major house dust mite allergens Der p 1 and Der p 2 for allergen‐specific immunotherapy
Authors: Asturias J. A. , Ibarrola I. , Arilla M. C. , Vidal C. , Ferrer A. , Gamboa P. M. , Viñuela J. , Sanz M. L. , Andreu C. , Martínez A.
Published: April 2009

Background
Specifically designed recombinant allergens with reduced IgE reactivity are promising candidates for a more defined, effective, and safer specific immunotherapy (SIT).

Objective
We sought to obtain hypoallergenic hybrid molecules which could potentially be applied to house dust mite (HDM) allergy treatment.

Methods
Two hybrid molecules (QM1 and QM2) derived from the two major Dermatophagoides pteronyssinus allergens, Der p 1 and Der p 2, were engineered by PCR, produced in Escherichia coli, and purified. The overall IgE‐binding capacity of the hybrids was compared with their single components by Western blot, specific IgE, skin prick test (SPT), and IgE‐inhibition assays. T cell proliferation assay were performed to confirm their retention of T cell reactivity. Immune responses to the hybrid molecules were studied in BALB/c mice.

Results
The IgE reactivity of both hybrid proteins was strongly reduced as evaluated by in vitro methods. Furthermore, in vivo SPTs performed on 106 HDM‐allergic patients showed that the hybrid proteins had a significantly lower potency to induce cutaneous reactions than the individual components. Hybrid molecules induced higher T cell proliferation responses than those produced by an equimolecular mixture of Der p 1 and Der p 2. Immunization of mice with the hybrid proteins induced Der p 1‐ and Der p 2‐specific IgG, which inhibited the binding of allergic patients' IgE to these natural allergens.

Conclusion
QM1 and QM2 hybrids exhibited less IgE‐binding activity but preserved immunogenicity and fulfilled the basic requirements for hypoallergenic molecules suitable for a future SIT of HDM allergy.
Effects of soil characteristics and human disturbance on tiger beetle oviposition
Authors: CORNELISSE TARA M. , HAFERNIK JOHN E.
Published: April 2009

Abstract 1. Understanding species‐specific habitat requirements is important in insect ecology. Co‐occurrence of closely related species can provide insight into microhabitat segregation. Tiger beetles are well suited for such studies, as they occur in multi‐species assemblages, exhibit species‐specific habitat requirements, and are sensitive to anthropogenic modifications of the environment.

2. This study investigated ovipositional microhabitat choice of two sympatric tiger beetles at Point Reyes National Seashore, California, U.S.A., and evaluates how human activity affects that choice. Cicindela oregona is widespread and common whereas C. hirticollis, an undescribed subspecies, is locally threatened. Laboratory experiments tested oviposition‐site selection of the two species in response to variations in moisture, pH, salinity, and grain size. Field experiments tested larval burrow location in response to experimental shading and experimental human disturbance.

3. Laboratory results indicated that while C. hirticollis females preferred a narrow range of moisture levels and fine sands, C. oregona females had more specific pH and salinity requirements and preferred coarser sands. They also differed in timing of activity. Preferences are probably related to prevention of fungal or bacterial infection and avoidance of desiccation and immersion.

4. In the field, significantly more larval burrows were found under experimental shading for both species. In addition, repeated human compaction of the sand significantly decreased the number of larval burrows.

5. Results suggest that protection of microhabitat, restoration of native plants, and limitation of human traffic are vital in the conservation management of tiger beetles.
Selenite interactions with some particulate organic and mineral fractions isolated from a natural grassland soil
Authors: Coppin F. , Chabroullet C. , Martin‐Garin A.
Published: April 2009

