bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure of R169 controls protein C activation and autoactivation
Authors: Pozzi Nicola , Barranco-Medina Sergio , Chen Zhiwei , Di Cera Enrico
Published: April 2012

Protein C is activated by thrombin with a value of kcat/Km = 0.11mM−1s−1 that increases 1700-fold in the presence of the cofactor thrombomodulin. The molecular origin of this effect triggering an important feedback loop in the coagulation cascade remains elusive. Acidic residues in the activation domain of protein C are thought to electrostatically clash with the active site of thrombin. However, functional and structural data reported here support an alternative scenario. The thrombin precursor prethrombin-2 has R15 at the site of activation in ionic interaction with E14e, D14l, and E18, instead of being exposed to solvent for proteolytic attack. Residues E160, D167, and D172 around the site of activation at R169 of protein C occupy the same positions as E14e, D14l, and E18 in prethrombin-2. Caging of R169 by E160, D167, and D172 is responsible for much of the poor activity of thrombin toward protein C. The E160A/D167A/D172A mutant is activated by thrombin 63-fold faster than wild-type in the absence of thrombomodulin and, over a slower time scale, spontaneously converts to activated protein C. These findings establish a new paradigm for cofactor-assisted reactions in the coagulation cascade.
The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model
Authors: Chiu Tsung-Lang , Wang Mei-Jan , Su Chin-Cheng
Published: April 2012

Background

Microglial cells are the predominant immune cells in malignant brain tumors, but tumors may release some factors to reduce their defensive functions. Restoration of the anti-cancer function of microglia has been proposed as a treatment modality for glioblastoma. We examined the effect of intra-cranially administered recombinant adeno-associated virus encoding interleukin-12 (rAAV2/IL12) on transfection efficiency, local immune activity and survival in a rat model of glioblastoma multiforme.

Methods

F344 rats were injected with rAAV2/IL12 and implanted with syngeneic RG2 cells (glioblastoma cell line). Intracerebral interleukin-12 and interferon-γ concentrations were determined by ELISA. Activation of microglia was determined by expressions of ED1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) which were evaluated by Western blotting and immunohistochemistry. The proliferation of cancer cells was evaluated with Ki67 immunohistochemistry and apoptosis of cancer cells with TUNEL.

Results

The brains treated with rAAV2/IL-12 maintained high expression of interleukin-12 and interferon-γ for at least two months. In syngeneic tumor model, brains treated with rAAV2/IL12 exhibited more infiltration of activated microglia cells as examined by ED1 and TRAIL stains in the tumor. In addition, the volume of tumor was markedly smaller in AAV2/IL12-treated group and the survival time was significantly longer in this group too.

Conclusion

The intra-cerebrally administered rAAV2/IL-12 efficiently induces long lasting expression of IL-12, the greater infiltration of activated microglia cells in the tumor associated improved immune reactions, resulting in the inhibited growth of implanted glioblastoma and the increased survival time of these rats.
Gene expression analysis of mammary tissue during fetal bud formation and growth in two pig breeds – indications of prenatal initiation of postnatal phenotypic differences
Authors: Chomwisarutkun Kunsuda , Murani Eduard , Ponsuksili Siriluck , Wimmers Klaus
Published: April 2012

Background

The mammary gland is key to all mammal species; in particular in multiparous species like pigs the number and the shape of functional mammary gland complexes are major determinants of fitness. Accordingly, we aimed to catalog the genes relevant to mammogenesis in pigs. Moreover, we aimed to address the hypothesis that the extent and timing of proliferation, differentiation, and maturation proccesses during prenatal development contribute to postnatal numerical, morphological and functional properties of the mammary gland. Thus we focused on differentially expressed genes and networks relevant to mammary complex development in two breeds that are subject to different selection pressure on number, shape and function of teats and show largely different prevalence of non-functional inverted teats. The expression patterns of fetal mammary complexes obtained at 63 and 91 days post conception (dpc) from German Landrace (GL) and Pietrain (PI) were analyzed by Affymetrix GeneChip Porcine Genome Arrays.

Results

The expression of 11,731 probe sets was analysed between the two stages within and among breeds. The analysis showed the largest distinction of samples of the breed GL at 63 dpc from all other samples. According to Ingenuity Pathways Analysis transcripts with abundance at the four comparisons made (GL63-GL91, PI63-PI93, GL63-PI63 and GL91-PI91) were predominantly assigned to biofunctions relevant to `cell maintenance, proliferation, differentiation and replacement´, `organismal, organ and tissue development´ and `genetic information and nucleic acid processing´. Moreover, these transcripts almost exclusively belong to canonical pathways related to signaling rather than metabolic pathways. The accumulation of transcripts that are up-regulated in GL compared to PI indicate a higher proliferating activity in GL, whereas processes related to differentiation, maturation and maintenance of cells are more prominent in PI. Differential expression was validated by quantitative RT-PCR of five genes (GAB1, MAPK9, PIK3C2B, PIK3C3 and PRKCH) that are involved in several relevant signaling pathways.

