bluuebunny/crossref_metadata_2025 huggingface dataset:
A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection
Authors: Marsolais David , Hahm Bumsuk , Walsh Kevin B. , Edelmann Kurt H. , McGavern Dorian , Hatta Yasuko , Kawaoka Yoshihiro , Rosen Hugh , Oldstone Michael B. A.
Published: January 2009

Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cell-mediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8
+
T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.
Bimodal modulation of the botulinum neurotoxin protein-conducting channel
Authors: Fischer Audrey , Nakai Yuya , Eubanks Lisa M. , Clancy Colin M. , Tepp William H. , Pellett Sabine , Dickerson Tobin J. , Johnson Eric A. , Janda Kim D. , Montal Mauricio
Published: January 2009

Clostridium botulinum
neurotoxin (BoNT) is the causative agent of botulism, a neuroparalytic disease. We describe here a semisynthetic strategy to identify inhibitors based on toosendanin, a traditional Chinese medicine reported to protect from BoNT intoxication. Using a single molecule assay of BoNT serotypes A and E light chain (LC) translocation through the heavy chain (HC) channel in neurons, we discovered that toosendanin and its tetrahydrofuran analog selectively arrest the LC translocation step of intoxication with subnanomolar potency, and increase the unoccluded HC channel propensity to open with micromolar efficacy. The inhibitory profile on LC translocation is accurately recapitulated in 2 different BoNT intoxication assays, namely the mouse protection and the primary rat spinal cord cell assays. Toosendanin has an unprecedented dual mode of action on the protein-conducting channel acting as a cargo-dependent inhibitor of translocation and as cargo-free channel activator. These results imply that the bimodal modulation by toosendanin depends on the dynamic interactions between channel and cargo, highlighting their tight interplay during the progression of LC transit across endosomes.
Inalienable possession as grammatical category and discourse pattern
Authors: Kockelman Paul
Published: January 2009

This essay analyzes the grammatical category of inalienable possession by examining the interaction of morphosyntatic forms, semantic features, pragmatic functions, and discourse frequencies. Using data from Q’eqchi’-Maya, it is argued that inalienable possession may be motivated relative to two dimensions: (1) whatever any person is strongly presumed to possess (identifiability); (2) whatever such personal possessions are referred to frequently (relevance). In regards to frequency, inalienable possessions are compared with possessed NPs, and possessed NPs are compared with all NPs, in regards to grammatical relation, information status, animacy rank, and semantic role. In regards to identifiability, it is argued that inalienable possessions are like deictics and prepositions in that they guide the addressee’s identification of a referent by encoding that referent’s relation to a ground; and inalienable possessions are different from deictics and prepositions in that the ground is a person and the referents are its parts or relations.
The intersection of the perfective and imperfective domains
Authors: Kim Minju
Published: January 2009

Using diachronic corpus data, this article examines the grammaticalization of three Korean aspectual markers, progressive ‑ko iss‑, resultative ‑e iss‑, and anterior ‑ess‑. It demonstrates that the three Korean aspectual markers emerged from the same source ‑e is(i)‑, which in the 15th C expressed both resultative and progressive meanings. This finding goes against Bybee, Perkins, and Pagliuca’s (1994) proposition that perfective and imperfective markers follow separate grammaticalization paths. In addition, the finding confirms that Shirai’s (1998) proposal about the murky distinction between perfective and imperfective domains also holds true in the diachronic development of aspectual markers.
Microtubule and Cell Contact Dependency of ER-bound PTP1B Localization in Growth Cones
Authors: Fuentes Federico , Arregui Carlos O.
Published: January 2009

PTP1B is an ER-bound protein tyrosine phosphatase implied in the regulation of cell adhesion. Here we investigated mechanisms involved in the positioning and dynamics of PTP1B in axonal growth cones and evaluated the role of this enzyme in axons. In growth cones, PTP1B consistently localizes in the central domain, and occasionally at the peripheral region and filopodia. Live imaging of GFP-PTP1B reveals dynamic excursions of fingerlike processes within the peripheral region and filopodia. PTP1B and GFP-PTP1B colocalize with ER markers and coalign with microtubules at the peripheral region and redistribute to the base of the growth cone after treatment with nocodazole, a condition that is reversible. Growth cone contact with cellular targets is accompanied by invasion of PTP1B and stable microtubules in the peripheral region aligned with the contact axis. Functional impairment of PTP1B causes retardation of axon elongation, as well as reduction of growth cone filopodia lifetime and Src activity. Our results highlight the role of microtubules and cell contacts in the positioning of ER-bound PTP1B to the peripheral region of growth cones, which may be required for the positive role of PTP1B in axon elongation, filopodia stabilization, and Src activity.
Phosphatidylinositol-4-phosphate 5-kinase 1α Mediates Extracellular Calcium-induced Keratinocyte Differentiation
Authors: Xie Zhongjian , Chang Sandra M. , Pennypacker Sally D. , Liao Er-Yuan , Bikle Daniel D.
Published: January 2009