The nature of the main selenium (Se) carrier phases in soil is in debate, with some authors emphasizing the role of minerals, and others the role of organic material. In this study, we address the role of the different soil components in Se sorption by determining its interaction with easily separable and workable fractions of bulk soil. Thus four separated fractions (two organic and two mineral) isolated by size density fractionation from a grassland soil were taken as models for soil Se carrier phases. Two concentrations of selenite were used to estimate its reactivity during experiments. In addition, SEM‐TEM analyses (coupled with EDS) were used to determine the chemical environment of Se sorbed onto the different fractions. The results showed that for the smaller selenite concentration nearly all the fractions gave the same selenite sorption (approximately 99%). For the larger concentration, selenite sorption ranged between 44% (mineral fractions) and 93% (organic fractions), indicating that the sorption capacities of organic fractions were greater than those of mineral fractions. In all soil fractions, elementary analyses and SEM/EDS and TEM/EDS observations revealed that Se sorption and the detection of Se hot spots on the soil particles correlated with the presence of Fe and Al. Although a direct association between Se and organic material could not be excluded, we suggest that Se sorption on organic particles is indirect, mainly resulting from association with surface Fe oxides or clays. These findings question the current view of a direct correlation between organic carbon and Se in natural soil samples.
Non‐homogeneity of variance components from spatially nested sampling of the soil
Authors: Lark R. M. , Corstanje R.
Published: April 2009

Spatially nested sampling and the associated nested analysis of variance by spatial scale is a well‐established methodology for the exploratory investigation of soil variation over multiple, disparate scales. The variance components that can be estimated this way can be accumulated to approximate the variogram. This allows us to identify the important scales of variation, and the general form of the spatial dependence, in order to plan more detailed sampling by design‐based or model‐based methods. Implicit in the standard analyses of nested sample data is the assumption of homogeneity in the variance, i.e. that all variations from sub‐station means at some scale represent a random variable of uniform variance. If this assumption fails then the comparable assumption of stationarity in the variance, which is an important assumption in geostatistics, will also be implausible. However, data from nested sampling may be analysed with a linear mixed model in which the variance components are parameters which can be estimated by residual maximum likelihood (REML). Within this framework it is possible to propose an alternative variance parameterization in which the variance depends on some auxiliary variable, and so is not generally homogeneous. In this paper we demonstrate this approach, using data from nested sampling of chemical and biogeochemical soil properties across a region in central England, and use land use as our auxiliary variable to model non‐homogeneous variance components. We show how the REML analysis allows us to make inferences about the need for a non‐homogeneous model. Variances of soil pH and cation exchange capacity at different scales differ between these land uses, but a homogeneous variance model is preferable to such non‐homogeneous models for the variance of soil urease activity at standard concentrations of urea.
Lax‐Wendroff and Nyström methods for seismic modelling
Authors: Chen Jing‐Bo
Published: April 2009

Lax‐Wendroff and Nyström methods are numerical algorithms of temporal approximations for solving differential equations. These methods provide efficient algorithms for high‐accuracy seismic modeling. In the context of spatial pseudospectral discretizations, I explore these two kinds of methods in a comparative way. Their stability and dispersion relation are discussed in detail. Comparison between the fourth‐order Lax‐Wendroff method and a fourth‐order Nyström method shows that the Nyström method has smaller stability limit but has a better dispersion relation, which is closer to the sixth‐order Lax‐Wendroff method. The structure‐preserving property of these methods is also revealed. The Lax‐Wendroff methods are a second‐order symplectic algorithm, which is independent of the order of the methods. This result is useful for understanding the error growth of Lax‐Wendroff methods. Numerical experiments based on the scalar wave equation are performed to test the presented schemes and demonstrate the advantages of the symplectic methods over the nonsymplectic ones.
Treatment of conflicting dips in the 3D common‐reflection‐surface stack
Authors: Müller Nils‐Alexander
Published: April 2009

The 3D common‐reflection‐surface stack is a tool to simulate zero‐offset sections from the prestack data. In conventional implementations conflicting dip situations, i.e., the contribution of more than one stacking operator per output location, are not taken into account. This leads to stacked sections with fragmentary events and to incomplete sets of stacking parameters. Subsequent applications based on the results of the common‐reflection‐surface stack and its attributes will show deteriorated quality.