Conclusions

The results indicate that mammary complex development in PI precedes GL. The differential expression between the two breeds at fetal stages likely reflects the prenatal initiation of postnatal phenotypes concerning the number and shape as well as functionality of teats.
Enhancer identification in mouse embryonic stem cells using integrative modeling of chromatin and genomic features
Authors: Chen Chih-yu , Morris Quaid , Mitchell Jennifer A
Published: April 2012

Background

Epigenetic modifications, transcription factor (TF) availability and differences in chromatin folding influence how the genome is interpreted by the transcriptional machinery responsible for gene expression. Enhancers buried in non-coding regions are found to be associated with significant differences in histone marks between different cell types. In contrast, gene promoters show more uniform modifications across cell types. Here we used histone modification and chromatin-associated protein ChIP-Seq data sets in mouse embryonic stem (ES) cells as well as genomic features to identify functional enhancer regions. Using co-bound sites of OCT4, SOX2 and NANOG (co-OSN, validated enhancers) and co-bound sites of MYC and MYCN (limited enhancer activity) as enhancer positive and negative training sets, we performed multinomial logistic regression with LASSO regularization to identify key features.

Results

Cross validations reveal that a combination of p300, H3K4me1, MED12 and NIPBL features to be top signatures of co-OSN regions. Using a model from 10 signatures, 83% of top 1277 putative 1 kb enhancer regions (probability greater than or equal to 0.8) overlapped with at least one TF peak from 7 mouse ES cell ChIP-Seq data sets. These putative enhancers are associated with increased gene expression of neighbouring genes and significantly enriched in multiple TF bound loci in agreement with combinatorial models of TF binding. Furthermore, we identified several motifs of known TFs significantly enriched in putative enhancer regions compared to random promoter regions and background. Comparison with an active H3K27ac mark in various cell types confirmed cell type-specificity of these enhancers.

Conclusions

The top enhancer signatures we identified (p300, H3K4me1, MED12 and NIPBL) will allow for the identification of cell type-specific enhancer regions in diverse cell types.
Functional requirements for inhibitory signal transmission by the immunomodulatory receptor CD300a
Authors: DeBell Karen E , Simhadri Venkateswara R , Mariano John L , Borrego Francisco
Published: April 2012

Background

Activation signals can be negatively regulated by cell surface receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). CD300a, an ITIM bearing type I transmembrane protein, is expressed on many hematopoietic cells, including subsets of lymphocytes.

Results

We have taken two approaches to further define the mechanism by which CD300a acts as an inhibitor of immune cell receptor signaling. First, we have expressed in Jurkat T cells a chimeric receptor consisting of the extracellular domains of killer-cell immunoglobulin-like receptor (KIR)2DL2 fused to the transmembrane and cytoplasmic segments of CD300a (KIR-CD300a) to explore surrogate ligand-stimulated inhibition of superantigen stimulated T cell receptor (TCR) mediated cell signaling. We found that intact CD300a ITIMs were essential for inhibition and that the tyrosine phosphorylation of these ITIMs required the src tyrosine kinase Lck. Tyrosine phosphorylation of the CD300a ITIMs created docking sites for both src homology 2 domain containing protein tyrosine phosphatase (SHP)-1 and SHP-2. Suppression of SHP-1 and SHP-2 expression in KIR-CD300a Jurkat T cells with siRNA and the use of DT40 chicken B cell lines expressing CD300a and deficient in several phosphatases revealed that SHP-1, but not SHP-2 or the src homology 2 domain containing inositol 5’ phosphatase SHIP, was utilized by CD300a for its inhibitory activity.

Conclusion

These studies provide new insights into the function of CD300a in tuning T and B cell responses.
The epidemiology of travel-related Salmonella Enteritidis in Ontario, Canada, 2010–2011
Authors: Tighe Mary-Kathryn , Savage Rachel , Vrbova Linda , Toolan Miriam , Whitfield Yvonne , Varga Csaba , Lee Brenda , Allen Vanessa , Maki Anne , Walton Ryan , Johnson Caitlin , Dhar Badal , Ahmed Rafiq , Crowcroft Natasha S , Middleton Dean
Published: April 2012

Background

Increases in the number of salmonellosis cases due to Salmonella Enteritidis (SE) in 2010 and 2011 prompted a public health investigation in Ontario, Canada. In this report, we describe the current epidemiology of travel-related (TR) SE, compare demographics, symptoms and phage types (PTs) of TR and domestically-acquired (DA) cases, and estimate the odds of acquiring SE by region of the world visited.

Methods

All incident cases of culture confirmed SE in Ontario obtained from isolates and specimens submitted to public health laboratories were included in this study. Demographic and illness characteristics of TR and DA cases were compared. A national travel survey was used to provide estimates for the number of travellers to various destinations to approximate rates of SE in travellers. Multivariate logistic regression was used to estimate the odds of acquiring SE when travelling to various world regions.

