bluuebunny/crossref_metadata_2025 huggingface dataset:
FOXO1 is a tumor suppressor in classical Hodgkin lymphoma
Authors: Xie Linka , Ushmorov Alexey , Leithäuser Frank , Guan Hanfeng , Steidl Christian , Färbinger Johanna , Pelzer Christin , Vogel Marion J. , Maier Harald J. , Gascoyne Randy D. , Möller Peter , Wirth Thomas
Published: February 2012

The FOXO transcription factors control proliferation and apoptosis in different cell types. Their activity is regulated by posttranslational modifications, mainly by the PI3K-PKB pathway, which controls nuclear export and degradation. We show that FOXO1 is highly expressed in normal germinal center B cells as well as in non-Hodgkin lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue non-Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma. In contrast, in 31 of 32 classical Hodgkin lymphoma (cHL) cases, Hodgkin and Reed-Sternberg cells were FOXO1 negative. Neoplastic cells of nodular lymphocyte-predominant Hodgkin lymphoma were negative in 14 of 20 cases. FOXO1 was down-regulated in cHL cell lines, whereas it was expressed in non-Hodgkin lymphoma cell lines at levels comparable with normal B cells. Ectopic expression of a constitutively active FOXO1 induced apoptosis in cHL cell lines and blocked proliferation, accompanied with cell-cycle arrest in the G0/G1 phase. We found that, in cHL cell lines, FOXO1 is inactivated by multiple mechanisms, including constitutive activation of AKT/PKB and MAPK/ERK kinases and up-regulation of microRNAs miR-96, miR-182, and miR-183. These results suggest that FOXO1 repression contributes to cHL lymphomagenesis.
Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics
Authors: Greenberg Alexandra J. , Rajkumar S. Vincent , Vachon Celine M.
Published: February 2012

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.
NHERF-2 maintains endothelial homeostasis
Authors: Bhattacharya Resham , Wang Enfeng , Dutta Shamit K. , Vohra Pawan K. , E Guangqi , Prakash Y. S. , Mukhopadhyay Debabrata
Published: February 2012

The Na+/H+ exchanger regulatory factor-2 (NHERF-2) is an integral component of almost all endothelial cells (ECs), yet its endothelial function is not known. Here, we found that NHERF-2, is a key regulator of endothelial homeostasis because NHERF-2–silenced ECs proliferate at a much higher rate even in the absence of mitogens such as VEGF compared with control ECs. We further show that the hyperproliferation phenotype of NHERF-2–silenced EC is because of an accelerated cell cycle that is probably caused by a combination of the following factors: increased cytoplasmic calcium, increased expression of c-Myc, increased expression of cyclin D1, and reduced expression of p27. Using an experimental mouse model of human hemangioma, we found that the endothelial neoplasms derived from NHERF-2–silenced cells were much larger in volume than those derived from control cells. Thus, NHERF-2 is a negative regulator of endothelial proliferation and may have important roles in endothelial homeostasis and vascular modeling.
Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes
Authors: Damm Frederik , Kosmider Olivier , Gelsi-Boyer Véronique , Renneville Aline , Carbuccia Nadine , Hidalgo-Curtis Claire , Della Valle Véronique , Couronné Lucile , Scourzic Laurianne , Chesnais Virginie , Guerci-Bresler Agnes , Slama Bohrane , Beyne-Rauzy Odile , Schmidt-Tanguy Aline , Stamatoullas-Bastard Aspasia , Dreyfus François , Prébet Thomas , de Botton Stéphane , Vey Norbert , Morgan Michael A. , Cross Nicholas C. P. , Preudhomme Claude , Birnbaum Daniel , Bernard Olivier A. , Fontenay Michaela
Published: February 2012

A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1mut patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2mut patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2mut patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2mut patients. U2AF35mut patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2mut/TET2wt (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.
Invasive fungal infection among hematopoietic stem cell transplantation patients with mechanical ventilation in the intensive care unit
Authors: Hung Chen-Yiu , Kao Kuo-Chin , Wang Po-Nan , Hu Han-Chung , Hsieh Meng-Jer , Fu Jui-Ying , Chang Chih-Hao , Li Li-Fu , Huang Chung-Chi , Tsai Ying-Huang , Yang Cheng-Ta
Published: February 2012

Background

Invasive fungal infection (IFI) is associated with high morbidity and high mortality in hematopoietic stem cell transplantation (HSCT) patientsThe purpose of this study was to assess the characteristics and outcomes of HSCT patients with IFIs who are undergoing MV at a single institution in Taiwan.