Extracellular calcium (Cao) is a major regulator of keratinocyte differentiation, but the mechanism is unclear. Phosphatidylinositol-4-phosphate 5-kinase 1α (PIP5K1α) is critical in synthesizing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. In this study, we sought to determine whether PIP5K1α plays a role in mediating the ability of Cao to induce keratinocyte differentiation. We found that treatment of human keratinocytes in culture with Cao resulted in increased PIP5K1α level and activity, as well as PI(4,5)P2level, binding of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3] to and activation of phospholipase C-γ1 (PLC-γ1), with the resultant increase in inositol 1,4,5-trisphosphate (IP3) and intracellular calcium (Cai). Knockdown of PIP5K1α in human keratinocytes blocked Cao-induced increases in the binding of PI(3,4,5)P3to PLC-γ1; PLC-γ1 activity; levels of PI(4,5)P2, IP3, and Cai; and induction of keratinocyte differentiation markers. Coimmunoprecipitation and confocal studies revealed that Cao stimulated PIP5K1α recruitment to the E-cadherin–catenin complex in the plasma membrane. Knockdown of E-cadherin or β-catenin blocked Cao-induced activation of PIP5K1α. These results indicate that after Cao stimulation PIP5K1α is recruited by the E-cadherin–catenin complex to the plasma membrane where it provides the substrate PI(4,5)P2for both PI3K and PLC-γ1. This signaling pathway is critical for Cao-induced generation of the second messengers IP3and Cai and keratinocyte differentiation.
Assessing the stock status of holobenthic octopus fisheries: is catch per unit effort sufficient?
Authors: Leporati Stephen C. , Ziegler Philippe E. , Semmens Jayson M.
Published: January 2009

Leporati, S. C., Ziegler, P. E., and Semmens, J. M. 2009. Assessing the stock status of holobenthic octopus fisheries: is catch per unit effort sufficient? – ICES Journal of Marine Science, 66: 478–487. Holobenthic and merobenthic octopus fisheries are commonly treated as biological equivalents, regardless of their contrasting life-history strategies. This is the consequence of a lack of species identification and relevant biological information for many species, which has led to a reliance on catch per unit effort (cpue) data for stock status assessments. Using the commercial Octopus pallidus fishery in southeast Australian waters as a case study, the reliability of commercial cpue data as an indicator of stock status for holobenthic octopus fisheries was assessed. To achieve this, cpue and biological information from a fixed position experimental research line were investigated for consistency in stock status patterns and compared with commercial fishery cpue trends. Research line results revealed that cpue could remain stable regardless of size-selective fishing mortality potentially impacting recruitment. The cpue in the commercial fishery was very seasonal and dominated by females during autumn, when both cpue and spawning periods peaked, so increasing the potential for negative fishery impacts on egg production. The inability of cpue to account for the effects of continual fishing pressure on recruitment or seasonal changes in sex-specific catchability, however, indicates that cpue alone cannot provide sufficient information on the status of a holobenthic octopus fishery.
Deep-sea mystery solved: astonishing larval transformations and extreme sexual dimorphism unite three fish families
Authors: Johnson G. David , Paxton John R , Sutton Tracey T , Satoh Takashi P , Sado Tetsuya , Nishida Mutsumi , Miya Masaki
Published: January 2009

The oceanic bathypelagic realm (1000–4000 m) is a nutrient-poor habitat. Most fishes living there have pelagic larvae using the rich waters of the upper 200 m. Morphological and behavioural specializations necessary to occupy such contrasting environments have resulted in remarkable developmental changes and life-history strategies. We resolve a long-standing biological and taxonomic conundrum by documenting the most extreme example of ontogenetic metamorphoses and sexual dimorphism in vertebrates. Based on morphology and mitogenomic sequence data, we show that fishes currently assigned to three families with greatly differing morphologies, Mirapinnidae (tapetails), Megalomycteridae (bignose fishes) and Cetomimidae (whalefishes), are larvae, males and females, respectively, of a single family Cetomimidae. Morphological transformations involve dramatic changes in the skeleton, most spectacularly in the head, and are correlated with distinctly different feeding mechanisms. Larvae have small, upturned mouths and gorge on copepods. Females have huge gapes with long, horizontal jaws and specialized gill arches allowing them to capture larger prey. Males cease feeding, lose their stomach and oesophagus, and apparently convert the energy from the bolus of copepods found in all transforming males to a massive liver that supports them throughout adult life.
Model validation of simple-graph representations of metabolism
Authors: Holme Petter
Published: January 2009

The large-scale properties of chemical reaction systems, such as metabolism, can be studied with graph-based methods. To do this, one needs to reduce the information, lists of chemical reactions, available in databases. Even for the simplest type of graph representation, this reduction can be done in several ways. We investigate different simple network representations by testing how well they encode information about one biologically important network structure—network modularity (the propensity for edges to be clustered into dense groups that are sparsely connected between each other). To achieve this goal, we design a model of reaction systems where network modularity can be controlled and measure how well the reduction to simple graphs captures the modular structure of the model reaction system. We find that the network types that best capture the modular structure of the reaction system are substrate–product networks (where substrates are linked to products of a reaction) and substance networks (with edges between all substances participating in a reaction). Furthermore, we argue that the proposed model for reaction systems with tunable clustering is a general framework for studies of how reaction systems are affected by modularity. To this end, we investigate statistical properties of the model and find, among other things, that it recreates correlations between degree and mass of the molecules.
High-resolution DNA-binding specificity analysis of yeast transcription factors
Authors: Zhu Cong , Byers Kelsey J.R.P. , McCord Rachel Patton , Shi Zhenwei , Berger Michael F. , Newburger Daniel E. , Saulrieta Katrina , Smith Zachary , Shah Mita V. , Radhakrishnan Mathangi , Philippakis Anthony A. , Hu Yanhui , De Masi Federico , Pacek Marcin , Rolfs Andreas , Murthy Tal , LaBaer Joshua , Bulyk Martha L.
Published: January 2009