In this paper, I present a modified workflow for the handling of the conflicting dip problem in context of the 3D common‐reflection‐surface stack. The strategy utilizes the path‐summation technique to obtain an improved input for the conflicting dip search in the zero‐offset domain. The actual detection is done by means of an adapted peak detection algorithm. For each detected event consistent sets of attributes are obtained by a newly introduced search step.

Two 3D real data applications show the applicability of the proposed technique. The strategy proves to resolve most of the conflicting dip situations even for poor signal‐to‐noise ratio. With only moderate additional computational cost the presented method provides superior results compared to the conventional 3D common‐reflection‐surface stack.
Indirect effects of soil moisture reverse soil C sequestration responses of a spring wheat agroecosystem to elevated CO2
Authors: MARHAN SVEN , KANDELER ELLEN , REIN STEFANIE , FANGMEIER ANDREAS , NIKLAUS PASCAL A.
Published: April 2009

Increased plant productivity under elevated atmospheric CO2 concentrations might increase soil carbon (C) inputs and storage, which would constitute an important negative feedback on the ongoing atmospheric CO2 rise. However, elevated CO2 often also leads to increased soil moisture, which could accelerate the decomposition of soil organic matter, thus counteracting the positive effects via C cycling. We investigated soil C sequestration responses to 5 years of elevated CO2 treatment in a temperate spring wheat agroecosystem. The application of 13C‐depleted CO2 to the elevated CO2 plots enabled us to partition soil C into recently fixed C (Cnew) and pre‐experimental C (Cold) by 13C/12C mass balance. Gross C inputs to soils associated with Cnew accumulation and the decomposition of Cold were then simulated using the Rothamsted C model ‘RothC.’ We also ran simulations with a modified RothC version that was driven directly by measured soil moisture and temperature data instead of the original water balance equation that required potential evaporation and precipitation as input. The model accurately reproduced the measured Cnew in bulk soil and microbial biomass C. Assuming equal soil moisture in both ambient and elevated CO2, simulation results indicated that elevated CO2 soils accumulated an extra ∼40–50 g C m−2 relative to ambient CO2 soils over the 5 year treatment period. However, when accounting for the increased soil moisture under elevated CO2 that we observed, a faster decomposition of Cold resulted; this extra C loss under elevated CO2 resulted in a negative net effect on total soil C of ∼30 g C m−2 relative to ambient conditions. The present study therefore demonstrates that positive effects of elevated CO2 on soil C due to extra soil C inputs can be more than compensated by negative effects of elevated CO2 via the hydrological cycle.
Scale and uncertainty in modeled soil organic carbon stock changes for US croplands using a process‐based model
Authors: OGLE STEPHEN M. , BREIDT F. JAY , EASTER MARK , WILLIAMS STEVE , KILLIAN KENDRICK , PAUSTIAN KEITH
Published: April 2009

Process‐based model analyses are often used to estimate changes in soil organic carbon (SOC), particularly at regional to continental scales. However, uncertainties are rarely evaluated, and so it is difficult to determine how much confidence can be placed in the results. Our objective was to quantify uncertainties across multiple scales in a process‐based model analysis, and provide 95% confidence intervals for the estimates. Specifically, we used the Century ecosystem model to estimate changes in SOC stocks for US croplands during the 1990s, addressing uncertainties in model inputs, structure and scaling of results from point locations to regions and the entire country. Overall, SOC stocks increased in US croplands by 14.6 Tg C yr−1 from 1990 to 1995 and 17.5 Tg C yr−1 during 1995 to 2000, and uncertainties were ±22% and ±16% for the two time periods, respectively. Uncertainties were inversely related to spatial scale, with median uncertainties at the regional scale estimated at ±118% and ±114% during the early and latter part of 1990s, and even higher at the site scale with estimates at ±739% and ±674% for the time periods, respectively. This relationship appeared to be driven by the amount of the SOC stock change; changes in stocks that exceeded 200 Gg C yr−1 represented a threshold where uncertainties were always lower than ±100%. Consequently, the amount of uncertainty in estimates derived from process‐based models will partly depend on the level of SOC accumulation or loss. In general, the majority of uncertainty was associated with model structure in this application, and so attaining higher levels of precision in the estimates will largely depend on improving the model algorithms and parameterization, as well as increasing the number of measurement sites used to evaluate the structural uncertainty.
The impacts of classical insect hormones on the expression profiles of a new digestive trypsin‐like protease (TLP) from the cotton bollworm, Helicoverpa armigera
Authors: Sui Y‐P. , Wang J‐X. , Zhao X‐F.
Published: April 2009