Methods

We performed an observational retrospective analysis of IFIs in HSCT patients undergoing mechanical ventilation (MV) in an intensive care unit (ICU) from the year 2000 to 2009. The characteristics of these HSCT patients and risk factors related to IFIs were evaluated. The status of discharge, length of ICU stay, date of death and cause of death were also recorded.

Results

There were 326 HSCT patients at the Linkou Chang-Gung Memorial Hospital (Taipei, Taiwan) during the study period. Sixty of these patients (18%) were transferred to the ICU and placed on mechanical ventilators. A total of 20 of these 60 patients (33%) had IFIs. Multivariate analysis indicated that independent risk factors for IFI were admission to an ICU more than 40 days after HSCT, graft versus host disease (GVHD), and high dose corticosteroid (p < 0.01 for all). The overall ICU mortality rate was 88% (53 of 60 patients), and was not significantly different for patients with IFIs (85%) and those without IFIs (90%, p = 0.676).

Conclusion

There was a high incidence of IFIs in HSCT patients requiring MV in the ICU in our study cohort. The independent risk factors for IFI are ICU admission more than 40 days after HSCT, GVHD, and use of high-dose corticosteroid.
L-Rhamnose induction of Aspergillus nidulans α-L-rhamnosidase genes is glucose repressed via a CreA-independent mechanism acting at the level of inducer uptake
Authors: Tamayo-Ramos Juan A , Flipphi Michel , Pardo Ester , Manzanares Paloma , Orejas Margarita
Published: February 2012

Background

Little is known about the structure and regulation of fungal α-L-rhamnosidase genes despite increasing interest in the biotechnological potential of the enzymes that they encode. Whilst the paradigmatic filamentous fungus Aspergillus nidulans growing on L-rhamnose produces an α-L-rhamnosidase suitable for oenological applications, at least eight genes encoding putative α-L-rhamnosidases have been found in its genome. In the current work we have identified the gene (rhaE) encoding the former activity, and characterization of its expression has revealed a novel regulatory mechanism. A shared pattern of expression has also been observed for a second α-L-rhamnosidase gene, (AN10277/rhaA).

Results

Amino acid sequence data for the oenological α-L-rhamnosidase were determined using MALDI-TOF mass spectrometry and correspond to the amino acid sequence deduced from AN7151 (rhaE). The cDNA of rhaE was expressed in Saccharomyces cerevisiae and yielded p NP-rhamnohydrolase activity. Phylogenetic analysis has revealed this eukaryotic α-L-rhamnosidase to be the first such enzyme found to be more closely related to bacterial rhamnosidases than other α-L-rhamnosidases of fungal origin. Northern analyses of diverse A. nidulans strains cultivated under different growth conditions indicate that rhaA and rhaE are induced by L-rhamnose and repressed by D-glucose as well as other carbon sources, some of which are considered to be non-repressive growth substrates. Interestingly, the transcriptional repression is independent of the wide domain carbon catabolite repressor CreA. Gene induction and glucose repression of these rha genes correlate with the uptake, or lack of it, of the inducing carbon source L-rhamnose, suggesting a prominent role for inducer exclusion in repression.

