bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixtures of common t-factor analyzers for clustering high-dimensional microarray data
Authors: Baek Jangsun , McLachlan Geoffrey J.
Published: March 2011

Motivation: Mixtures of factor analyzers enable model-based clustering to be undertaken for high-dimensional microarray data, where the number of observations n is small relative to the number of genes p. Moreover, when the number of clusters is not small, for example, where there are several different types of cancer, there may be the need to reduce further the number of parameters in the specification of the component-covariance matrices. A further reduction can be achieved by using mixtures of factor analyzers with common component-factor loadings (MCFA), which is a more parsimonious model. However, this approach is sensitive to both non-normality and outliers, which are commonly observed in microarray experiments. This sensitivity of the MCFA approach is due to its being based on a mixture model in which the multivariate normal family of distributions is assumed for the component-error and factor distributions.

Results: An extension to mixtures of t-factor analyzers with common component-factor loadings is considered, whereby the multivariate t-family is adopted for the component-error and factor distributions. An EM algorithm is developed for the fitting of mixtures of common t-factor analyzers. The model can handle data with tails longer than that of the normal distribution, is robust against outliers and allows the data to be displayed in low-dimensional plots. It is applied here to both synthetic data and some microarray gene expression data for clustering and shows its better performance over several existing methods.

Availability: The algorithms were implemented in Matlab. The Matlab code is available at http://blog.naver.com/aggie100.

Contact:  jbaek@jnu.ac.kr

Supplementary information:  Supplementary data are available at Bioinformatics online.
The effect of shear on acoustic cloaking
Authors: Smith John D. , Verrier Patricia E.
Published: March 2011

The effect of a non-zero shear modulus on two-dimensional acoustic cloaking based on the transformation technique is investigated. Using the method of multiple scales, approximate solutions are found to the elastic equations with anisotropic density when the ratio of the shear modulus to the bulk modulus is small. These solutions indicate that a non-zero shear modulus causes the cloaking effect to become limited to a band of frequency, which becomes wider as the shear modulus is reduced. Resonances associated with shear waves are seen in the tangential component of displacement but do not affect the scattering to first order in the asymptotic expansions. No finite solutions exist for the case when the transformation shrinks the cloaked object to zero size (perfect cloaking).
Allopatric distribution and diversification without niche shift in a bryophyte-feeding basal moth lineage (Lepidoptera: Micropterigidae)
Authors: Imada Yume , Kawakita Atsushi , Kato Makoto
Published: March 2011

The Lepidoptera represent one of the most successful radiations of plant-feeding insects, which predominantly took place within angiosperms beginning in the Cretaceous period. Angiosperm colonization is thought to underlie the evolutionary success of the Lepidoptera because angiosperms provide an enormous range of niches for ecological speciation to take place. By contrast, the basal lepidopteran lineage, Micropterigidae, remained unassociated with angiosperms since Jurassic times but nevertheless achieved a modest diversity in the Japanese Archipelago. We explored the causes and processes of diversification of the Japanese micropterigid moths by performing molecular phylogenetic analysis and extensive ecological surveying. Phylogenetic analysis recovered a monophyletic group of approximately 25 East Asian endemic species that feed exclusively on the liverwort
Conocephalum conicum
, suggesting that niche shifts hardly played a role in their diversification. Consistent with the low flying ability of micropterigid moths, the distributions of the
Conocephalum
specialists are each localized and allopatric, indicating that speciation by geographical isolation has been the major process shaping the diversity of Japanese Micropterigidae. To our knowledge, this is the largest radiation of herbivorous insects that does not accompany any apparent niche differentiation. We suggest that the significance of non-ecological speciation during the diversification of the Lepidoptera is commonly underestimated.
The lipopolysaccharide of the mastitis isolate Escherichia coli strain 1303 comprises a novel O-antigen and the rare K-12 core type
Authors: Duda Katarzyna A. , Lindner Buko , Brade Helmut , Leimbach Andreas , Brzuszkiewicz Elżbieta , Dobrindt Ulrich , Holst Otto
Published: March 2011