Transcription factors (TFs) regulate the expression of genes through sequence-specific interactions with DNA-binding sites. However, despite recent progress in identifying in vivo TF binding sites by microarray readout of chromatin immunoprecipitation (ChIP-chip), nearly half of all known yeast TFs are of unknown DNA-binding specificities, and many additional predicted TFs remain uncharacterized. To address these gaps in our knowledge of yeast TFs and their cis regulatory sequences, we have determined high-resolution binding profiles for 89 known and predicted yeast TFs, over more than 2.3 million gapped and ungapped 8-bp sequences (“k-mers”). We report 50 new or significantly different direct DNA-binding site motifs for yeast DNA-binding proteins and motifs for eight proteins for which only a consensus sequence was previously known; in total, this corresponds to over a 50% increase in the number of yeast DNA-binding proteins with experimentally determined DNA-binding specificities. Among other novel regulators, we discovered proteins that bind the PAC (Polymerase A and C) motif (GATGAG) and regulate ribosomal RNA (rRNA) transcription and processing, core cellular processes that are constituent to ribosome biogenesis. In contrast to earlier data types, these comprehensive k-mer binding data permit us to consider the regulatory potential of genomic sequence at the individual word level. These k-mer data allowed us to reannotate in vivo TF binding targets as direct or indirect and to examine TFs' potential effects on gene expression in ∼1700 environmental and cellular conditions. These approaches could be adapted to identify TFs and cis regulatory elements in higher eukaryotes.
Prevention of proliferative changes of forestomach mucosa by blood glucose control with insulin in alloxan‐induced diabetic rats
Authors: Sano Tomoya , Ozaki Kiyokazu , Kodama Yasushi , Matsuura Tetsuro , Narama Isao
Published: January 2009

Diabetes mellitus is one of the risk factors for carcinogenesis. Recently we reported that alloxan induces squamous cell carcinoma (SCC) with coincidental inflammation, bacteria/fungal infections, and a severe diabetic condition. The present study was conducted to examine the effects of blood glucose control with insulin on the proliferative changes of the forestomach in alloxan‐induced diabetic rats. Male 15‐week‐old WBN/Kob rats were divided into a control group of non‐treated rats with naturally occurring diabetes after 40 weeks of age (non‐treated group), alloxan‐induced diabetic rats (AL group), and alloxan‐induced diabetic rats given insulin implant treatment (AL + In group). The animals were sacrificed at 90 weeks of age for histopathologic examination. The blood glucose and urinary glucose level of the AL + In group fluctuated variously from high to normal levels compared with a constantly high level of AL (for 75 weeks) as well as in the non‐treated group (for 50 weeks). The mucosal hyperplasia in the forestomach developed in 88.2% of the AL group and 37.5% of the non‐treated group, but in only 10.0% of the AL + In group. SCC was only detected in 23.5% of the AL group. Hyperplastic changes were constantly accompanied by inflammation and fungal/bacterial infections in the AL and non‐treated groups, whereas inflammation and fungal infection were completely suppressed in the AL + In group. These findings demonstrate that blood glucose control suppressed neoplastic changes in alloxan‐induced diabetic rats. We postulate that inflammation together with bacterial/fungal infections under prolonged severe diabetic conditions play a pivotal role in carcinogenesis. (Cancer Sci 2009; 100: 595–600)
Physiology of Membrane Oestrogen Receptor Signalling in Reproduction
Authors: Micevych P. , Kuo J. , Christensen A.
Published: January 2009

The best characterised oestrogen receptors (ERs) that are responsible for membrane‐initiated oestradiol signalling are the classic ERs, ERα and ERβ. When in the nucleus, these proteins are oestradiol activated transcription factors but, when trafficked to the cell membrane, ERα and ERβ rapidly activate protein kinase pathways, alter membrane electrical properties, modulate ion flux and can mediate long‐term effects through gene expression. To initiate cell signalling, membrane ERs transactivate metabotropic glutamate receptors (mGluRs) to stimulate Gq signalling through pathways using PKC and calcium. In this review, we discuss the interaction of membrane ERα with metabotropic glutamate receptor 1a (mGluR1a) to initiate rapid oestradiol cell signalling and its critical roles in female reproduction: sexual behaviour and oestrogen positive feedback of the luteinising hormone (LH) surge. Although long considered to be regulated by the long‐term actions of oestradiol on gene transcription, recent results indicate that membrane oestradiol cell signalling is vital for a full display of sexual receptivity. Similarly, the source of pre‐ovulatory progesterone necessary for initiating the LH surge is hypothalamic astrocytes. Oestradiol rapidly amplifies progesterone synthesis through the release of intracellular calcium stores. The ERα‐mGluR1a interaction is necessary for critical calcium flux. These two examples provide support for the hypothesis that membrane ERs are not themselves G‐protein receptors; rather, they use mGluRs to signal.
Modulation of Gonadotrophin‐Releasing Hormone Pulse Generator Activity by the Pheromone in Small Ruminants
Authors: Murata K. , Wakabayashi Y. , Kitago M. , Ohara H. , Watanabe H. , Tamogami S. , Warita Y. , Yamagishi K. , Ichikawa M. , Takeuchi Y. , Okamura H. , Mori Y.
Published: January 2009