Results

Overall, 51.9% of SE cases were TR during the study period. This ranged from 35.7% TR cases in the summer travel period to 65.1% TR cases in the winter travel period. Compared to DA cases, TR cases were older and were less likely to seek hospital care. For Ontario travellers, the adjusted odds of acquiring SE was the highest for the Caribbean (OR 37.29, 95% CI 17.87-77.82) when compared to Europe. Certain PTs were more commonly associated with travel (e.g., 1, 4, 5b, 7a, Atypical) than with domestic infection. Of the TR cases, 88.9% were associated with travel to the Caribbean and Mexico region, of whom 90.1% reported staying on a resort. Within this region, there were distinct associations between PTs and countries.

Conclusions

There is a large burden of TR illness from SE in Ontario. Accurate classification of cases by travel history is important to better understand the source of infections. The findings emphasize the need to make travellers, especially to the Caribbean, and health professionals who provide advice to travellers, aware of this risk. The findings may be generalized to other jurisdictions with travel behaviours in their residents similar to Ontario residents.
Exploring functionally related enzymes using radially distributed properties of active sites around the reacting points of bound ligands
Authors: Ueno Keisuke , Mineta Katsuhiko , Ito Kimihito , Endo Toshinori
Published: April 2012

Background

Structural genomics approaches, particularly those solving the 3D structures of many proteins with unknown functions, have increased the desire for structure-based function predictions. However, prediction of enzyme function is difficult because one member of a superfamily may catalyze a different reaction than other members, whereas members of different superfamilies can catalyze the same reaction. In addition, conformational changes, mutations or the absence of a particular catalytic residue can prevent inference of the mechanism by which catalytic residues stabilize and promote the elementary reaction. A major hurdle for alignment-based methods for prediction of function is the absence (despite its importance) of a measure of similarity of the physicochemical properties of catalytic sites. To solve this problem, the physicochemical features radially distributed around catalytic sites should be considered in addition to structural and sequence similarities.

Results

We showed that radial distribution functions (RDFs), which are associated with the local structural and physicochemical properties of catalytic active sites, are capable of clustering oxidoreductases and transferases by function. The catalytic sites of these enzymes were also characterized using the RDFs. The RDFs provided a measure of the similarity among the catalytic sites, detecting conformational changes caused by mutation of catalytic residues. Furthermore, the RDFs reinforced the classification of enzyme functions based on conventional sequence and structural alignments.

Conclusions

Our results demonstrate that the application of RDFs provides advantages in the functional classification of enzymes by providing information about catalytic sites.
Racial differences in the built environment—body mass index relationship? A geospatial analysis of adolescents in urban neighborhoods
Authors: Duncan Dustin T , Castro Marcia C , Gortmaker Steven L , Aldstadt Jared , Melly Steven J , Bennett Gary G
Published: April 2012

Background

Built environment features of neighborhoods may be related to obesity among adolescents and potentially related to obesity-related health disparities. The purpose of this study was to investigate spatial relationships between various built environment features and body mass index (BMI) z-score among adolescents, and to investigate if race/ethnicity modifies these relationships. A secondary objective was to evaluate the sensitivity of findings to the spatial scale of analysis (i.e. 400- and 800-meter street network buffers).

Methods

Data come from the 2008 Boston Youth Survey, a school-based sample of public high school students in Boston, MA. Analyses include data collected from students who had georeferenced residential information and complete and valid data to compute BMI z-score (n = 1,034). We built a spatial database using GIS with various features related to access to walking destinations and to community design. Spatial autocorrelation in key study variables was calculated with the Global Moran’sIstatistic. We fit conventional ordinary least squares (OLS) regression and spatial simultaneous autoregressive error models that control for the spatial autocorrelation in the data as appropriate. Models were conducted using the total sample of adolescents as well as including an interaction term for race/ethnicity, adjusting for several potential individual- and neighborhood-level confounders and clustering of students within schools.

Results

We found significant positive spatial autocorrelation in the built environment features examined (Global Moran’sImost ≥ 0.60; allp = 0.001) but not in BMI z-score (Global Moran’sI = 0.07,p = 0.28). Because we found significant spatial autocorrelation in our OLS regression residuals, we fit spatial autoregressive models. Most built environment features were not associated with BMI z-score. Density of bus stops was associated with a higher BMI z-score among Whites (Coefficient: 0.029,p < 0.05). The interaction term for Asians in the association between retail destinations and BMI z-score was statistically significant and indicated an inverse association. Sidewalk completeness was significantly associated with a higher BMI z-score for the total sample (Coefficient: 0.010,p < 0.05). These significant associations were found for the 800-meter buffer.