Mastitis represents one of the most significant health problems of dairy herds. The two major causative agents of this disease areEscherichia coliandStaphylococcus aureus. Of the first, its lipopolysaccharide (LPS) is thought to play a prominent role during infection. Here, we report the O-antigen (OPS, O-specific polysaccharide) structure of the LPS from bovine mastitis isolateE. coli1303. The structure was determined utilizing chemical analyses, mass spectrometry, and 1D and 2D NMR spectroscopy methods. The O-repeating unit was characterized as -[→4)-β-d-Quip3NAc-(1→3)-α-l-Fucp2OAc-(1→4)-β-d-Galp-(1→3)-α-d-GalpNAc-(1→]- in which theO-acetyl substitution was non-stoichiometric. The nucleotide sequence of the O-antigen gene cluster ofE. coli1303 was also determined. This cluster, located between thegndandgalFgenes, contains 13 putative open reading frames, most of which represent unknown nucleotide sequences that have not been described before. The O-antigen ofE. coli1303 was shown to substitute O-7 of the terminalld-heptose of the K-12 core oligosaccharide. Interestingly, the non-OPS-substituted core oligosaccharide represented a truncated version of the K-12 outer core – namely terminalld-heptose and glucose were missing; however, it possessed a third Kdo residue in the inner core. On the basis of structural and genetic data we show that the mastitis isolateE. coli1303 represents a new serotype and possesses the K-12 core type, which is rather uncommon among human and bovine isolates.
Characterization of nuclear localization signals in the type III effectors HsvG and HsvB of the gall-forming bacterium Pantoea agglomerans
Authors: Weinthal Dan M. , Barash Isaac , Tzfira Tzvi , Gaba Victor , Teper Doron , Sessa Guido , Manulis-Sasson Shulamit
Published: March 2011

HsvG and HsvB, two paralogous type III effectors of the gall-forming bacteria Pantoea agglomerans pv. gypsophilae and P. agglomerans pv. betae, determine host specificity on gypsophila and beet, respectively. They were previously shown to be DNA-binding proteins imported into host and non-host nuclei and might act as transcriptional activators. Sequence analysis of these effectors did not detect canonical nuclear localization signals (NLSs), but two basic amino acid clusters designated putative NLS1 and NLS2 were detected in their N-terminal and C-terminal regions, respectively. pNIA assay for nuclear import in yeast and bombardment of melon leaves with each of the NLSs fused to a 2xYFP reporter indicated that putative NLS1 and NLS2 were functional in transport of HsvG into the nucleus. A yeast two-hybrid assay showed that HsvB, HsvG, putative NLS1, putative NLS2, HsvG converted into HsvB, or HsvB converted into HsvG by exchanging the repeat domain, all interacted with AtKAP-α and importin-α3 of Arabidopsis thaliana. Deletion analysis of the NLS domains in HsvG suggested that putative NLS1 or NLS2 were required for pathogenicity on gypsophila cuttings and presumably for import of HsvG into the nucleus. This study demonstrates the presence of two functional NLSs in the type III effectors HsvG and HsvB.
Preparation of Meiotic Chromosomes from Adult Drosophila Testes
Authors: Bonaccorsi Silvia , Giansanti Maria G. , Cenci Giovanni , Gatti Maurizio
Published: March 2011

INTRODUCTION

Several techniques have been developed for the preparation of Drosophila male meiotic chromosomes. All of these techniques allow a clear visualization of chromosomes, but not of other cellular structures such as the cytoskeleton and the spindle. The protocol described here is particularly useful for the analysis of adult testes.
Sonoporation for Gene Transfer into Embryos
Authors: Ohta Sho , Yukiko Ogino , Suzuki Kentro , Kamimura Mika , Tachibana Katsuro , Yamada Gen
Published: March 2011

INTRODUCTION

Sonoporation is a method for the introduction of genes into tissues such as those of chick embryos. It enables gene incorporation into target tissue by the combination of ultrasound exposure and subsequent rupture of microbubbles. Sonoporation has several advantages: (1) It is simple, involving two main steps—preparation of a microbubble–DNA mixture, followed by injection and ultrasound treatment of the target tissue; (2) it allows highly efficient gene incorporation into mesenchymal tissues; (3) it does not induce significant tissue damage—most of the sonoporated chick embryos survived without showing significant embryonic abnormalities or cell death; and (4) it can be used to introduce genes into several chick embryonic tissues (e.g., branchial arch and lateral plate mesoderm). To demonstrate the utility of sonoporation, an expression vector containing the Sonic hedgehog (Shh) gene was incorporated into the developing chick limb bud, leading to additional digit formation in the Shh-expressing embryos. Sonoporation may not be appropriate for the introduction of genes into tissues with cavitated or open structures. Sonoporation into the neural tube and limb ectoderm often resulted in dispersed gene expression due to diffusion of the injected microbubbles before ultrasound treatment. Despite these problems, sonoporation is a useful method for the analysis of gene function(s) in vivo and brings a new area of gene transfer to medical, molecular, and developmental biology. This protocol describes the use of sonoporation to introduce vectors into embryonic chick limb bud.
Liposome-Mediated Transfection
Authors: Dean David A. , Gasiorowski Joshua Z.
Published: March 2011