In small ruminants, such as goats and sheep, a primer pheromone produced by males induces an out‐of‐seasonal ovulation in anoestrous females, a phenomenon known as the male effect. The male effect is unique in that an external chemical stimulus can immediately modulate the activity of the hypothalamic gonadotrophin‐releasing hormone (GnRH) pulse generator. We have established a monitoring method of the GnRH pulse generator activity in Shiba goat. Using this method as a sensitive bioassay to assess the male effect pheromone activity, we have shown that the male effect pheromone is synthesised in an androgen‐dependent manner in the sebaceous glands or their vicinity in specific body regions in goats. Although chemical identity of the pheromone is yet to be determined, analyses of male goat hair extracts by gas chromatography fractionation suggest that the male effect pheromone is a volatile substance with relatively small molecular weight. From morphological and molecular biological studies in goats, it is suggested that the pheromone molecule is detected by a member of the V1R family located on both the olfactory neurones and the vomeronasal sensory neurones, and the pheromone signal is conveyed to the medial nucleus of amygdala via the main olfactory and vomeronasal pathways and, subsequently, to the hypothalamic GnRH pulse generator to enhance its activity.
Increased abscisic acid levels in transgenic tobacco over‐expressing 9 cis‐epoxycarotenoid dioxygenase influence H2O2 and NO production and antioxidant defences
Authors: ZHANG YIMING , TAN JIALI , GUO ZHENFEI , LU SHAOYUN , HE SIJIAN , SHU WEI , ZHOU BIYAN
Published: January 2009

Abscisic acid (ABA) regulates the plant's adaptive responses to abiotic stresses. Over‐expression of the 9‐cis‐epoxycarotenoid dioxygenase gene (SgNCED1) in the transgenic tobaccos increased ABA content and tolerance to drought and salt stresses. H2O2 and nitric oxide (NO) contents were enhanced in guard cells and mesophyll cells of the transgenic plants, accompanied with increased transcripts and activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR). The enhancements of H2O2 and NO and transcripts and activities of antioxidant enzymes in the transgenic plants were blocked by pre‐treatments with inhibitor of ABA biosynthesis, scavengers of H2O2 and NO, and inhibitors of NADPH oxidase and NO synthase‐like (NOS‐like). The elevated production of NO in the transgenic plants was blocked by scavenger of H2O2 and inhibitors of NADPH oxidase, whereas H2O2 level was not affected by scavenger of NO and inhibitor of NOS‐like, indicating that H2O2 is essential for the elevated production of NO. The results demonstrate that the increased drought and salt tolerance in the transgenic plants is associated with ABA‐induced production of H2O2 via NADPH oxidase and NO via NOS‐like, which sequentially induce transcripts and activities of SOD, CAT, APX and GR.
Genetic diversity of Chinese domestic goat based on the mitochondrial DNA sequence variation
Authors: Liu Y.‐P. , Cao S.‐X. , Chen S.‐Y. , Yao Y.‐G. , Liu T.‐Z.
Published: January 2009

The aim of this study was to characterize the genetic diversity of domestic goat in China. For this purpose, we determined the sequence of the mitochondrial DNA (mtDNA) control region in 72 individuals of the Yangtze River delta white goat, and reanalysed 723 published samples from 31 breeds/populations across China. All goat haplotypes were classified into four haplogroups (A–D) previously described. The phylogenetic pattern that emerged from the mtDNA control region sequence was confirmed by the analysis of the entire cytochrome b sequence of eight goats representative of the four haplogroups. It appeared that in Chinese domestic goat, haplogroups A and B were dominant and distributed in nearly all breeds/populations, while haplogroups C and D were only found in seven breeds/populations. Four breeds/populations contained all four haplogroups. When grouping the breeds/populations into five geographic groups based on their geographic distributions and ecological conditions, the southern pasturing area had the highest diversity whereas the northern farming area had the lowest diversity. 84.29% and 11.37% of the genetic variation were distributed within breeds and among breeds within the ecologically geographical areas, respectively; only 4% of genetic variation was observed among the five geographic areas. We speculate that the traditional seasonal pastoralism, the annual long‐distance migrations that occurred in the past, and the commercial trade would account for the observed pattern by having favoured gene flows.
SHOULD KANTIANS BE CONSEQUENTIALISTS?
Authors: Ross Jacob
Published: January 2009

Parfit argues that a form of rule consequentialism can be derived from the most plausible formulation of the fundamental principle of Kantian ethics. And so he concludes that Kantians should be consequentialists. I argue that we have good reason to reject two of the auxiliary premises that figure in Parfit's derivation of rule consequentialism from Kantianism.1
UK INFLATION: PERSISTENCE, SEASONALITY AND MONETARY POLICY
Authors: Osborn Denise R. , Sensier Marianne
Published: January 2009

In the light of the changes to UK monetary policy since the early 1980s, we study the existence and nature of changes in the properties of retail price inflation over this period. A feature of our analysis is the attention paid to the marked seasonal pattern of monthly UK inflation. After taking account of seasonality, both univariate and Phillips curve models provide strong evidence of changes in the level and persistence of inflation around the end of 1992, at the time of the introduction of inflation targeting. Indeed, all models point to the effective disappearance of inflation persistence after this date, implying that constant‐parameter models estimated using both pre‐ and post‐inflation targeting data periods should be treated with considerable caution.
MONEY DEMAND STABILITY AND INFLATION PREDICTION IN THE FOUR LARGEST EMU COUNTRIES
Authors: Carstensen Kai , Hagen Jan , Hossfeld Oliver , Neaves Abelardo Salazar
Published: January 2009