Conclusion

Some relationships between the built environment and adolescent BMI z-score were in the unexpected direction. Our findings overall suggest that the built environment does not explain a large proportion of the variation in adolescent BMI z-score or racial disparities in adolescent obesity. However, there are some differences by race/ethnicity that require further research among adolescents.
Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades
Authors: Kunigal Sateesh , Ponnusamy Moorthy P , Momi Navneet , Batra Surinder K , Chellappan Srikumar P
Published: April 2012

Background

The membrane-bound mucins are thought to play an important biological role in cell–cell and cell–matrix interactions, in cell signaling and in modulating biological properties of cancer cell. MUC4, a transmembrane mucin is overexpressed in pancreatic tumors, while remaining undetectable in the normal pancreas, thus indicating a potential role in pancreatic cancer pathogenesis. The molecular mechanisms involved in the regulation of MUC4 gene are not yet fully understood. Smoking is strongly correlated with pancreatic cancer and in the present study; we elucidate the molecular mechanisms by which nicotine as well as agents like retinoic acid (RA) and interferon-γ (IFN-γ) induce the expression of MUC4 in pancreatic cancer cell lines CD18, CAPAN2, AsPC1 and BxPC3.

Results

Chromatin immunoprecipitation assays and real-time PCR showed that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression at the transcriptional level. IFN-γ and RA could collaborate with nicotine in elevating the expression of MUC4, utilizing E2F1 and STAT1 transcription factors. Depletion of STAT1 or E2F1 abrogated the induction of MUC4; nicotine-mediated induction of MUC4 appeared to require α7-nicotinic acetylcholine receptor subunit. Further, Src and ERK family kinases also mediated the induction of MUC4, since inhibiting these signaling molecules prevented the induction of MUC4. MUC4 was also found to be necessary for the nicotine-mediated invasion of pancreatic cancer cells, suggesting that induction of MUC4 by nicotine and other agents might contribute to the genesis and progression of pancreatic cancer.

Conclusions

Our studies show that agents that can promote the growth and invasion of pancreatic cancer cells induce the MUC4 gene through multiple pathways and this induction requires the transcriptional activity of E2F1 and STAT1. Further, the Src as well as ERK signaling pathways appear to be involved in the induction of this gene. It appears that targeting these signaling pathways might inhibit the expression of MUC4 and prevent the proliferation and invasion of pancreatic cancer cells.
Radiation effect on viscous flow of a nanofluid and heat transfer over a nonlinearly stretching sheet
Authors: Hady Fekry M , Ibrahim Fouad S , Abdel-Gaied Sahar M , Eid Mohamed R
Published: April 2012

In this work, we study the flow and heat transfer characteristics of a viscous nanofluid over a nonlinearly stretching sheet in the presence of thermal radiation, included in the energy equation, and variable wall temperature. A similarity transformation was used to transform the governing partial differential equations to a system of nonlinear ordinary differential equations. An efficient numerical shooting technique with a fourth-order Runge-Kutta scheme was used to obtain the solution of the boundary value problem. The variations of dimensionless surface temperature, as well as flow and heat-transfer characteristics with the governing dimensionless parameters of the problem, which include the nanoparticle volume fraction ϕ, the nonlinearly stretching sheet parameter n, the thermal radiation parameter N

R
, and the viscous dissipation parameter Ec, were graphed and tabulated. Excellent validation of the present numerical results has been achieved with the earlier nonlinearly stretching sheet problem of Cortell for local Nusselt number without taking the effect of nanoparticles.
Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia
Authors: Tamayev Robert , D’Adamio Luciano
Published: April 2012

Background

A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer’s disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI). β-cleavage of APP yields the β-carboxyl-terminal (β-CTF) and the amino-terminal-soluble APPβ (sAPPβ) fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDDKI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss.

Results

Here, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of γ-secretase activity.

Conclusion

This harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.
Brain structure and joint hypermobility: Relevance to the
expression of psychiatric symptoms
Authors: Eccles J. A. , Beacher F. D. C. , Gray M. A. , Jones C. L. , Minati L. , Harrison N. A. , Critchley H. D.
Published: April 2012

Joint hypermobility is overrepresented among people with anxiety and can be
associated with abnormal autonomic reactivity. We tested for associations
between regional cerebral grey matter and hypermobility in 72 healthy
volunteers using voxel-based morphometry of structural brain scans.
Strikingly, bilateral amygdala volume distinguished those with from those
without hypermobility. The hypermobility group scored higher for
interoceptive sensitivity yet were not significantly more anxious. Our
findings specifically link hypermobility to the structural integrity of a
brain centre implicated in normal and abnormal emotions and physiological
responses. Our observations endorse hypermobility as a multisystem phenotype
and suggest potential mechanisms mediating clinical vulnerability to
neuropsychiatric symptoms.
Androgens Inhibit the Stimulatory Action of 17β-Estradiol on Normal Human Breast Tissue in Explant Cultures
Authors: Eigėlienė Natalija , Elo Teresa , Linhala Mari , Hurme Saija , Erkkola Risto , Härkönen Pirkko
Published: April 2012

Background:

The data concerning the effects and safety of androgen in human breast tissue are conflicting.

Objective:

Our aim was to analyze the effects of androgens on normal human breast tissue (HBT).

Approach:

We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5α-dihydrotestosterone (DHT) or in combination with 17β-estradiol (E2) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant, respectively.