Conclusions

The A. nidulans rhaE gene encodes an α-L-rhamnosidase phylogenetically distant to those described in filamentous fungi, and its expression is regulated by a novel CreA-independent mechanism. The identification of rhaE and the characterization of its regulation will facilitate the design of strategies to overproduce the encoded enzyme - or homologs from other fungi - for industrial applications. Moreover, A. nidulans α-L-rhamnosidase encoding genes could serve as prototypes for fungal genes coding for plant cell wall degrading enzymes regulated by a novel mechanism of CCR.
Targeting different types of human meningioma and glioma cells using a novel adenoviral vector expressing GFP-TRAIL fusion protein from hTERT promoter
Authors: Li Jessica T , Bian Ka , Zhang Alan L , Kim Dong H , Ashley William W , Nath Rahul , McCutcheon Ian , Fang Bingliang , Murad Ferid
Published: February 2012

Objective

The objective of this study was to evaluate the anti-tumor effects of Ad/gTRAIL (an adenoviral vector in which expression of GFP and TRAIL is driven by a human telomerase reverse transcriptase promoter, hTERT) on malignant meningiomas and gliomas.

Background

Gliomas and meningiomas are the two most common types of human brain tumors. Currently there is no effective cure for recurrent malignant meningiomas or for gliomas. Ad/gTRAIL has been shown to be effective in killing selected lung, colon and breast cancer cells, but there have been no studies reporting its antitumor effects on malignant meningiomas. Therefore, we tested the antitumor effect of Ad/gTRAIL for the first time in human malignant meningioma and glioma cell lines, and in intracranial M6 and U87 xenografts.

Methods

Materials and Methods: Human malignant meningioma and glioma cells were infected with adenoviruses, Ad/gTRAIL and Ad/CMV-GFP. Cell viability was determined by proliferation assay. FACS analysis and quantification of TRAIL were used to measure apoptosis in these cells. We injected Ad/gTRAIL viruses in intracranial M6 and U87 xenografts, and measured the brain tumor volume, quantified apoptosis by TUNEL assay in the brain tumor tissue.

Results

Our studies demonstrate that in vitro/in vivo treatment with Ad/gTRAIL virus resulted in significant increase of TRAIL activity, and elicited a greater tumor cell apoptosis in malignant brain tumor cells as compared to treatment with the control, Ad/CMV-GFP virus without TRAIL activity.

Conclusions

We showed for the first time that adenovirus Ad/gTRAIL had significant antitumor effects against high grade malignant meningiomas as well as gliomas. Although more work needs to be done, our data suggests that Ad/gTRAIL has the potential to be useful as a tool against malignant brain tumors.
Formation mechanism of SiGe nanorod arrays by combining nanosphere lithography and Au-assisted chemical etching
Authors: Lai Chih-Chung , Lee Yun-Ju , Yeh Ping-Hung , Lee Sheng-Wei
Published: February 2012

The formation mechanism of SiGe nanorod (NR) arrays fabricated by combining nanosphere lithography and Au-assisted chemical etching has been investigated. By precisely controlling the etching rate and time, the lengths of SiGe NRs can be tuned from 300 nm to 1μm. The morphologies of SiGe NRs were found to change dramatically by varying the etching temperatures. We propose a mechanism involving a locally temperature-sensitive redox reaction to explain this strong temperature dependence of the morphologies of SiGe NRs. At a lower etching temperature, both corrosion reaction and Au-assisted etching process were kinetically impeded, whereas at a higher temperature, Au-assisted anisotropic etching dominated the formation of SiGe NRs. With transmission electron microscopy and scanning electron microscopy analyses, this study provides a beneficial scheme to design and fabricate low-dimensional SiGe-based nanostructures for possible applications.
5, 8, 11, 14-eicosatetraynoic acid suppresses CCL2/MCP-1 expression in IFN-γ-stimulated astrocytes by increasing MAPK phosphatase-1 mRNA stability
Authors: Lee Jee Hoon , Kim Hyunmi , Woo Joo Hong , Joe Eun-hye , Jou Ilo
Published: February 2012

Background

The peroxisome proliferator-activated receptor (PPAR)-α activator, 5,8,11,14-eicosatetraynoic acid (ETYA), is an arachidonic acid analog. It is reported to inhibit up-regulation of pro-inflammatory genes; however, its underlying mechanism of action is largely unknown. In the present study, we focused on the inhibitory action of ETYA on the expression of the chemokine, CCL2/MCP-1, which plays a key role in the initiation and progression of inflammation.