INTRODUCTION

The efficient delivery of exogenous DNA to cells for expression and function studies is an essential technique of modern cell biology. Cationic liposomes are the most widely used class of carrier for transfection and a number of products are available commercially: Lipofectin (a 1:1 mixture of DOTMA [N-[1(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride] and DOPE [dioleoyl phosphatidylethanolamine]), Transfectam, and DOTAP [1,2-dioleoyloxy-3-trimethylammonium propane]:DOPE. However, all these reagents are costly; it can be less expensive to purchase purified lipids and formulate homemade transfection reagents by adding equimolar amounts of each lipid suspended in chloroform, mixing, and drying under inert gas. The reagents can be stored until they are reconstituted in an appropriate buffer. Although each manufacturer provides detailed instructions for the use of its reagent, the following general steps are used for essentially all formulations; times, concentrations, and volumes might differ slightly. The following volumes are sufficient for transfecting a 35-mm dish or one well of a six-well dish.
Immunogenic enhancement and clinical effect by type‐I interferon of anti‐apoptotic protein, survivin‐derived peptide vaccine, in advanced colorectal cancer patients
Authors: Kameshima Hidekazu , Tsuruma Tetsuhiro , Torigoe Toshihiko , Takahashi Akari , Hirohashi Yoshihiko , Tamura Yasuaki , Tsukahara Tomohide , Ichimiya Shingo , Kanaseki Takayuki , Iwayama Yuji , Sato Noriyuki , Hirata Koichi
Published: March 2011

We previously identified a human leukocyte antigen (HLA)‐A24‐restricted antigenic peptide, survivin‐2B80‐88, recognized by CD8+ cytotoxic T lymphocytes (CTL). Subsequently, we attempted clinical trials with this epitope peptide alone for some malignancies, resulting in clinical and immunological responses, although their potential was not strong enough for routine clinical use as a cancer vaccine. In the current study, to assess whether immunogenicity of the survivin‐2B80‐88 peptide could be enhanced with other vaccination protocols, we performed clinical trials in advanced colon cancer patients with two vaccination protocols: (i) survivin‐2B80‐88 plus incomplete Freund’s adjuvant (IFA); and (ii) survivin‐2B80‐88 plus IFA and a type‐I interferon (IFN), IFNα. Our data clearly indicated that, although the effect of survivin‐2B80‐88 plus IFA was not significantly different from that with survivin‐2B80‐88 alone, treatment with the vaccination protocol of survivin‐2B80‐88 plus IFA and IFNα resulted in clinical improvement and enhanced immunological responses of patients. Tetramer analysis of survivin‐2B80‐88 peptide‐specific CTL demonstrated that such CTL were increased at least twofold after vaccination with this protocol in four of eight patients. In these patients, enzyme‐linked immunosorbent spot (ELISPOT) results were also enhanced. Subsequent study of single‐cell clone separation by cell sorting of peptide‐specific CTL showed that each CTL clone was indeed not only peptide‐specific but also cytotoxic against human cancer cells in the context of the expression of both HLA‐A24 and survivin molecules. Taken together, these results indicate that vaccination of colon cancer patients with survivin‐2B80‐88 plus IFA and IFNα can be considered to be a very potent immunotherapeutic regimen, and that this protocol might work for other cancers. (Cancer Sci 2011; 102: 1181–1187)
Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition
Authors: Li Xiaoyan , Kong Xiaoli , Huo Qiang , Guo Haiyang , Yan Shi , Yuan Cunzhong , Moran Meena S. , Shao Changshun , Yang Qifeng
Published: March 2011

The epithelial–mesenchymal transition (EMT) is a process in which polarized epithelial cells are converted into motile mesenchymal cells. During cancer development, EMT is conducive to tumor dissemination and metastatic spread. While overexpression of metadherin (MTDH) in breast cancer cell lines and tissues has been found to be associated with aggressive tumor behavior, its precise role in invasion and metastasis is largely unknown. Here we report that MTDH overexpression could significantly enhance the invasion and migration of breast cancer cells by inducing EMT. Metadherin overexpression led to upregulation of mesenchymal marker fibronectin, downregulation of epithelial marker E‐cadherin, and the nuclear accumulation of beta‐catenin. Also, transcription factors Snail and Slug were upregulated in breast cancer cells overexpressing MTDH. Overexpression of MTDH enhanced the invasiveness and migration ability of breast cancer cells in vitro. In addition, overexpression of MTDH led to increased acquisition of CD44+/CD24−/low markers that are characteristic of breast cancer stem cells. We also showed that NF‐kappa was involved in the expression of EMT‐related markers. Taken together, our results suggest that MTDH could promote EMT in breast cancer cells in driving the progression of their aggressive behavior. (Cancer Sci 2011; 102: 1151–1157)
Clinicopathological features of 171 cases of primary thyroid lymphoma: a long‐term study involving 24 553 patients with Hashimoto’s disease
Authors: Watanabe Natsuko , Noh Jaeduk Y. , Narimatsu Hiroto , Takeuchi Kengo , Yamaguchi Takuhiro , Kameyama Kaori , Kobayashi Kazuhiko , Kami Masahiro , Kubo Atsushi , Kunii Yo , Shimizu Taeko , Mukasa Koji , Otsuka Fumiko , Miyara Ayako , Minagawa Akinobu , Ito Koichi , Ito Kunihiko
Published: March 2011