Trypsin proteinases perform important roles in the protein digestion of an insect midgut. A 1042 bp full‐length cDNA was cloned from Helicoverpa armigera. The gene encoded a 32 kDa protein, with a predicted isoelectric point of 5.7. The amino acid sequence of the protein had a trypsin‐like serine protease domain, and the gene was named Ha‐TLP. The expression of the gene was tissue‐specific and the transcript of Ha‐TLP existed only in the midgut and was not found in the head‐thorax, integument, fat body and haemocytes from 5th instar larvae, with similar expression levels between those in feeding larvae and in molting larvae. In the midgut, the gene transcription level declined from 6th instar 72 h after the larvae entered the wandering stage, and disappeared from 6th instar at 96 h until the pupal stage. By immunohistochemistry, Ha‐TLP was detected in the cytoplasm of the midgut epithelial cells of the 6th instar feeding stage worms. The expression of Ha‐TLP could be up‐regulated by a juvenile hormone (JH) analog methoprene and down‐regulated by 20‐hydroxyecdysone (20E). These facts indicate that Ha‐TLP was involved in food digestion during larval growth and probably up‐regulated by JH and suppressed by extra 20E in vivo.
An investigation to determine the nutritional adequacy and individuals experience of a very low fat diet used to treat type V hypertriglyceridaemia
Authors: Whitfield‐Brown L. , Hamer O. , Ellahi B. , Burden S. , Durrington P.
Published: April 2009

Background:  The management of Type V hypertriglyceridaemia at some centres involves the use of a very low fat diet (15% energy as fat). There is no published research examining compliance with, or nutritional adequacy, of this treatment. This study assesses the nutritional adequacy of the diet and examines barriers and enablers to adherence.

Methods:  Fifty‐four eligible patients were invited to take part. Eight males and one female agreed to participate. One male later withdrew. The mean age of participants was 49.4 years (SD 12.9 years), their mean BMI was 30.4 kg m−2 (SD 3.4 kg m−2) and their mean triglyceride level was 8.5 mmol L−1 (SD 5.6 mmol L−1). To assess nutritional adequacy and compliance, 3‐day dietary records and telephone based diet histories were used and analysed using CompEat. Patients’ experience was investigated using semi‐structured telephone based qualitative interviews. Qualitative data was recorded, transcribed and analysed using thematic analysis to allow elucidation of emerging themes.

Results:  Fat accounted for 22.5% of dietary energy and compliance was considered difficult. Barriers included lack of accessible nutritional information, increased patient burden defined as inconvenience and the persistent awareness of potential or actual ill health, lack of appropriate food choices, other peoples’ ignorance, lack of flavour and variety, a desire to broaden the palate, cost, social pressure and prior negative experiences with dietitians. Enablers to compliance included nutritional awareness, desire to maintain good health, building on their nutritional knowledge base, behaviour and lifestyle modification, developing a routine, the support of family and friends and supportive eating environments.