Methods

To determine the effect of ETYA, primary cultured rat astrocytes and microglia were stimulated with IFN-γ in the presence of ETYA and then, expression of CCL2/MCP-1 and MAPK phosphatase (MKP-1) were determined using RT-PCR and ELISA. MKP-1 mRNA stability was evaluated by treating actinomycin D. The effect of MKP-1 and human antigen R (HuR) was analyzed by using specific siRNA transfection system. The localization of HuR was analyzed by immunocytochemistry and subcellular fractionation experiment.

Results

We found that ETYA suppressed CCL2/MCP-1 transcription and secretion of CCL2/MCP-1 protein through up-regulation of MKP-1mRNA levels, resulting in suppression of c-Jun N-terminal kinase (JNK) phosphorylation and activator protein 1 (AP1) activity in IFN-γ-stimulated brain glial cells. Moreover, these effects of ETYA were independent of PPAR-α. Experiments using actinomycin D revealed that the ETYA-induced increase in MKP-1 mRNA levels reflected an increase in transcript stability. Knockdown experiments using small interfering RNA demonstrated that this increase in MKP-1 mRNA stability depended on HuR, an RNA-binding protein known to promote enhanced mRNA stability. Furthermore, ETYA-induced, HuR-mediated mRNA stabilization resulted from HuR-MKP-1 nucleocytoplasmic translocation, which served to protect MKP-1 mRNA from the mRNA degradation machinery.

Conclusion

ETYA induces MKP-1 through HuR at the post-transcriptional level in a receptor-independent manner. The mechanism revealed here suggests eicosanoids as potential therapeutic modulators of inflammation that act through a novel target.
Krüppel-like factor 4 (KLF4) promotes the survival of natural killer cells and maintains the number of conventional dendritic cells in the spleen
Authors: Shik Park Chun , Lee Ping-Hsien , Yamada Takeshi , Burns Audrea , Shen Ye , Puppi Monica , Lacorazza H Daniel
Published: February 2012

The development and survival of NK cells rely on a complex, spatiotemporal gene expression pattern regulated by specific transcription factors in NK cells and tissue-specific microenvironments supported by hematopoietic cells. Here, we show that somatic deletion of the KLF4 gene, using inducible and lineage-specific cre-transgenic mice, leads to a significant reduction of NK cells (NK1.1+ TCR-β−) in the blood and spleen but not in the BM, liver, or LNs. Functional and immunophenotypic analyses revealed increased apoptosis of CD27+/− CD11b+ NK cells in the spleen of KLF4-deficient mice, although remaining NK cells were able to lyse tumor target cells and produce IFN-γ. A normal recovery of adoptively transferred KLF4-deficient NK cells in WT hosts suggested that the survival defect was not intrinsic of NK cells. However, BM chimeras using KLF4-deficient mice as donors indicated that reduced survival of NK cells depended on BM-derived hematopoietic cells in the spleen. The number of CD11chi DCs, which are known to support NK cell survival, was reduced significantly in the spleen of KLF4-deficient mice, likely a result of a lower number of precDC progenitor cells in this tissue. Taken together, our data suggest that the pluripotency-associated gene KLF4 is required for the maintenance of DCs in the spleen and consequently, survival of differentiated NK cells in this tissue.
Apoptosis signaling in influenza virus propagation, innate host defense, and lung injury
Authors: Herold Susanne , Ludwig Stephan , Pleschka Stephan , Wolff Thorsten
Published: February 2012

A review of mechanisms of apoptosis induction in influenza virus-infected cells, and the impact of apoptotic signaling on viral propagation, immune responses, and tissue injury.