Results:

The hormone responsiveness of cultured breast tissue was assessed by assaying apolipoprotein-D and prostate-specific antigen expression increased by androgens and amphiregulin and trefoil factor-1 expression induced by E2 treatment. T and DHT reduced proliferation and increased apoptosis in breast epithelium, the effects of which were reversed by bicalutamide. In combination with E2, they suppressed E2-stimulated proliferation and cell survival. DHT also inhibited basal (P < 0.05) and E2-induced expression of cyclin-D1 mRNA (P < 0.05). Immunohistochemistry showed that T (P < 0.05) and DHT (P < 0.05) increased the relative number of AR-positive cells, whereas ERα-positive (P < 0.001) cell numbers were strongly decreased. The percentage of ERβ-positive cells remained unchanged. E2 treatment increased ERα-positive (P < 0.01) cells, whereas AR- (P < 0.05) and ERβ-expressing (P < 0.001) cells diminished. These effects were repressed in combination cultures of E2 with T and DHT.

Conclusion:

T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT and opposed E2-stimulated proliferation and cell survival in an AR-dependent manner. These effects were associated with changes in the proportions of ERα- and AR-positive epithelial cells.
Metabolic Slowing with Massive Weight Loss despite Preservation of Fat-Free Mass
Authors: Johannsen Darcy L. , Knuth Nicolas D. , Huizenga Robert , Rood Jennifer C. , Ravussin Eric , Hall Kevin D.
Published: April 2012

Context:

An important goal during weight loss is to maximize fat loss while preserving metabolically active fat-free mass (FFM). Massive weight loss typically results in substantial loss of FFM potentially slowing metabolic rate.

Objective:

Our objective was to determine whether a weight loss program consisting of diet restriction and vigorous exercise helped to preserve FFM and maintain resting metabolic rate (RMR).

Participants and Intervention:

We measured body composition by dual-energy x-ray absorptiometry, RMR by indirect calorimetry, and total energy expenditure by doubly labeled water at baseline (n = 16), wk 6 (n = 11), and wk 30 (n = 16).

Results:

At baseline, participants were severely obese (×± sd; body mass index 49.4 ± 9.4 kg/m2) with 49 ± 5% body fat. At wk 30, more than one third of initial body weight was lost (−38 ± 9%) and consisted of 17 ± 8% from FFM and 83 ± 8% from fat. RMR declined out of proportion to the decrease in body mass, demonstrating a substantial metabolic adaptation (−244 ± 231 and −504 ± 171 kcal/d at wk 6 and 30, respectively, P < 0.01). Energy expenditure attributed to physical activity increased by 10.2 ± 5.1 kcal/kg·d at wk 6 and 6.0 ± 4.1 kcal/kg·d at wk 30 (P < 0.001 vs. zero).

Conclusions:

Despite relative preservation of FFM, exercise did not prevent dramatic slowing of resting metabolism out of proportion to weight loss. This metabolic adaptation may persist during weight maintenance and predispose to weight regain unless high levels of physical activity or caloric restriction are maintained.
BMP and Delta/Notch signaling control the development of amphioxus epidermal sensory neurons: insights into the evolution of the peripheral sensory system
Authors: Lu Tsai-Ming , Luo Yi-Jyun , Yu Jr-Kai
Published: April 2012

The evolution of the nervous system has been a topic of great interest. To gain more insight into the evolution of the peripheral sensory system, we used the cephalochordate amphioxus. Amphioxus is a basal chordate that has a dorsal central nervous system (CNS) and a peripheral nervous system (PNS) comprising several types of epidermal sensory neurons (ESNs). Here, we show that a proneural basic helix-loop-helix gene (Ash) is co-expressed with the Delta ligand in ESN progenitor cells. Using pharmacological treatments, we demonstrate that Delta/Notch signaling is likely to be involved in the specification of amphioxus ESNs from their neighboring epidermal cells. We also show that BMP signaling functions upstream of Delta/Notch signaling to induce a ventral neurogenic domain. This patterning mechanism is highly similar to that of the peripheral sensory neurons in the protostome and vertebrate model animals, suggesting that they might share the same ancestry. Interestingly, when BMP signaling is globally elevated in amphioxus embryos, the distribution of ESNs expands to the entire epidermal ectoderm. These results suggest that by manipulating BMP signaling levels, a conserved neurogenesis circuit can be initiated at various locations in the epidermal ectoderm to generate peripheral sensory neurons in amphioxus embryos. We hypothesize that during chordate evolution, PNS progenitors might have been polarized to different positions in various chordate lineages owing to differential regulation of BMP signaling in the ectoderm.
Endosperm cellularization defines an important developmental transition for embryo development
Authors: Hehenberger Elisabeth , Kradolfer David , Köhler Claudia
Published: April 2012