Conclusion:  Compliance could be improved through extensive education on labelling, eating during special occasions such as Christmas, birthdays and eating out.
Determination of the lactose and galactose content of cheese for use in the galactosaemia diet
Authors: Portnoi P. A. , MacDonald A.
Published: April 2009

Background:  Treatment of galactosaemia requires a low galactose diet. In the UK, traditionally, all cheeses have been excluded from the diet, although some types of mature hard cheese are likely to be low in lactose and galactose. The present study aimed to determine the lactose and galactose content of mature cheeses.

Methods:  Over 6 years, the UK Galactosaemia Support Group commissioned the analysis of 109 samples (by two laboratories) of 12 cheese types, in eight batches throughout the year. Cheeses, obtained from retail outlets, were homogenised, sugars were extracted using water or 40% alcohol for fatty samples, and samples were deproteinised. Enzymatic analysis using measuring light absorbance was conducted on filtered extracts.

Results:  Cheeses containing undetectable quantities of lactose (<2.8 mg 100 g−1, Leatherhead Food International, Leatherhead, UK (LFI) analysis; <10 mg 100 g−1, Laboratory of Government Chemist, Teddington, UK (LGC Limited) analysis) and galactose were: Gruyere (five samples); Emmental (block, sliced and grated) (16 samples); Jarlsberg (six samples); Parmigiano Reggiano and Grana Padano Italian Parmesan (block and grated) (16 samples); and mature Cheddar cheese from the UK West Country Farmhouse Cheese Makers Association (35 samples) only. Lactose containing cheeses included other mature Cheddar cheeses, Gouda and Edam.

Conclusions:  Gruyere, Emmental, Jarlsberg, Italian Parmesan (Parmigiano Reggiano and Grana Padano), and mature Cheddar cheese produced in one area of England where the manufacturing process is standardised and guaranteed are now allowed in the UK galactosaemia diet.
Health‐related quality of life in patients with home nutritional support
Authors: Wanden‐Berghe C. , Nolasco A. , Sanz‐Valero J. , Planas M. , Cuerda C. ,   for the Group NADYA‐SENPE
Published: April 2009

Background:  Home nutritional support (HNS) aims to improve or maintain the patient’s quality of life. Given the high social cost of such treatment, however, it is important to investigate whether the perceived quality of life of patients receiving HNS does in fact reflect these objectives. The present study aimed to evaluate the health‐related quality of life (HRQoL) of patients who receive HNS.

Methods:  A multicentre, cross‐sectional study of 267 patients was carried out. HRQoL was evaluated using the EuroQoL‐5‐Dimensions (EQ‐5D) questionnaire. The Visual Analogue Scale (VAS) was used to complement the EQ‐5D, aiming to provide an overall estimation of patient quality of life.

Results:  The EQ‐5D questionnaire showed that 25% of the subjects valued their HRQoL at between −0.08 and 0.15, 50% at between 0.16 and 0.69 and 25% at between 0.70 and 1. Results from the VAS showed that 75% of patients claimed to have a HRQoL > 40. The median for the VAS was 50.

Pathologies were oncological (44.0%), neurological (36.6%) and others (19.3%). The results obtained demonstrate that neurological patients placed a lower value on their HRQoL compared to those of other groups (P < 0.001). In addition, women rated their quality of life lower than men in all pathologies (P = 0.006).

Conclusions:  Perceived HRQoL varied depending on pathology and sex. It was difficult to draw conclusions concerning the impact of HNS because of a lack of baseline data and relevant validated measurement tools. The present study highlights the need for more research into the relationship between HNS and HRQoL.
Epidemic hepatitis C virus infection in Egypt: estimates of past incidence and future morbidity and mortality
Authors: Lehman E. M. , Wilson M. L.
Published: April 2009