Programmed cell death is a crucial cellular response frequently observed in IV-infected tissue. This article reviews the current knowledge on the molecular virus–host interactions that induce apoptosis pathways in an IV-infected cell and the functional implications of these cellular signaling events on viral propagation at distinct steps during the viral replication cycle. Furthermore, it summarizes the role of IV-induced apoptosis pathways in equilibrating the hostˈs antiviral immune response between effective viral clearance and development of severe apoptotic lung injury.
Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells
Authors: Busch Tobias , Armacki Milena , Eiseler Tim , Joodi Golsa , Temme Claudia , Jansen Julia , von Wichert Götz , Omary M. Bishr , Spatz Joachim , Seufferlein Thomas
Published: February 2012

Cell migration and invasion are largely dependent on the complex organization of the various cytoskeletal components. Whereas the role of actin filaments and microtubules in cell motility is well established, the role of intermediate filaments in this process is incompletely understood. Organization and structure of the keratin cytoskeleton, which consists of heteropolymers of at least one type 1 and one type 2 intermediate filament, are in part regulated by post-translational modifications. In particular, phosphorylation events influence the properties of the keratin network. Sphingosylphosphorylcholine (SPC) is a bioactive lipid with the exceptional ability to change the organization of the keratin cytoskeleton, leading to reorganization of keratin filaments, increased elasticity, and subsequently increased migration of epithelial tumor cells. Here we investigate the signaling pathways that mediate SPC-induced keratin reorganization and the role of keratin phosphorylation in this process. We establish that the MEK–ERK signaling cascade regulates both SPC-induced keratin phosphorylation and reorganization in human pancreatic and gastric cancer cells and identify Ser431 in keratin 8 as the crucial residue whose phosphorylation is required and sufficient to induce keratin reorganization and consequently enhanced migration of human epithelial tumor cells.
The Vam6-Gtr1/Gtr2 pathway activates TORC1 in response to amino acids in fission yeast
Authors: Valbuena Noelia , Guan Kun-Liang , Moreno Sergio
Published: February 2012

The Rag family of GTPases has been implicated in TORC1 activation in Drosophila and in mammalian cells in response to amino acids. We have investigated the role of Rag GTPases, Gtr1 and Gtr2, in TORC1 regulation in Schizosaccharomyces pombe. Fission yeast Gtr1 and Gtr2 are non-essential proteins that enhance cell growth in the presence of amino acids in the medium. The function of Gtr1 and Gtr2 in nutrient signaling is further supported by the observation that even in rich medium the deletion of either gene results in the promotion of mating, meiosis and sporulation, consistent with the downregulation of TORC1. We show that Gtr1 and Gtr2 colocalize with TORC1 in vacuoles, where TORC1 is presumably activated. Epistasis analyses indicated that Gtr1/Gtr2 functions downstream of Vam6 and upstream of TORC1 in response to amino acid signals. Our data demonstrate the existence of an evolutionarily conserved pathway with Vam6-Gtr1/Gtr2 activating TORC1, which in turns stimulates cell growth and inhibits sexual differentiation.
RSK2 protects mice against TNF-induced bone loss
Authors: Böhm Christina , Derer Anja , Axmann Roland , Hillienhoff Ulrike , Zaiss Mario M. , Luther Julia , Zech Christine , Stock Michael , Scholtysek Carina , Engelke Klaus , Hess Andreas , Tuckermann Jan P. , Schett Georg , David Jean-Pierre
Published: February 2012

Tumor necrosis factor (TNF)-α is a key cytokine regulator of bone and precipitates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNFα is poorly defined. Here, we demonstrate that inactivating the pro-osteoblastogenic ERK activated ribosomal S6 kinase RSK2 leads to a drastically accelerated and amplified systemic bone loss in mice ectopically expressing TNF-α (human TNF transgenic, hTNFtg mice). The phenotype is associated with a decreased bone formation by osteoblasts which are strongly reduced in the hTNFtg mice lacking RSK2 as well as a drastic increased bone destruction by osteoclasts. The molecular basis is a cell autonomous increased sensitivity of osteoblasts as well as of osteocytes to TNF-induced apoptosis combined to an enhancement of their osteoclasts supportive activity. Thus, RSK2 exerts a strong negative regulatory loop on TNF-induced bone loss.
GAS2L3, a novel target gene of the dream complex, is required for proper cytokinesis and genomic stability
Authors: Wolter Patrick , Schmitt Kathrin , Fackler Marc , Kremling Heidi , Probst Leona , Hauser Stefanie , Gruss Oliver J. , Gaubatz Stefan
Published: February 2012