The endosperm is a terminal seed tissue that is destined to support embryo development. In most angiosperms, the endosperm develops initially as a syncytium to facilitate rapid seed growth. The transition from the syncytial to the cellularized state occurs at a defined time point during seed development. Manipulating the timing of endosperm cellularization through interploidy crosses negatively impacts on embryo growth, suggesting that endosperm cellularization is a critical step during seed development. In this study, we show that failure of endosperm cellularization in fertilization independent seed 2 (fis2) and endosperm defective 1 (ede1) Arabidopsis mutants correlates with impaired embryo development. Restoration of endosperm cellularization in fis2 seeds by reducing expression of the MADS-box gene AGAMOUS-LIKE 62 (AGL62) promotes embryo development, strongly supporting an essential role of endosperm cellularization for viable seed formation. Endosperm cellularization failure in fis2 seeds correlates with increased hexose levels, suggesting that arrest of embryo development is a consequence of failed nutrient translocation to the developing embryo. Finally, we demonstrate that AGL62 is a direct target gene of FIS Polycomb group repressive complex 2 (PRC2), establishing the molecular basis for FIS PRC2-mediated endosperm cellularization.
Clathrin and AP-1 regulate apical polarity and lumen formation duringC. eleganstubulogenesis
Authors: Zhang Hongjie , Kim Ahlee , Abraham Nessy , Khan Liakot A. , Hall David H. , Fleming John T. , Gobel Verena
Published: April 2012

Clathrin coats vesicles in all eukaryotic cells and has a well-defined role in endocytosis, moving molecules away from the plasma membrane. Its function on routes towards the plasma membrane was only recently appreciated and is thought to be limited to basolateral transport. Here, an unbiased RNAi-based tubulogenesis screen identifies a role of clathrin (CHC-1) and its AP-1 adaptor in apical polarity during de novo lumenal membrane biogenesis in the C. elegans intestine. We show that CHC-1/AP-1-mediated polarized transport intersects with a sphingolipid-dependent apical sorting process. Depleting each presumed trafficking component mislocalizes the same set of apical membrane molecules basolaterally, including the polarity regulator PAR-6, and generates ectopic lateral lumens. GFP::CHC-1 and BODIPY-ceramide vesicles associate perinuclearly and assemble asymmetrically at polarized plasma membrane domains in a co-dependent and AP-1-dependent manner. Based on these findings, we propose a trafficking pathway for apical membrane polarity and lumen morphogenesis that implies: (1) a clathrin/AP-1 function on an apically directed transport route; and (2) the convergence of this route with a sphingolipid-dependent apical trafficking path.
Accuracy of MRI with an endorectal coil for staging endometrial cancer
Authors: Alt Céline D , Brocker Kerstin A , Eichbaum Michael , Sohn Christof , Kopp-Schneider Annette , Kauczor Hans-Ulrich , Hallscheidt Peter
Published: April 2012

Background

The very good results of magnetic resonance imaging (MRI) using an endorectal coil in staging prostate cancer at 1.5T suggested that this imaging technique might be able to be used to stage endometrial cancer, the most common tumor in postmenopausal women.

Purpose

To evaluate the accuracy of MRI with an endorectal surface coil for staging primary endometrial carcinoma.

Material and Methods

A total of 33 consecutive patients with biopsy-proven endometrial cancer underwent 1.5T MRI with an endorectal surface coil (eMRI) using sagittal and axial T2-weighted (T2w) turbo spin echo (TSE), axial T1 gradient echo 2D fat-saturated (fs), sagittal T1 gradient echo 3D with and without contrast enhancement (CE), and axial T1 TSE fs CE sequence. Evaluation of local tumor extension was based on the revised standard TNM classification for endometrial cancer. eMRI staging was compared with the histopathological results after surgery.

Results

A total of 33 consecutive patients underwent eMRI for staging endometrial cancer, and 21 of these underwent primary surgery. The histological stages were as follows: T1a ( n = 8), T1b ( n = 10), T2b ( n = 2), and T3a ( n = 1). Overall staging accuracy by eMRI was 71% (15 of 21). With regard to depth of myometrial invasion, eMRI correctly diagnosed stage T1a in 75% (6/8) and stage T1b in 80% (8/10). eMRI overstaged the tumor in four patients and understaged it in two.

Conclusion

eMRI is highly accurate in staging myometrial invasion. However, eMRI at 1.5T does not seem to be significantly more accurate than pelvic MRI without an endorectal coil at 1.5T for staging primary endometrial cancer. eMRI for endometrial carcinoma therefore might not meet expectations compared with the results obtained using eMRI for staging prostate cancer at 1.5T.
In-phase and out-of-phase gradient-echo imaging in abdominal studies: intra-individual comparison of three different techniques
Authors: Ramalho Miguel , Herédia Vasco , de Campos Rafael OP , Dale Brian M , Azevedo Rafael M , Semelka Richard C
Published: April 2012

Background

T1-weighted gradient-echo in-phase and out-of-phase imaging is an essential component of comprehensive abdominal MR exams. It is useful for the study of fat-containing lesions and to identify various disease states related to the presence of fat in the liver.