There are few large‐scale reports of primary thyroid lymphoma (PTL). This study clinically and pathologically reviewed 171 patients with PTL and 24 553 patients with Hashimoto’s disease at Ito Hospital between January 1990 and December 2004, to investigate the clinical features and the treatment outcomes of PTL. The median age of the patients with PTL was 67 years (range, 27–90 years). The pathological diagnosis of PTL patients included diffuse large B‐cell lymphoma (DLBCL) (n = 74), DLBCL with mucosa‐associated lymphoid tissue (MALT) lymphoma (n = 13), MALT lymphoma (n = 80) and others (n = 4). Of the 167 patients with B‐cell lymphoma, treatment included combined modality therapy (CMT) (n = 95), radiation therapy (RT) alone (n = 60) and chemotherapy alone (n = 6). Information on treatment was not available in six patients. Information on treatment response was available in 154 patients; 149 patients (97%) responded to treatment. According to the institutional treatment strategy of Ito Hospital, 45 of 54 patients with stage IE disease received RT alone, and 87 of 113 stage IIE patients received CMT. The 5‐year overall survival rate was 85% (95% confidence interval, 79–91%). This study demonstrated that PTL showed good response to radiotherapy and chemotherapy and had a favourable prognosis.
Interaction of Vasopressins and Linear N‐Terminal ACTH Fragments in the Induction of Natriuresis
Authors: Cort J. , Nováková J. , ŝkopková J. , Cort J. H.
Published: March 2011

Abstract. Because a) a mixture of alpha‐melanotropin (MSH) and corticotropin (1–13)‐tridecapeptide (1–13 ACTH) has apparently been isolated from natriuretic fractions of posterior pituitary which also contained arginine‐vasopressin, and b) the natriuretic activity of the isolated fraction was greater than that of any of the above three peptides (synthetic) given separately, possible interaction was studied with model substances in the chloralosed cat preparation. It was found that with both alpha‐MSH and lysine‐vasopressin, extracted samples were more natriuretic than synthetic samples despite an equivalence of pressor activities. When combined with arginine‐vasopressin in one injectate, synthetic alpha‐MSH, 1–4 ACTH, 1–13 ACTH‐amide and 1–18 ACTH all showed potentiation of natriuretic activities with no effect on pressor activity. This effect was not shown by synthetic 4–10 ACTH and 5–18 ACTH, or by extracted alpha‐MSH. It was concluded that the 1–4 sequence Ser‐Tyr‐Ser‐Met, regardless of whether the N‐terminal is free or blocked, can potentiate the natriuretic action of vasopressin.
Pharmacokinetic study of minipooled solvent/detergent‐filtered cryoprecipitate factor VIII
Authors: EL‐EKIABY M. , GOUBRAN H. A. , RADOSEVICH M. , ABD‐ALLAH A. , EL‐EKIABY A. , BURNOUF T.
Published: March 2011

Summary.  Eighteen cryoprecipitate minipools, each made of 30 units of low volume, concentrated cryoprecipitate, have been treated by solvent‐detergent and filtration (S/D‐F) in a single‐use CE‐marked bag system. The S/D‐F cryoprecipitate contained a mean of 10.5 IU mL−1 factor VIII (FVIII), 17 mg mL−1 clottable fibrinogen, and >10 IU mL−1 von Willebrand factor ristocetin co‐factor, and anti‐A and anti‐B isoagglutinins were undetectable. The products have been infused in 11 severe (FVIII <1%) haemophilia A patients (mean age: 17.4 years; mean weight: 57.6 kg) at a dose close to 40 IU kg−1. Patients were hospitalized for at least 36 h to determine FVIII recovery, half‐life and clearance. They were also closely monitored for possible adverse events. None of the infused patients demonstrated reactions or adverse events even though they did not receive anti‐allergic drugs or corticosteroids prior to infusion. The mean recovery of FVIII 10 min postinfusion was 69.7%. Mean FVIII half‐life was 14.2 h and clearance was 2.6 mL h−1 kg−1. All patients had a bleeding‐free interval of 8–10 days postS/D‐F cryoprecipitate infusion. The data show that S/D‐F cryoprecipitate FVIII presents a normal pharmacokinetics profile, and support that it could be safely used for the control of acute and chronic bleeding episodes in haemophilia A patients.
Social rehabilitation in long‐term conditions: learning about the process
Authors: Portillo Mari Carmen , Cowley Sarah
Published: March 2011

portillo m.c. & cowley s. (2011) Social rehabilitation in long‐term conditions: learning about the process. Journal of Advanced Nursing67(6), 1329–1340.

Aim.  This paper is a report of a study of the process of social rehabilitation, and the analysis of the main elements and influencing factors which are important in the process.

Background.  The process of social rehabilitation lacks conceptual and empirical understanding in Neurology because most rehabilitation programmes have focused on cognitive and physical recovery.