In this paper, we analyze the money demand functions of the four largest EMU countries and of the four‐country (EMU‐4) aggregate. We identify reasonable and stable money demand relationships for Germany, France and Spain as well as the EMU‐4 aggregate. For the case of Italy, results are less clear. From the estimated money demand functions, we derive both EMU‐4 and country‐specific measures of money overhang. We find that the EMU‐4 overhang measure strongly correlates with the country‐specific measures, particularly since the start of EMU, and is useful to predict country‐specific inflation. However, it generally does not encompass country‐specific money overhang measures as predictors of inflation. Hence, aggregate money overhang is an important, but by far not an exhaustive, indicator for the disaggregate level.
Credit Portfolio Loss Forecasts for Economic Downturns
Authors: Rösch Daniel , Scheule Harald
Published: January 2009

Recent studies find a positive correlation between default and loss given default rates of credit portfolios. In response, financial regulators require financial institutions to base their capital on ‘Downturn’ loss rates given default which are also known as Downturn LGDs. This article proposes a concept for the Downturn LGD which incorporates econometric properties of credit risk as well as the information content of default and loss given default models. The concept is compared to an alternative proposal by the Department of the Treasury, the Federal Reserve System and the Federal Insurance Corporation. An empirical analysis is provided for US American corporate bond portfolios of different credit quality, seniority and security.
Effects of intermodal attention on the auditory steady‐state response and the event‐related potential
Authors: Saupe Katja , Widmann Andreas , Bendixen Alexandra , Müller Matthias M. , Schröger Erich
Published: January 2009

The aim of the present study was to simultaneously measure and compare intermodal attention effects in event‐related brain potentials (ERPs) and auditory steady‐state responses (ASSRs). For this purpose, 40‐Hz amplitude modulated tones and a visual fixation cross were presented concurrently. By means of target detection tasks either on the sounds or on the fixation cross, participants' attention was directed to the respective modality. Attended sounds elicited a negative difference (Nd) in the ERP relative to unattended sounds. Nd was divided into an early and a late part as often observed for intramodal attention. Moreover, attention to the sounds led to a significant enhancement of the ASSR. This modulation of the ASSR by intermodal attention is demonstrated for the first time in the EEG. The present data suggest that ASSRs could provide a useful tool for the investigation of the neural dynamics of intermodal attentional processes.
Malawi's special needs education (SNE): perspectives and comparisons of practice and progress
Authors: Itimu Ambumulire Nellie , Kopetz Patricia B.
Published: January 2009

The sub‐Saharan country of Malawi is steeped in a robust educational reform movement to ensure ‘Education for All’. Based upon country immersion experience and a review of the literature, this report highlights Malawi's nationwide support for its special needs education (SNE) campaign. First discussed is a brief overview of Malawi, its people and its educational philosophy regarding SNE. Comparisons of sub‐Saharan countries’ educational provisions for students with special learning needs follow, as do explanations of the country's classroom practices and its national SNE Policy (revised in 2007). Described along with ‘best practices’ and the country's history of SNE teacher preparation initiatives is the structure of Malawi's SNE implementation, its design in the classroom, teacher preparation particulars and SNE programme milestones. Partners (organisations), integral to the success of Malawi's SNE efforts, are emphasised; and related policies and provisions are presented, along with closing discussion of assessment, diagnosis, programming, and future implications and conclusions.
Sonic Hedgehog signaling in astrocytes is dependent on p38 mitogen‐activated protein kinase and G‐protein receptor kinase 2
Authors: Atkinson Peter J. , Dellovade Tammy , Albers David , Von Schack David , Saraf Kathryn , Needle Elie , Reinhart Peter H. , Hirst Warren D.
Published: January 2009

The molecular determinants of Sonic Hedgehog (Shh) signaling in mammalian cells and, in particular, those of the CNS are unclear. Here we report that primary cortical astrocyte cultures are highly responsive to both Shh protein and Hh Agonist 1.6, a selective, small molecule Smoothened agonist. Both agonists produced increases in mRNA expression of Shh‐regulated gene targets, Gli‐1 and Patched in a cyclopamine‐ and forskolin‐sensitive manner. Using this model we show for the first time that Shh pathway activation mediates rapid increases in p38 MAPK phosphorylation, without altering phosphorylation of either extracellular‐signal‐regulated kinases or c‐jun N‐terminal kinases. Selective inhibition of p38 MAPK significantly attenuated Shh‐dependent up‐regulation of Gli‐1, inter‐alpha trypsin inhibitor and thrombomodulin mRNA, however did not affect expression of insulin‐like growth factor 2 or a novel Shh target, membrane‐associated guanylate kinase p55 subfamily member 6. Using RNAi and a constitutively‐active mutant we show that Shh signaling to p38 MAPK and subsequent Gli‐1 transcription requires G‐protein receptor kinase 2. Taken together, these findings provide evidence for a central role of G‐protein receptor kinase 2‐dependent p38 MAPK activity in regulating Shh‐mediated gene transcription in astrocytes.
Role of Genetic Refuges in the Restoration of Native Gene Pools of Brown Trout
Authors: ARAGUAS ROSA M. , SANZ NÚRIA , FERNÁNDEZ RAQUEL , UTTER FRED M. , PLA CARLES , GARCÍA‐MARÍN JOSÉ‐LUIS
Published: January 2009