Purpose

To compare three T1-weighted in-phase and out-of-phase (IP/OP) gradient-echo imaging sequences in an intra-individual fashion, and to determine whether advantages exist for each of these sequences for various patient types.

Material and Methods

One hundred and eighteen consecutive subjects (74 men, 44 women; mean age 53.9 ± 13.8 years) who had MRI examinations containing all three different IP/OP sequences (two-dimensional spoiled gradient-echo [2D-GRE], three-dimensional gradient-echo [3D-GRE], and magnetization-prepared gradient-recall echo [MP-GRE]) were included. Two different reviewers independently and blindly qualitatively evaluated IP/OP sequences to determine image quality, extent of artifacts, lesion detectability and conspicuity, and subjective grading of liver steatosis for the various sequences. Quantitative analysis was also performed. Qualitative and quantitative data were subjected to statistical analysis.

Results

Respiratory ghosting, parallel imaging, and truncation artifacts as well as shading and blurring were more pronounced with 3D-GRE IP/OP imaging. Overall image quality was higher with 2D-GRE ( P < 0.05). Detectability of low-fluid content lesions was lower with IP/OP MP-GRE sequences. MP-GRE sequences had the lowest SNRs ( P < 0.001). Liver-to-spleen and liver-to-lesion CNRs were significantly lower with 3D-GRE and MP-GR, respectively ( P < 0.001). Fat liver indexes showed strongly positive correlation between all sequences.

Conclusion

Currently, 2D-GRE remains the best approach for clinical IP/OP imaging. The good image quality of MP-GRE sequences acquired in a free-breathing manner should recommend its use in patients unable to suspend breathing.
Clinical and laboratory profile of enteric fever in children in northern India
Authors: Dheer Geetika , Kundra Shaveta , Singh Tejinder
Published: April 2012

The diagnosis of enteric fever poses several problems due to the non-specific and wide array of clinical features. A five-year retrospective study enrolling 136 culture-proven cases of enteric fever was undertaken in order to estimate the clinical and laboratory characteristics, fever clearance time and outcome. The common symptoms and signs were: fever, vomiting, cough, anorexia, diarrhoea, abdominal pain, hepatomegaly, splenomegaly and coated tongue. Enteric fever should be considered in the differential diagnosis of febrile patients with abdominal symptoms.
Efavirenz Severe Hypersensitivity Reaction: Case Report and Rapid Desensitization Protocol Development
Authors: Khalili Hossein , Farasatinasab Maryam , Hajiabdolbaghi Mahboobeh
Published: April 2012

Objective:

Long-term efavirenz desensitization protocols have been reported; however, publication of a rapid desensitization protocol has not been noted to date. We report a case of severe hypersensitivity reaction that was successfully managed using a rapid desensitization protocol.

Case Summary:

In a 52-year old HIV-positive woman, antiretroviral therapy was started with lamivudine 150 mg twice daily, zidovudine 300 mg twice daily, and efavirenz 600 mg daily. Nine days after starting antiretroviral therapy, she developed a generalized maculopapular rash. Despite concomitant chlorpheniramine administration, the rash did not improve. With suspicion of efavirenz hypersensitivity reaction, efavirenz was discontinued for 5 days and when the patient's rash resolved, the drug was restarted at 600 mg daily. The patient developed a severe generalized pruritic rash the next day and all antiretroviral agents were discontinued. One week later, lamivudine and zidovudine were restarted and were well tolerated. An objective causality assessment revealed that an efavirenz hypersensitivity reaction was probable. A 7-hour efavirenz desensitization protocol, starting with a 1:20,000 solution of the target therapeutic dose, was successful. The patient was followed for 6 weeks and had no further signs or symptoms of a hypersensitivity reaction.

Discussion:

Efavirenz hypersensitivity reactions typically include cutaneous reactions that are observed in the first 2 weeks of treatment, are often mild to moderate without systemic manifestation, and improve with continued therapy. Previously, successful desensitization protocols have been described in patients receiving efavirenz who developed rash without systemic symptoms, but these protocols were carried out over 7 or 14 days. This case report indicates a rapid desensitization protocol that may be an available option for some patients.

Conclusions:

Considering that efavirenz can be the cornerstone of many antiretroviral therapy regimens and hypersensitivity reactions can restrict regimen options, effective desensitization protocols are valuable, especially in the developing countries with limited available antiretroviral drugs.
External Economic Exploitation in the DRC: 1990–2005
Authors: Kabamba Patience
Published: April 2012

In his conclusion to his seminal book,Politics in the Congo(1965), Crawford Young wrote the following:

Belgium … constructed in Africa a colonial state which stood out by the thoroughness of its organization, the formidable accretion of power through an interlocking alliance of state, church, and capital, and the ambition of its economic and social objectives. The very strength of the system as a colonial structure, and its steadfast refusal to face effectively the problem of political adaptation until it began to disintegrate, made an ordered transfer of power peculiarly difficult. A colonizer who suddenly lost the profound conviction of the righteousness of his policy was confronted with a revolution by the colonized which lacked both structure and ideology. Total colonialism was replaced by total independence virtually overnight, yet the very completeness of the victory of the colonized had as its concomitant an impotence which emptied success of its substance. (1965:572)
The Political Economy of Reforms in Kenya: The Post-2007 Election Violence and a New Constitution
Authors: Kanyinga Karuti , Long James D.
Published: April 2012