Methods.  An action research project was undertaken in two neurological wards of a highly specialized hospital in Spain, and was completed in 2006. A social rehabilitation programme based on the assessment of social needs and individualized social education was planned with health professionals, and implemented and evaluated with patients and carers. Several instruments were used to explore how patients and carers perceived the process of social rehabilitation before and after the programme: semi‐structured interviews, socio‐demographic forms, field notes, participant observations, and scales of activities of daily living, social impairment and adjustment. Comparative content and statistical analyses were undertaken.

Findings.  Social rehabilitation was identified as a dynamic process in which the environment, activities, social interaction, self‐recognition and awareness of social problems, coping and satisfaction played an essential role. Some defining criteria for social rehabilitation related to patients’ and carers’ attitudes, behaviour and the external implications that the socialization process had for them.

Conclusion.  This study shows the advantages of multidisciplinary work, and user and family involvement in social rehabilitation and provides in‐depth knowledge about how patients and carers experience and could face barriers to develop a role in their family environment, social groups and society.
Making DNA without iron – induction of a manganese‐dependent ribonucleotide reductase in response to iron starvation
Authors: Andrews Simon C.
Published: March 2011

Ribonucleotide reductases supply cells with their deoxyribonucleotides. Three enzyme types are known, classes I, II and III. Class II enzymes are anaerobic whereas class I enzymes are aerobic, and so class I and II enzymes are often produced by the same organism under opposing oxygen regimes. Escherichia coli contains two types of class I enzyme (Ia and Ib) with the Fe‐dependent Ia enzyme (NrdAB) performing the major role aerobically, leaving the purpose of the Ib enzyme (NrdEF) unclear. Several papers have recently focused on the class Ib enzymes showing that they are Mn (rather than Fe) dependent and suggesting that the E. coli NrdEF may function under redox‐stress conditions. A paper published in this issue of Molecular Microbiology from James Imlay's group confirms that this unexplained NrdEF Ib enzyme is Mn‐dependent, but shows that it does not substitute for NrdAB during redox stress. Instead, a role during iron restriction is demonstrated. Thus, the purpose of NrdEF (and possibly other class Ib enzymes) is to enhance growth under aerobic, low‐iron conditions, and to functionally replace the Fe‐dependent NrdAB when iron is unavailable. This finding reveals a new mechanism by which bacteria adjust to life under iron deprivation.
The protective shell: sclereids and their mechanical function in corollas of some species of Camellia (Theaceae)
Authors: Zhang W. , Wang X.‐Q. , Li Z.‐Y.
Published: March 2011

Studies of rain‐wash effects on pollen have shown that flower structures can protect susceptible pollen from rain. It remains unclear, however, how a thin corolla can withstand external force and perform its protective function. The sclereids in petals of several species of Camellia (Theaceae) were anatomically investigated to determine their mechanical properties. To examine the effects of changing physical environment on the occurrence of sclereids in petals, sclereid density in petals of six species, including wild samples from different rainfall zones and samples from a greenhouse under mild conditions without wind and rain, were examined and statistically analysed. The results showed that the occurrence of sclereids in petals varied with physical environment. The number of sclereids in the same species increased with the increasing rainfall. There were abundant sclereids in petals of the wild species, but few or no sclereids in species cultivated in the greenhouse. Moreover, the anatomical features of sclereids, especially the unique distribution pattern that has not hitherto been described, were correlated with external environmental pressures. Our observations reveal a novel mechanical system in the corolla and provide further evidence for the hypothesis that flower structures may protect rain‐susceptible pollen.
Decreased structural defence of an invasive thistle under warming
Authors: Zhang R. , Leshak A. , Shea K.
Published: March 2011

Plant structural defences play a key role in preventing fitness loss due to herbivory. However, how structural defences are affected by potential climate change is rarely examined. We examined how leaf morphological traits that relate to the structural defence of an invasive thistle, Carduus nutans, change in a warmer climate. We manipulated warming using open‐top chambers (OTCs) and examined the morphology of leaves at three different positions (the 5th, 10th and 15th leaves, counted from the top of the plant) in two destructive summer censuses. We found that structural defence traits were different under ambient versus warmed conditions. Prickle densities (both the number of prickles per leaf area and the number of prickles per leaf mass) were significantly lower in plants grown in a warmer climate. Our results suggest that plant structural defences may be reduced under warming, and therefore should be considered when examining species’ responses to climate change.
Langerhans cells in anaplastic Kaposi sarcoma with a paucivascular phenotype: A potential diagnostic pitfall
Authors: Ramdial Pratistadevi K. , Sing Yetish , Naicker Shaun , Calonje Eduardo , Sewram Vikash , Singh Bhugwan
Published: March 2011