Abstract:  Captive‐bred animals derived from native, alien, or hybrid stocks are often released in large numbers in natural settings with the intention of augmenting harvests. In brown trout (Salmo trutta), stocking with hatchery‐reared non‐native fish has been the main management strategy used to maintain or improve depleted wild brown trout populations in Iberian and other Mediterranean regions. This measure has become a serious threat to the conservation of native genetic diversity, mainly due to introgressive hybridization. Aware of this risk, the agency responsible for management of brown trout in the eastern Pyrenees (Spain) created “brown trout genetic refuges” to preserve the integrity of brown trout gene pools in this region. Within refuge areas, the prerefuge status with respect to fishing activities has been maintained, but hatchery releases have been banned completely. We evaluated this management strategy through a comparison of the stocking impact on native populations that accounted for stocking histories before and after refuge designations and fishing activities. In particular we examined the relevant scientific, cultural, and political challenges encountered. Despite agency willingness to change fishery policies to balance exploitation and conservation, acceptance of these new policies by anglers and genetic monitoring of refuge populations should also be considered. To improve management supported by genetic refuges, we suggest focusing on areas where the public is more receptive, considering the situation of local native diversity, and monitoring of adjacent introgressed populations. We recommend the use of directional supportive breeding only when a population really needs to be enhanced. In any case, management strategies should be developed to allow for protection within the context of human use.
Eccrine Angiomatous Hamartoma: Report of Five Congenital Cases
Authors: Larralde Margarita , Bazzolo Eleonora , Boggio Paula , Abad María Eugenia , Santos Muñoz Andrea
Published: January 2009

Abstract:  Eccrine angiomatous hamartoma is a rare entity characterized histologically by the combination of proliferative eccrine and vascular elements. It generally arises before puberty, as solitary or multiple lesions, with a heterogeneous clinical appearance, affecting predominantly the distal extremities, with or without associated pain or hyperhidrosis. It may require surgical treatment due to cosmetic concern, progressive enlargement or the presence of pain or excessive hyperhidrosis. We report five congenital cases of eccrine angiomatous hamartoma, emphasizing a clinically uncommon tumor‐like appearance, with numerous telangiectasias on their surfaces resembling vascular lesions, in two of them.
Obama, Look East
Authors: MAHBUBANI KISHORE
Published: January 2009

America is more a creed than a nation. Our promise has always been that all individuals, despite race, religion or gender, have the equal chance to make it. The election of Barack Hussein Obama as president of the United States is thus a “soft power” coup for America's global image, which had lost its luster during the Bush years. Obama is the anti‐Bush who will lead by the power of example instead of the example of power. Yet, there are real limits. Can the power of example stop the North Korean or Iranian nuclear programs? Can it stop jihadists bent on establishing a new Caliphate across South Asia? Can it limit China's ambitions as the new power in Asia? In this section commentators from across the world offer their views.
An improved cost‐effective, reproducible method for evaluation of bone loss in a rodent model
Authors: Fine Daniel H. , Schreiner Helen , Nasri‐Heir Cibele , Greenberg Barbara , Jiang Shuying , Markowitz Kenneth , Furgang David
Published: January 2009

Aim: This study was designed to investigate the utility of two “new” definitions for assessment of bone loss in a rodent model of periodontitis.

Material and Methods: Eighteen rats were divided into three groups. Group 1 was infected by Aggregatibacter actinomycetemcomitans (Aa), group 2 was infected with an Aa leukotoxin knock‐out, and group 3 received no Aa (controls). Microbial sampling and antibody titres were determined. Initially, two examiners measured the distance from the cemento‐enamel‐junction to alveolar bone crest using the three following methods; (1) total area of bone loss by radiograph, (2) linear bone loss by radiograph, (3) a direct visual measurement (DVM) of horizontal bone loss. Two “new” definitions were adopted; (1) any site in infected animals showing bone loss >2 standard deviations above the mean seen at that site in control animals was recorded as bone loss, (2) any animal with two or more sites in any quadrant affected by bone loss was considered as diseased.

Results: Using the “new” definitions both evaluators independently found that infected animals had significantly more disease than controls (DVM system; p<0.05).

Conclusions: The DVM method provides a simple, cost effective, and reproducible method for studying periodontal disease in rodents.
Mutational and expressional analysis of BNIP3, a pro‐apoptotic Bcl‐2 member, in gastric carcinomas
Authors: LEE SUNG HAK , JEONG EUN GOO , YOO NAM JIN , LEE SUG HYUNG
Published: January 2009