This article explores the package of “Agenda item 4” reforms undertaken by the Kenyan government in the mediation process following the 2007–8 postelection violence, including those relating to long-standing issues over constitutional revision. It situates the previous lack of reforms within Kenya's political economy and demonstrates how political and economic interests thwarted progress and produced the postelection crisis. It also examines the more recent attempts to address reforms following the signing of the National Accord and the creation of a power-sharing government, and finds strong public support for constitutional revision. It concludes that these pressures from below, along with a realignment of political interests and institutional change from power-sharing, helped support reform.
The Continuing Process of Decolonization in the Congo: Fifty Years Later
Authors: Newbury David
Published: April 2012

Introduction

While independence negotiations in the Congo were succinct, decolonization was a long and tortuous process. Indeed, in some respects it continues today, at least in the eyes of many people in eastern Congo, who feel that the formal demands of the colonial state are reflected in the informal impositions of the current state—and of neighboring states. Certainly many Congolese today feel that they have no adequate state structure to address their collective needs as a people, or to represent them on an international stage, or even to protect them from invasion, extraction, and occupation. Lacking effective state structures to protect their interests is not new: the colonial state in the Congo was marked by its intrusive presence in mobilizing labor, requiring crop production, and imposing taxes, among many other demands. But the character of life in the Congo today does not reflect anyone's vision of what independence would bring. At best, the last fifty years can be seen as a process of an aborted decolonization, and in some ways the violence now present in the Congo can be seen as the result of the unfulfilled aspirations of decolonization—or as the deferred violence of a decolonization gone awry (see Newbury 2009).
Reform and Political Impunity in Kenya: Transparency without Accountability
Authors: Gīthīnji Mwangi wa , Holmquist Frank
Published: April 2012

Kenya has been going through a period of political reform since 1991, when section 2A of the constitution, which had made Kenya a de jure one-party state, was repealed. This reform followed a prolonged struggle on the part of citizens both inside and outside the country, and their call for democracy was one that, after the fall of the Berlin Wall, was embraced by Western countries. Via diplomatic pressure and conditionality on aid, Western donors played an important role in the repeal of section 2A, the return of multiparty elections, and the creation and reform of a number of political institutions and offices via a separation of powers. But although these changes were supported by the political opposition and much of civil society in Kenya, they did not rise organically from the national struggle over political power. Nor did these reforms lead to a determination in the country to hold the political elite accountable for their transgressions. This article argues that modern Kenya's history of economic and political inequality has resulted in a population whose very divisions make it difficult for politicians to be disciplined. Accountability has two dimensions: the horizontal accountability among branches of government that is assured by checks and balances, and the vertical accountability of the state to its citizens. Vertical accountability depends on a constituency of like-minded citizens defending broad national interests, or an electorate with a collective identity or set of identities attached to the Kenyan nation. But in the absence of such shared goals and demands, narrow personal and local interests prevail, and politicians remain unaccountable to the nation as a whole.
China in Ethiopia: Diplomacy and Economics of Sino-optimism
Authors: Adem Seifudein
Published: April 2012

This article examines the motive behind China's increased activities in Ethiopia in recent years and concludes that it lies in Ethiopia's perceived diplomatic usefulness. If China's relations with many African countries could be described as one of “infrastructure for natural resources,” the Sino-Ethiopian relationship can be described “infrastructure for diplomatic support.” After exploring the nature and scope of Ethiopia's relations with China and highlighting areas of divergence of interest, the article seeks to demonstrate how the convergence of interests between the two countries has ushered in a period of Sino-optimism among Ethiopia's elite and rising expectations among ordinary Ethiopians.
Land Conflict and Distributive Politics in Kenya
Authors: Boone Catherine
Published: April 2012

This paper argues that even with the incorporation of land policy provisions into Kenya's new constitution, there is every reason to believe that in the near future, highly politicized land conflict will continue. This is because land politics in Kenya is a redistributive game that creates winners and losers. Given the intensely redistributive potential of the impending changes in Kenya's land regime—and the implications of the downward shift in the locus of control over land allocation through decentralization of authority to county governments—there is no guarantee that legislators or citizens will be able to agree on concrete laws to realize the constitution's calls for equity and justice in land matters. This article traces the main ways in which state power has been used to distribute and redistribute land (and land rights) in the Rift Valley, focusing on post-1960 smallholder settlement schemes, land-buying companies, and settlement in the forest reserves, and it highlights the long-standing pattern of political contestation over the allocation of this resource. It then traces the National Land Policy debate from 2002 to 2010, focusing on the distributive overtones and undertones of the policy and of the debate over the new constitution that incorporated some of its main tenets.