Anaplastic Kaposi sarcoma (AKS), a rare variant of Kaposi sarcoma, has a poorly recognized histomorphologic spectrum, including a paucivascular phenotype, that mimics a range of undifferentiated malignancies. This study, that highlights the hitherto undocumented phenomenon of S100‐protein‐positive Langerhans cells (SLCs) as a potential diagnostic pitfall in paucivascular AKS, involved review of nine such AKS that required diagnostic immunohistochemical (IHC) work‐up. All biopsies had a predominant or exclusive spindle or epithelioid cell infiltrate. The first three tumors were diagnosed as malignant peripheral nerve sheath tumor (2) and metastatic melanoma (1), based on S100‐protein immunopositivity. Biopsy of a co‐existent pigmented sole lesion (patient 3) demonstrated nodular KS. Subsequent IHC investigation of these three tumors demonstrated an endothelial phenotype and HHV8 immunopositivity, confirming AKS. CD1a and langerin staining of the S100‐protein‐positive cells confirmed Langerhans cells as the cause of the diagnostic pitfall. Subsequently, six further paucivascular AKS with intratumoral SLCs were recognized on histomorphological and IHC appraisal. In conclusion, heightened awareness of the histomorphologic spectrum, appropriate IHC investigation, and informed appraisal thereof, are critical to the diagnosis of AKS with an undifferentiated phenotype, and the avoidance of IHC pitfalls, such as those caused by under‐recognition and misinterpretation of bystander SLCs in AKS.
Development of a genetic system for the moderately halophilic bacterium Halobacillus halophilus: generation and characterization of mutants defect in the production of the compatible solute proline
Authors: Köcher Saskia , Averhoff Beate , Müller Volker
Published: March 2011

A procedure for markerless mutagenesis gene deletions was developed for the moderately halophilic model strain Halobacillus halophilus. Gene transfer was achieved by protoplast fusion and allelic replacement by a two‐step procedure. In the first step the non‐replicating plasmid integrated over the upstream or the downstream region of the target gene or operon into the chromosome to obtain single‐crossover mutants. When cells were grown under non‐selective conditions a second homologous recombination happened (segregation). This resulted in either the wild‐type or the mutated allele. The method was used to delete the proHJA operon from H. halophilus. The mutant still produced proline and thus was not proline auxotroph but it completely lost the ability to produce proline as a compatible solute. However, growth was not impaired and the loss of the solute proline was compensated for by an increase in glutamate, glutamine and ectoine concentration. Expressions of the genes encoding the biosynthesis enzymes of theses solutes were upregulated and the activity of the key enzyme in glutamine biosynthesis, the glutamine synthetase, was increased. A model for the proline biosynthesis in the ΔproHJA mutant is discussed.
Facilitating disaster preparedness through local radio broadcasting
Authors: Romo‐Murphy Eila , James Ross , Adams Mike
Published: March 2011

The 2008 Disaster Mitigation Preparedness (DMP) study took place in Aceh province, Indonesia. It sought to help develop radio programmes and messages to increase resilience to disasters. The role of radio was evaluated during and after the 2004 Asian tsunami disaster. The study team interviewed 984 tsunami survivors from nine sub‐districts of Banda Aceh, and local nongovernmental organisations convened eight focus groups around the area of Aceh Besar. Six key informant interviews were held with government disaster management agencies. The DMP survey is the first of its kind to interview a representative random sample of Banda Aceh residents. It reveals the importance of community and social networks, during disaster situations, when essential communications are down. A disaster warning information system based on a multi‐media approach needs to be developed. The wider community should be involved in the planning, education and training of Banda Aceh and Aceh Besar residents to facilitate appropriate personal and community survival strategies.
Human resources for health through conflict and recovery: lessons from African countries
Authors: Pavignani Enrico
Published: March 2011

A protracted conflict affects human resources for health (HRH) in multiple ways. In most cases, the inflicted damage constitutes the main obstacle to health sector recovery. Interventions aimed at healing derelict human resources are however fraught with difficulties of a political, technical, financial and administrative order. The experience accumulated in past recovery processes has made some important players aware of the cost incurred by neglecting human resource development. Several transitions from conflict to peace have been documented, even if largely in unpublished reports. This paper presents condensed descriptions of some African HRH‐related recovery processes, which provide useful lessons. The technical work demanded to resuscitate a derelict health workforce is fairly well understood. In most situations, the highest hurdles lie outside of the health domain, and are of a political and administrative nature. Success stories are rare. But useful lessons are taught by failure as well as by success.
The burden of cardiovascular disease associated with high body mass index in the Asia–Pacific region
Authors: Lee C. M. Y. , Colagiuri S. , Ezzati M. , Woodward M.
Published: March 2011