The mammalian DREAM complex is key regulator of cell cycle regulated gene transcription and drives the expression of many gene products required for mitosis and cytokinesis. In this study we characterized a novel target gene of DREAM, GAS2L3, which belongs to the GAS2 family of proteins with putative actin and microtubule binding domains. We found that GAS2L3 localizes to the spindle midzone and the midbody during anaphase and cytokinesis, respectively. Biochemical studies show that GAS2L3 binds to and bundles microtubules as well as F-actin in vitro. Strikingly, the RNAi-mediated knock-down of GAS2L3 results in chromosome segregation defects, in multinucleated cells and cells with multi-lobed nuclei. Likewise, chronic downregulation of GAS2L3 causes chromosome loss and aneuploidy. Time-lapse video microscopy experiments in GAS2L3 knock-down cells reveal abnormal oscillation of chromatin and the spindle during cytokinesis. Taken together, our data reveal novel, important roles of GAS2L3 for faithful cell division. Our work thus contributes to the understanding of how DREAM regulates cytokinesis.
Contrasting roles of condensin I and II in mitotic chromosome formation
Authors: Green Lydia C. , Kalitsis Paul , Chang Tsz M. , Cipetic Miri , Kim Ji Hun , Marshall Owen , Turnbull Lynne , Whitchurch Cynthia B. , Vagnarelli Paola , Samejima Kumiko , Earnshaw William C. , Choo K. H. Andy , Hudson Damien F.
Published: February 2012

In vertebrates, two condensin complexes exist, condensin I and II, which have differing but unresolved roles in organizing mitotic chromosomes. To accurately dissect the role of each complex in mitosis, we have made and studied the first vertebrate conditional knockouts of the condensin I subunit CAP-H and condensin II subunit CAP-D3 in chicken DT40 cells. Live-cell imaging reveals highly distinct segregation defects. CAP-D3/condensin II KO results in masses of chromatin forming anaphase bridges. CAP-H/condensin I KO anaphases have a more subtle defect, with chromatids showing fine chromatin fibres that are associated with failure of cytokinesis and cell death. Super-resolution microscopy reveals condensin I-depleted mitotic chromosomes as wider and shorter with a diffuse chromosome scaffold, while condensin II-depleted chromosomes retain a more defined scaffold with chromosomes more stretched and seemingly lacking in axial rigidity. We conclude condensin II is required primarily to provide rigidity by establishing an initial chromosome axis around which condensin I can arrange loops of chromatin.
Identification of new surfaces of Cofilin that link mitochondrial function to the control of multi-drug resistance
Authors: Kotiadis Vassilios N. , Leadsham Jane E. , Bastow Emma L. , Gheeraert Aline , Whybrew Jennafer M , Bard Martin , Lappalainen Pekka , Gourlay Campbell W.
Published: February 2012

ADF/cofilin family proteins are essential regulators of actin cytoskeletal dynamics. Recent evidence also implicates cofilin in the regulation of mitochondrial function. Here, we identify new functional surfaces of cofilin that are linked with mitochondrial function and stress responses in the budding yeast S. cerevisiae. Our data links surfaces of cofilin that are involved in separable activities of actin filament disassembly or stabilisation, to the regulation of mitochondrial morphology and the activation status of Ras respectively. Importantly, charge alterations to conserved surfaces of cofilin that do not interfere with its actin regulatory activity leads to a dramatic increase in respiratory function that triggers a retrograde signal to up-regulate a battery of ABC transporters and concurrent metabolic changes that support multi-drug resistance. We hypothesise that cofilin functions within a novel bio-sensing system that connects the cytoskeleton and mitochondrial function to environmental challenge.
Functional specialization of the yeast Rho1 GTP exchange factors
Authors: Krause Sue Ann , Cundell Michael J. , Poon Pak P. , McGhie Josephine , Johnston Gerry C. , Price Clive , Gray Joseph V.
Published: February 2012