Summary.  Hepatitis C virus (HCV) infection is gaining increasing attention as a global health crisis. Egypt reports the highest prevalence of HCV worldwide, ranging from 6% to more than 40% among regions and demographic groups. Predicting the impact of the epidemic has been difficult because of the long‐latency period and low‐resource setting. Accordingly, we sought to estimate historic incidence and predict the future impact of HCV using Markov simulation modelling techniques. Age‐specific HCV incidence rates (IRs) were estimated using previously acquired age‐specific HCV prevalence data. Data for this analysis were from a highly detailed, community‐based seroprevalence study from 2003. Future HCV‐related morbidity and mortality were estimated using a computer cohort simulation of HCV natural history in the Egyptian population. Population and natural history parameters were defined using results from a meta‐analysis and existing comprehensive literature reviews. Incidence model estimates ranged from 2.01 to 25.47 HCV cases per 1000 person‐years (PYs). The highest IRs were calculated among those over 35 years of age. Our Markov model predicted 127 821 deaths from chronic liver disease and 117 556 deaths from hepatocellular carcinoma in Egypt over the next 20 years. During this period, it was estimated that HCV would yield 750 210 PY of decompensated cirrhosis, 132 894 PY of hepatocellular carcinoma, and a total loss of 32.86 million years of life compared to a non‐infected cohort. Our results support the claim of high HCV incidence in Egypt and suggest that HCV may lead to a substantial health and, consequently, economic burden over the next 10–20 years.
AglZ regulates adventurous (A‐) motility in Myxococcus xanthus through its interaction with the cytoplasmic receptor, FrzCD
Authors: Mauriello Emilia M. F. , Nan Beiyan , Zusman David R.
Published: April 2009

Myxococcus xanthus moves by gliding motility powered by type IV pili (S‐motility) and distributed motor complexes (A‐motility). The Frz chemosensory pathway controls reversals for both motility systems. However, it is unclear how the Frz pathway can communicate with these different systems. In this article, we show that FrzCD, the Frz pathway receptor, interacts with AglZ, a protein associated with A‐motility. Affinity chromatography and cross‐linking experiments showed that the FrzCD–AglZ interaction occurs between the uncharacterized N‐terminal region of FrzCD and the N‐terminal pseudo‐receiver domain of AglZ. Fluorescence microscopy showed AglZ–mCherry and FrzCD–GFP localized in clusters that occupy different positions in cells. To study the role of the Frz system in the regulation of A‐motility, we constructed aglZ frzCD double mutants and aglZ frzCD pilA triple mutants. To our surprise, these mutants, predicted to show no A‐motility (A‐S+) or no motility at all (A‐S‐), respectively, showed restored A‐motility. These results indicate that AglZ modulates a FrzCD activity that inhibits A‐motility. We hypothesize that AglZ–FrzCD interactions are favoured when cells are isolated and moving by A‐motility and inhibited when S‐motility predominates and A‐motility is reduced.
Manganese import is a key element of the OxyR response to hydrogen peroxide in Escherichia coli
Authors: Anjem Adil , Varghese Shery , Imlay James A.
Published: April 2009

Very little manganese is imported into Escherichia coli under routine growth conditions: the import system is weakly expressed, the manganese content is low, and a manganese‐dependent enzyme is not correctly metallated. Mutants that lack MntH, the importer, grow at wild‐type rates, indicating that manganese plays no critical role. However, MntH supports the growth of iron‐deficient cells, suggesting that manganese can substitute for iron in activating at least some metalloenzymes. MntH is also strongly induced when cells are stressed by hydrogen peroxide. This adaptation is essential, as E. coli cannot tolerate peroxide stress if mntH is deleted. Other workers have observed that manganese improves the ability of a variety of microbes to tolerate oxidative stress, and the prevailing hypothesis is that manganese does so by chemically scavenging hydrogen peroxide and/or superoxide. We found that manganese does not protect peroxide‐stressed cells by scavenging peroxide. Instead, the beneficial effects of manganese correlate with its ability to metallate mononuclear enzymes. Because iron‐loaded enzymes are vulnerable to the Fenton reaction, the substitution of manganese may prevent protein damage. Accordingly, during H2O2 stress, mutants that cannot import manganese and/or are unable to sequester iron suffer high rates of protein oxidation.
TagR promotes PpkA‐catalysed type VI secretion activation in Pseudomonas aeruginosa
Authors: Hsu FoSheng , Schwarz Sandra , Mougous Joseph D.
Published: April 2009