Studying obesity in the Asia–Pacific region is difficult because of the diverse ethnic background and different stages of economic and nutrition transition. The burden of cardiovascular disease associated with overweight (defined as body mass index ≥25 kg m−2) was previously estimated for countries within the region. However, using the conventional cut‐point of 25 kg m−2 ignores the continuous association between body mass index and cardiovascular disease from approximately 20 kg m−2. By estimating the proportion of cardiovascular disease that would be prevented if the theoretical mean body mass index in the population was shifted to 21 kg m−2, nationally representative data from 15 countries suggested the population attributable fractions for cardiovascular disease were approximately three times higher than the previous estimates. Coronary heart disease attributable to body mass index other than 21 kg m−2 ranged from 2% in India to 58% in American Samoa. Similarly, the population attributable fraction for ischaemic stroke ranged from 3% in India to 64% in American Samoa. If cardiovascular risk increases from 21 kg m−2 applies to all populations, most countries in the region will need to aim towards substantially reducing their current population mean body mass index in order to lower the burden of cardiovascular disease associated with excess weight.
Preventing chronic diseases by promoting healthy diet and lifestyle: public policy implications for China
Authors: Hu F. B. , Liu Y. , Willett W. C.
Published: March 2011

Fuelled by rapid urbanization and changes in dietary and lifestyle choices, chronic diseases have emerged as a critical public health issue in China. The Healthy China 2020 programme recently announced by the Chinese government has set an overarching goal of promoting public health and making health care accessible and affordable for all Chinese citizens by year 2020. One of important components of the programme is to reduce chronic diseases by promoting healthy eating and active lifestyles. Chronic diseases not only affect health and quality of life, but also have economical and social consequences. With a limited infrastructure for chronic disease care, China is ill‐equipped to deal with the escalating chronic disease epidemic, which threatens to reverse the gains of economic development in recent decades. Population‐based intervention studies conducted in China and elsewhere have demonstrated the efficacy and effectiveness of several preventive strategies to reduce risk of chronic diseases in high‐risk individuals and the general population. However, translating these findings into practice requires changes in health systems and public policies. To achieve the goals set by the Healthy China 2020 programme, prevention of chronic diseases should be elevated to a national public policy priority.
College students' intentions to use e‐portfolios: From the perspectives of career‐commitment status and weblog‐publication behaviours
Authors: Tzeng Jeng‐Yi , Chen Ssu‐Han
Published: March 2011

The growing popularity of a school‐wide e‐portfolio system in colleges and universities has raised concerns regarding whether students will use it or consider it important to have an e‐portfolio system, especially when its use is not required by their curriculum. This study investigated college students' intentions to use and the students' attitudes towards using an e‐portfolio system, and did so from the perspectives of career‐commitment status and weblog‐publication behaviours. The results indicate that career‐commitment status substantially influences college students' intentions and attitudes relative to using an e‐portfolio system. Also, overlap in the functions of weblogs and e‐portfolios (which allow people to use them interchangeably) does not directly result in higher or lower levels of intention to use an e‐portfolio system. A composite system providing career services, goal‐oriented self‐presentation and personality‐driven self‐expression is recommended.
Chronic treatment with angiotensin‐(1‐7) improves renal endothelial dysfunction in apolipoproteinE‐deficient mice
Authors: Stegbauer J , Potthoff SA , Quack I , Mergia E , Clasen T , Friedrich S , Vonend O , Woznowski M , Königshausen E , Sellin L , Rump LC
Published: March 2011

BACKGROUND AND PURPOSE ApolipoproteinE‐deficient [apoE (−/−)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin‐(1‐7) [Ang‐(1‐7)], acting through its specific GPCR, the Mas receptor, has endothelium‐dependent vasodilator properties. Here we have investigated if chronic treatment with Ang‐(1‐7) improved endothelial dysfunction in apoE (−/−) mice.

EXPERIMENTAL APPROACH ApoE (−/−) mice fed on a lipid‐rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang‐(1‐7) (82 µg·kg−1·h−1) or the same dose of Ang‐(1‐7) together with D‐Ala‐Ang‐(1‐7) (125 µg·kg−1·h−1) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys.

KEY RESULTS Ang‐(1‐7)‐treated apoE (−/−) mice showed improved renal endothelium‐dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (−/−) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium‐dependent vasorelaxation in kidneys of saline‐treated apoE (−/−) mice whereas no effect was observed in Ang‐(1‐7)‐treated mice. Chronic treatment with D‐Ala‐Ang‐(1‐7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang‐(1‐7) on endothelium‐dependent vasorelaxation. Renal endothelium‐independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang‐(1‐7)‐treated mice, compared with untreated mice, whereas eNOS expression was increased.

CONCLUSION AND IMPLICATIONS Chronic infusion of Ang‐(1‐7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.
Evidence for a differential opioidergic involvement in the analgesic effect of antidepressants: prediction for efficacy in animal models of neuropathic pain?
Authors: Wattiez A‐S , Libert F , Privat A‐M , Loiodice S , Fialip J , Eschalier A , Courteix C
Published: March 2011

BACKGROUND AND PURPOSE

Antidepressants are one of the recommended treatments for neuropathic pain. However, their analgesic action remains unpredictable, and there are no selection criteria for clinical use. Better knowledge of their mechanism of action could help highlight differences underlying their unequal efficacy.