Rho GTPases are regulated in complex spatiotemporal patterns that may be dependent, in part at least, on the multiplicity of their GTP exchange factors (GEFs). Here, we examine the extent of and basis for functional specialization of the Rom2 and Tus1 GEFs that activate the yeast Rho1 GTPase, the ortholog of mammalian RhoA. First, we find that these GEFs selectively activate different Rho1-effector branches. Second, the synthetic genetic networks around ROM2 and TUS1 confirm very different global in vivo roles for these GEFs. Third, the GEFs are not functionally interchangeable: Tus1 cannot replace the essential role of Rom2, even when overexpressed. Fourth, we find that Rom2 and Tus1 localize differently: Rom2 to the growing bud surface and to the bud neck at cytokinesis; Tus1 only to the bud neck but in a distinct pattern. Finally, we find that these GEFs are dependent on different protein co-factors: Rom2 function and localization is largely dependent on Ack1, a SEL1 domain containing protein; Tus1 function and localization is largely dependent on the Tus1-interacting protein Ypl066w (which we name Rgl1). We have revealed a surprising level of diversity among the Rho1 GEFs that contributes another level of complexity to the spatiotemporal control of Rho1.
N-Glycosylation Alters Cadherin-Mediated Intercellular Binding Kinetics
Authors: Langer Matthew D. , Guo Huabei , Shashikanth Nitesh , Pierce J. Michael , Leckband Deborah E.
Published: February 2012

These results present direct evidence that the N-glycosylation state of neural cadherin impacts the intrinsic kinetics of cadherin-mediated intercellular binding. Micropipette manipulation measurements quantified the effect of N-glycosylation mutations intercellular binding dynamics. The wild type protein exhibits a two-stage binding process in which a fast, initial binding step is followed by a short lag and second, slower transition to the final binding stage. Mutations that ablate N-glycosylation at three sites on the extracellular domains 2 and 3 (EC2-3) of neural cadherin alter this kinetic fingerprint. Glycosylation does not affect the affinities between the adhesive N-terminal domains, but instead modulates additional cadherin interactions, which govern the dynamics of intercellular binding. These results, together with prior findings that these hypo-glycosylation mutations increase the prevalence of cis dimers on cell membranes, suggest a binding mechanism in which initial adhesion is followed by additional cadherin interactions, which enhance binding but are modulated by N-glycosylation. Given that oncogene expression drives specific changes in N-glycosylation, these results provide insight into possible mechanisms altering cadherin function during tumor progression.
STIL is required for centriole duplication in human cells
Authors: Vulprecht Julia , David Ahuvit , Tibelius Alexandra , Castiel Asher , Konotop Gleb , Liu Fengying , Bestvater Felix , Raab Marc S. , Zentgraf Hanswalter , Izraeli Shai , Krämer Alwin
Published: February 2012

Centrioles are key structural elements of centrosomes and primary cilia. In mammals, only a few proteins including PLK4, CPAP (CENPJ), SAS6, CEP192, CEP152 and CEP135 have thus far been identified to be required for centriole duplication. STIL (SCL/TAL1 interrupting locus, also known as SIL) is a centrosomal protein that is essential for mouse and zebrafish embryonic development and mutated in primary microcephaly. Here, we show that STIL localizes to the pericentriolar material surrounding parental centrioles. Its overexpression results in excess centriole formation. siRNA-mediated depletion of STIL leads to loss of centrioles and abrogates PLK4-induced centriole overduplication. Additionally, we show that STIL is necessary for SAS6 recruitment to centrioles, suggesting that it is essential for daughter centriole formation, interacts with the centromere protein CPAP and rapidly shuttles between the cytoplasm and centrioles. Consistent with the requirement of centrioles for cilia formation, Stil–/– mouse embryonic fibroblasts lack primary cilia – a phenotype that can be reverted by restoration of STIL expression. These findings demonstrate that STIL is an essential component of the centriole replication machinery in mammalian cells.
Hypertension in pregnancy: a review of therapeutic options
Authors: Kernaghan D , Duncan A C , McKay G A
Published: February 2012