Cell death deregulation is a hallmark of human cancers. BNIP3 was initially identified as a pro‐apoptotic member of the Bcl‐2 family and plays an important role in apoptosis, necrosis and autophagy. The aim of this study was to see whether alterations of BNIP3 protein expression and somatic mutation of the BNIP3 gene are characteristics of human cancers. We analyzed the expression of BNIP3 protein in 60 gastric adenocarcinomas by immunohistochemistry. In addition, we analyzed BNIP3 mutation in the DNA sequences encoding BH3 (Bcl‐2 homology3) and TM (transmembrane) domains that are important in the cell death function of BNIP3 by single‐strand conformation polymorphism (SSCP) in 48 colorectal, 48 gastric, and 48 breast carcinomas, and 48 acute leukemias. By immunohistochemistry, BNIP3 protein was detected in 40 of the 60 carcinomas (67%). Both early and advanced gastric carcinomas expressed BNIP3. There was no significant association between BNIP3 expression and clinicopathologic characteristics, including invasion, metastasis and stage. In contrast to the cancer cells, epithelial cells in normal gastric mucosa showed no or weak expression of BNIP3. Mutational analysis revealed BNIP3 mutation in neither the BH3 nor the TM domain, suggesting that BNIP3 mutation in these domains is not a direct target of inactivation in gastric, colorectal and breast carcinomas, and acute leukemias. Increased expression of BNIP3 in the malignant gastric epithelial cells compared to the normal mucosal epithelial cells suggests that BNIP3 expression might play a role in gastric carcinoma development.
Protection afforded by live attenuated SIV is associated with rapid killing kinetics of CTLs
Authors: Rollman Erik , Mason Rosemarie D. , Lin Jie , Brooks Andrew G. , Kent Stephen J.
Published: January 2009

Background  Live attenuated SIV vaccines are highly efficacious, but how they mediate protection is poorly understood. A feature of the effectiveness of live attenuated vaccines is their ability to control high dose challenge viruses early, without a large peak of acute viraemia. We hypothesized that long‐lived antigen exposure from live attenuated SIV may result in CD8+ cytotoxic T lymphocytes persistently capable of rapidly cytolytic potential.

Methods  We employed a kinetic degranulation assay to study multiple tetramer+ SIV‐specific CTL specificities before and after the SIVmac251 challenge of pigtail macaques inoculated with a live attenuated SIV.

Results  Live attenuated SIV‐vaccinated animals rapidly controlled a subsequent challenge, with minimal viraemia after exposure. For over 9 months after the initial vaccination with live attenuated SIV we could detect both Gag‐ and Tat‐specific CTLs that maintained a long‐term capacity to rapidly degranulate (CD107a expression) and release granzyme B within 30 minutes of antigen exposure. This rapid cytolytic phenotype was maintained throughout the early period after challenge, despite the absence of a marked enhancement in CTL frequencies.

Conclusions  Our results suggest that highly functional CTLs may contribute to the remarkable efficacy of live attenuated SIV vaccines. Studying the killing kinetics of CTLs induced by other, safer, HIV vaccines could facilitate a better understanding of the requirements for an effective HIV vaccine.
Allergy in day care children: prevalence and environmental risk factors
Authors: Hatakka Katja , Piirainen Laura , Pohjavuori Sara , Poussa Tuija , Savilahti Erkki , Korpela Riitta
Published: January 2009

Aim: To investigate the prevalence of atopic disease among Finnish day care children and the relationship between atopy and environmental factors.

Methods: A cross‐sectional study of 594 day care children aged 1–6 years from Helsinki, Finland. Each child's history of atopic diseases and environmental exposure was collected in a questionnaire completed by the parents.

Results: The prevalence of diagnosed asthma was 0.9% for the 1–3‐year olds and 5.5% for the 4–6‐year olds, atopic eczema/dermatis was 16% in both groups, and allergic rhinitis 5% in the younger group, 9% in the older group. According to multivariable logistic regression models, breastfeeding (exclusive ≥4 months or partial ≥6 months) reduced the risk of atopic diseases (OR = 0.60; CI95 0.39–0.93, p = 0.021). Atopic diseases were more common in the oldest age group, 5–6‐year olds, compared to the youngest, 1–2‐year olds (OR = 2.18; CI95 1.14–4.15, p = 0.018). One parent with atopic disease increased the child's risk (OR = 1.89; CI95 1.20–2.97, p = 0.006), more so if both parents had a history (OR = 3.17; CI95 1.48–6.78, p = 0.003).

Conclusion: Our results support the hypothesis that breastfeeding for at least six months may protect against atopic diseases. The child's greater age (5–6 years) and parental history of atopic diseases increased the risk of atopy.
A Potent Gelatinase Inhibitor with Anti‐Tumor‐Invasive Activity and its Metabolic Disposition
Authors: Lee Mijoon , Celenza Giuseppe , Boggess Bill , Blase Jennifer , Shi Qicun , Toth Marta , Bernardo M. Margarida , Wolter William R. , Suckow Mark A. , Hesek Dusan , Noll Bruce C. , Fridman Rafael , Mobashery Shahriar , Chang Mayland
Published: January 2009

Metastatic tumors lead to more than 90% fatality. Despite the importance of invasiveness of tumors to poor disease outcome, no anti‐invasive compounds have been commercialized. We describe herein the synthesis and evaluation of 4‐(4‐(thiiranylmethylsulfonyl)phenoxy)‐phenyl methanesulfonate (compound 2) as a potent and selective inhibitor of gelatinases (matrix metalloproteinases‐2 and ‐9), two enzymes implicated in invasiveness of tumors. It was demonstrated that compound 2 significantly attenuated the invasiveness of human fibrosarcoma cells (HT1080). The metabolism of compound 2 involved hydroxylation at the α‐methylene, which generates sulfinic acid, thiirane ring‐opening, followed by methylation and oxidation, and cysteine conjugation of both the thiirane and phenyl rings.
Chiral N‐Phosphonyl Imine Chemistry: Asymmetric Synthesis of α‐Alkyl β‐Amino Ketones by Reacting Phosphonyl Imines with Ketone‐Derived Enolates
Authors: Ai Teng , Han Jianlin , Chen Zhong‐Xiu , Li Guigen
Published: January 2009