EXPERIMENTAL APPROACH

We compared the activity of a tricyclic antidepressant (clomipramine) with selective 5‐HT and noradrenaline reuptake inhibitors (milnacipran and duloxetine) in streptozocin‐induced diabetic and chronic constriction nerve injury‐induced neuropathic rats, after repeated injections. We looked for an opioidergic mechanism in their action.

KEY RESULTS

Abolition of mechanical hyperalgesia was observed in mononeuropathic rats after five injections of clomipramine (5 mg·kg−1, s.c.) and milnacipran (10 or 20 mg·kg−1, i.p.) and in diabetic rats after clomipramine. An additional antinociceptive effect was obtained with five injections of duloxetine (3 mg·kg−1, i.p.) in both models and milnacipran (10 mg·kg−1, i.p.) in diabetic rats. These effects were observed with plasma antidepressant concentrations similar to those found in patients treated for neuropathic pain. Naloxone (1 mg·kg−1, i.v.) only suppressed the anti‐hyperalgesic effects of clomipramine in both models of pain and of milnacipran in the traumatic model.

CONCLUSIONS AND IMPLICATIONS

The opioid system appears to be involved in the mechanism of action of antidepressants that only have an anti‐hyperalgesic effect but not in those that have a stronger (i.e. antinociceptive) effect. These differences between the antidepressants occurred whatever the aetiology of the neuropathy and, if confirmed in clinical trials, could be used to decide which antidepressant is administered to a patient with neuropathic pain.
Animal models in the drug discovery pipeline for Alzheimer's disease
Authors: Van Dam Debby , De Deyn Peter Paul
Published: March 2011

With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease‐modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease‐modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease‐related research as valid models enable the appraisal of early pathological processes – which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence‐accelerated mice, chemical and lesion‐induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions.

LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Predictive validity of behavioural animal models for chronic pain
Authors: Berge Odd‐Geir
Published: March 2011

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature‐based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well‐controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target.

LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Constitutive expression of hypoxia‐inducible factor‐1 α in keratinocytes during the repair of skin wounds in horses
Authors: Deschene Karine , Céleste Christophe , Boerboom Derek , Theoret Christine L.
Published: March 2011

As a transient hypoxic state exists within skin wounds in horses and may be important for the healing process, this study sought to identify a molecular hypoxia response occurring in horse limb and body wounds healing by second intention. Hypoxia‐inducible factor 1α (HIF1α) protein expression was studied throughout repair by Western blotting and immunofluorescence. Paradoxically, HIF1α was strongly expressed in intact skin and its expression decreased dramatically following wounding (p<0.01), despite the expected hypoxic state within the wounded tissue. HIF1α levels reincreased in parallel with the epithelialization process, and more rapidly in body wounds than in limb wounds (p<0.01). HIF1α localized predominantly to the keratinocyte layer, in which it was constitutively expressed throughout healing. The HIF1α target gene cyclin‐dependent kinase inhibitor 1A (CDKN1A) showed a pattern of expression similar to HIF1α throughout the healing process and also localized to the keratinocyte layer, suggesting that HIF1α may regulate its constitutive expression. The HIF1α target genes vascular endothelial growth factor A (VEGFA) and solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) however did not have a pattern of expression similar to HIF1α, at the mRNA level. We conclude that HIF1α is expressed in a continuous and hypoxia‐independent manner in equine keratinocytes in both intact and wounded skin, and may regulate the expression of CDKN1A in this cell type.
The reinnervation and revascularization of wounds is temporarily altered after treatment with interleukin 10
Authors: Henderson James , Ferguson Mark W.J. , Terenghi Giorgio
Published: March 2011

Denervated wounds fail to heal normally, and hypertrophic scars are abnormally innervated. Wounds can be manipulated with cytokines to reduce subsequent scarring. Wounds treated with the antiscarring cytokine interleukin 10 (IL10) were investigated to assess if the treatment alterered patterns of reinnervation and revascularization as the wounds matured into scars. Thirty CD1 mice underwent intradermal injection of 100 μL phosphate‐buffered saline (PBS) containing 125 ng IL10 or placebo at the margins of 1 cm2 full thickness dorsal skin excisions at the time of wounding and at 24 hours after wounding. Wounds were not dressed. Six IL10‐treated and six control were harvested days 7, 14, 21, 42 and 84 postoperatively. Sections underwent histological scar assessment along with immunohistochemical staining for protein gene product 9.5 (PGP9.5), a pan‐neuronal marker, and the sensory neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP). The endothelial marker von Willebrand factor (VWF) was used to allow co‐localization and quantification of blood vessels. Quantitative analysis was performed on the periphery and center of wounds. Wounds treated with IL10 healed with dermal collagen organized into a pattern more closely resembling normal skin than control wounds. IL10 changed the pattern of CGRP reinnervation during the healing process, but at 84 days, the density levels of all nerve fiber types were similar to controls. Wounds treated with IL10 were more vascular than untreated wounds during healing, but by 84 days, VWF density was that of unwounded skin.