Type VI secretion systems (T6SSs) contribute to interactions of bacterial pathogens and symbionts with their hosts. Previously, we showed that Pseudomonas aeruginosa T6S is posttranslationally activated upon phosphorylation of Fha1, an FHA domain protein, by PpkA, a membrane‐spanning threonine kinase. Herein, additional structural, enzymatic and genetic requirements for PpkA‐catalysed T6SS activation are identified. We found that PpkA plays an essential structural role in the T6SS, and that this role is intimately linked to its ability to promote secretion and phosphorylate Fha1. Protein localization and protein–protein interaction studies show that a complex containing Fha1 and the T6S ATPase, ClpV1 is recruited to the T6S apparatus in a phosphorylation‐dependent manner. The mechanism of PpkA activation was also investigated. We identified critical PpkA autophosphorylation sites and showed that small molecule‐induced dimerization of the extracellular domains of PpkA is sufficient to activate the T6SS. Finally, we discovered TagR, a component of the T6S posttranslational regulatory pathway that functions upstream of PpkA to promote kinase activity. We present a model whereby an unknown cue causes dimerization of the extracellular domains of PpkA, leading to its autophosphorylation, recruitment of the Fha1‐ClpV1 complex, phosphorylation of Fha1, and T6SS activation. Our findings should facilitate approaches for identifying physiological activators of T6S.
Molecular analysis of restriction endonuclease EcoRII from Escherichia coli reveals precise regulation of its enzymatic activity by autoinhibition
Authors: Szczepek Michal , Mackeldanz Petra , Möncke‐Buchner Elisabeth , Alves Jürgen , Krüger Detlev H. , Reuter Monika
Published: April 2009

Bacterial restriction endonuclease EcoRII requires two recognition sites to cleave DNA. Proteolysis of EcoRII revealed the existence of two stable domains, EcoRII‐N and EcoRII‐C. Reduction of the enzyme to its C‐terminal domain, EcoRII‐C, unleashed the enzyme activity; this truncated form no longer needed two recognition sites and cleaved DNA much more efficiently than EcoRII wild‐type. The crystal structure of EcoRII showed that probably the N‐terminal domain sterically occludes the catalytic site, thus apparently controlling the cleavage activity. Based on these data, EcoRII was the first restriction endonuclease for which an autoinhibition mechanism as regulatory strategy was proposed. In this study, we probed this assumption and searched for the inhibitory element that mediates autoinhibition. Here we show that repression of EcoRII‐C is achieved by addition of the inhibitory domain EcoRII‐N or by single soluble peptides thereof in trans. Moreover, we perturbed contacts between the N‐ and the C‐terminal domain of EcoRII by site‐directed mutagenesis and proved that β‐strand B1 and α‐helix H2 are essential for autoinhibition; deletion of either secondary structural element completely relieved EcoRII autoinhibition. This potent regulation principle that keeps EcoRII enzyme activity controlled might protect bacteria against suicidal restriction of rare unmodified recognition sites in the cellular genome.
FtsN‐like proteins are conserved components of the cell division machinery in proteobacteria
Authors: Möll Andrea , Thanbichler Martin
Published: April 2009