A series of new chiral syn‐α‐branched β‐amino ketones has been synthesized by reacting chiral phosphonyl imines with ketone‐derived enolates. The N‐protection group on imine auxiliary was found to be crucial to the asymmetric induction. The absolute stereochemistry has been unambiguously determined by converting a product to a known sample.
Uterine adenomyosis in an orang‐utan (Pongo abelii/pygmaeus)
Authors: Graham KJ , Hulst FA , Vogelnest L , Fraser IS , Shilton CM
Published: January 2009

A 48‐year‐old, multiparous, female hybrid orang‐utan (Pongo abelii/pygmaeus) was investigated after a 3‐year history of irregular and excessively heavy menstrual bleeding. Opportunistic pelvic examinations over a 2.5‐year period were non‐diagnostic. Medical therapy was not effective. A subtotal hysterectomy with bilateral salpingo‐ovariectomy was performed. A pedunculated mass spanning 90% of the uterine lumen was seen grossly, and histopathology confirmed uterine adenomyosis. Adenomyosis is defined as the ectopic occurrence or diffuse implantation of endometrial tissue, including glands and stroma, into the myometrium. It is common in older, usually premenopausal, multiparous women and is frequently associated with other uterine pathology, including endometrial hyperplasia and leiomyomas. The most common clinical signs are dysmenorrhoea and heavy menstrual bleeding; however, up to 35% of women are asymptomatic. Diagnosis is difficult and requires myometrial sampling and an experienced pathologist. A hysterectomy in this case was diagnostic and curative. There have been few reports of uterine adenomyosis in non‐human primates and none reported in an orang‐utan. Uterine adenomyosis should be considered in the differential diagnosis in any multiparous, aged, non‐human female primate with irregular and excessively heavy menstrual bleeding, and hysterectomy with bilateral salpingo‐ovariectomy is recommended as a diagnostic and therapeutic solution.
Isolation of sixteen autosomal loci and a sex‐linked polymorphic microsatellite locus from the Milne‐Edwards’ sportive lemur (Lepilemur edwardsi)
Authors: CRAUL M. , DAWSON D. A. , RADESPIEL U. , ZIMMERMANN E. , BRUFORD M. W.
Published: January 2009

We isolated 21 microsatellites from the Milne‐Edwards’ sportive lemur, Lepilemur edwardsi. Eighteen microsatellite sequences possessed sufficient flanking DNA for primer design. Seventeen loci amplified and were found to be polymorphic displaying two to 17 alleles in 32 unrelated individuals from a population from the National Park of Ankarafantsika in northwest Madagascar. One locus (Led‐12) was found to be sex linked located on the X chromosome and can be used to sex‐type 40% of female L. edwardsi lemurs. These 17 loci were characterized to investigate family structure and the phylogeography of L. edwardsi.
Development and characterization of microsatellite loci in western larch (Larix occidentalis Nutt.)
Authors: CHEN C. , LIEWLAKSANEEYANAWIN C. , FUNDA T. , KENAWY A. , NEWTON C. H. , EL‐KASSABY Y. A.
Published: January 2009

Western larch (Larix occidentalis Nutt.) is an important ecological and commercial species in the Pacific Northwest. We isolated nine microsatellite loci with variable polymorphism ranging from five to 19 alleles per locus. Observed and expected heterozygosities averaged 0.42 and 0.64 and ranged from 0.11 to 0.83 and from 0.48 to 0.80, respectively. These markers, along with those already existing, will be useful for the species’ gene resource management activities.
Isolation of 10 polymorphic microsatellite loci in the marine midge Clunio marinus (Chironomidae, Diptera) and their efficient characterization by heteroduplex analysis
Authors: KAISER TOBIAS S , HECKEL DAVID G
Published: January 2009

Ten polymorphic microsatellite loci were cloned and characterized for the marine midge Clunio marinus (Chironomidae, Diptera). The number of alleles ranged from three to 31, the observed heterozygosity ranged from 0.06 to 0.83. During preliminary tests for polymorphisms, we identified subtly differing alleles due to the heteroduplexes they formed on nondenaturing gels. This allowed for the use of unlabelled primers in standard lower resolution PAGE and thus saved time and money in primer testing.
Isolation and characterization of microsatellite loci in the entomopathogenic nematode Heterorhabditis bacteriophora
Authors: BAI XIAODONG , SAEB AMR T. M. , MICHEL ANDREW , GREWAL PARWINDER S.
Published: January 2009

Twenty microsatellite loci were identified from genomic DNA enrichment and expressed sequence tags of entomopathogenic nematode Heterorhabditis bacteriophora. Eight loci were found to be polymorphic in a Northeast Ohio H. bacteriophora population. Levels of polymorphism were evaluated in 31–56 individuals and the number of alleles ranged from two to three. The values of observed and expected heterozygosities ranged from 0 to 0.536 and from 0.223 to 0.616, respectively. All eight loci showed heterozygote deficiencies, but three conformed to Hardy–Weinberg equilibrium at the subpopulation level. This is the first set of microsatellite markers in entomopathogenic nematodes.