In bacteria, cytokinesis is mediated by a ring‐shaped multiprotein complex, called divisome. While some of its components are widely conserved, others are restricted to certain bacterial lineages. FtsN is the last essential cell division protein to localize to the division septum in Escherichia coli and is poorly conserved outside the enteric bacteria. We have identified a homologue of FtsN in the α‐proteobacterium Caulobacter crescentus and show that it is essential for cell division. C. crescentus FtsN is recruited to the divisome significantly after cell division initiates and remains associated with the new cell poles after cytokinesis is finished. All determinants necessary for localization and function are located in a largely unstructured periplasmic segment of the protein. Its conserved SPOR‐domain, by contrast, is dispensable for cytokinesis, although it supports targeting of FtsN to the division site. Interestingly, the SPOR‐domain is recruited to the division plane when produced in isolated form and retains its localization potential in a heterologous host background. Searching for proteins that share the characteristic features of FtsN from E. coli and C. crescentus, we identified FtsN‐like cell division proteins in β‐ and δ‐proteobacteria, suggesting that FtsN is widespread among bacteria, albeit highly variable at the sequence level.
Prevalence and risk factors for anaemia in pregnant women: a population‐based prospective cohort study in China
Authors: Zhang Qiaoyi , Li Zhu , Ananth Cande V.
Published: April 2009

Maternal anaemia is a common pregnancy complication in developing countries; however, its epidemiology remains largely unexplored in China. This study was designed to explore the epidemiology and risk factors of anaemia during pregnancy. A prospective cohort study was conducted, using data from a population‐based pregnancy‐monitoring system in 13 counties in East China (1993–96). Women who delivered singleton infants at 20–44 weeks with at least one haemoglobin assessment during pregnancy were included (n = 164 667). The prevalence of anaemia (haemoglobin < 10 g/dL) during pregnancy as well as in each trimester was estimated. Multivariable log‐binomial regression models were used to evaluate risk factors.

The overall prevalence of anaemia in pregnancy was 32.6%, with substantial variations across trimesters (11.2%, 20.1% and 26.2% in the 1st, 2nd and 3rd trimesters respectively). Risk factors for anaemia included older maternal age, education below junior high school (prevalence rate ratio [RR] 1.10, 95% confidence interval [CI] 1.08, 1.12), farming occupation (1.05, 95% CI 1.03, 1.06), and mild pregnancy‐induced hypertension (PIH) (RR 1.09, 95% CI 1.05, 1.13) and severe PIH (RR 1.13, 95% CI 1.06, 1.19). Peri‐conception folic acid use was associated with a reduced risk for anaemia in the 1st trimester (RR 0.75, 95% CI 0.72, 0.78). Initiating prenatal care after the 1st trimester was associated with increased risk of anaemia in the 2nd and 3rd trimesters. Our study found anaemia during pregnancy is highly prevalent in this indigenous Chinese population. The risk increases with the severity of hypertensive disorders. Folic acid supplementation during the peri‐conception period is associated with reduced risk of 1st trimester anaemia.
Maternal obesity in pregnancy and respiratory health in early childhood
Authors: Håberg Siri E. , Stigum Hein , London Stephanie J. , Nystad Wenche , Nafstad Per
Published: April 2009

Obesity is associated with systemic inflammation, immunological changes, increased risk of respiratory infections and chronic respiratory illness. Maternal obesity in pregnancy increases the risk of pregnancy complications, caesarean sections and adverse birth outcomes, which have in turn been associated with respiratory illness in children. To our knowledge, the possible influence of maternal obesity in pregnancy on respiratory illness in early childhood beyond the newborn period has not been explored. We examined the relationship between a high maternal body mass index (BMI) in pregnancy and lower respiratory tract infections and wheeze up to 18 months of age in the Norwegian Mother and Child Study (MoBa), a population‐based cohort study that includes 100 000 pregnant women, conducted at the Norwegian Institute of Public Health. We analysed data from the first 33 192 children, born between 1999 and 2005.

In unadjusted analyses maternal obesity in pregnancy was related to both respiratory infections and wheeze in the children. In multivariable analyses, only an effect on wheeze remained. The risk of wheeze increased linearly with maternal BMI in pregnancy, and was 3.3% higher [95% CI 1.2, 5.3] for children with mothers who were obese during pregnancy, than for children of mothers with normal BMI. This effect was not mediated through obesity‐related pregnancy complications, low birthweight, preterm birth or caesarean section.