Hypertensive disorders in pregnancy are common and can occur as a result of pre-existing hypertension or as new onset hypertension usually in the second half of pregnancy. In either situation there is potential for considerable perinatal and maternal morbidity and mortality. This review article aims to compare therapeutic options outlined in a selection of national guidelines and to look in more detail at the most commonly prescribed drugs – labetalol, methyldopa and nifedipine – with respect to their pharmacology and the evidence for their use in pregnancy. We will also consider the rationale for identifying and treating hypertension in pregnancy and the effect this can have on short- and long-term maternal and neonatal outcomes.
Jobs encompassing prolonged sitting in cramped positions and risk of venous thromboembolism: cohort study
Authors: Suadicani Poul , Hannerz Harald , Bach Elsa , Gyntelberg Finn
Published: February 2012

Objectives

There is mounting evidence that prolonged cramped sitting in connection with long-lasting air travel increases the risk of deep vein thrombosis of the legs and pulmonary embolism, i.e. venous thromboembolism (VTE). Prolonged cramped sitting may occur even in various jobs unrelated to air travel, and, theoretically, be associated with an increased risk of VTE. The issue is unsettled.

Design

A dynamic cohort study (open for both entry and departure) in Danish national registers 1997–2006.

Participants

20–59-year-old manual workers. The cohort consisted of an exposed group with job functions basically characterised as sedentary ( n= 105,564) and a control group with more dynamic work ( n = 283,966).

Setting

Denmark.

Main outcome measures

Deaths and hospital contacts due to pulmonary embolism and deep vein thrombosis.

Results

Compared with occupations characterized by dynamic physical activity, the group encompassing those who would potentially be exposed to prolonged sitting in ergonomically adverse positions, had a significantly higher risk of pulmonary embolism ( n = 77, relative risk 1.28; 95% CI 0.97–1.67, P = 0.04 in one-sided test). With respect to deep vein thrombosis they had a slightly but not significantly higher risk ( n =256, relative risk 1.09; 95% CI 0.94–1.26, P = 0.12).

Conclusion

Despite the crude method used allowing for no control of individual risk factors, occupations encompassing longer and shorter periods of sitting in potentially adverse ergonomic positions, i.e. cramped sitting, had a higher risk of VTE, than a socioeconomically comparable group with more dynamic physical work demands.
RNA:RNA interaction can enhance RNA localization in Drosophila oocytes
Authors: Hartswood Eve , Brodie Jim , Vendra Georgia , Davis Ilan , Finnegan David J.
Published: February 2012

RNA localization is a key mechanism for targeting proteins to particular subcellular domains. Sequences necessary and sufficient for localization have been identified, but little is known about factors that affect its kinetics. Transcripts of gurken and the I factor, a non-LTR retrotransposon, colocalize at the nucleus in the dorso–antero corner of the Drosophila oocyte directed by localization signals, the GLS and ILS. I factor RNA localizes faster than gurken after injection into oocytes, due to a difference in the intrinsic localization ability of the GLS and ILS. The kinetics of localization of RNA containing the ILS are enhanced by the presence of a stem–loop, the A loop. This acts as an RNA:RNA interaction element in vivo and in vitro, and stimulates localization of RNA containing other localization signals. RNA:RNA interaction may be a general mechanism for modulating RNA localization and could allow an mRNA that lacks a localization signal to hitchhike on another RNA that has one.
Das Materielle der Gefühle: Aufwachsen in familialen Dingwelten
Authors: Nohl Arnd-Michael
Published: February 2012

So wichtig materielle Dinge für die menschliche Sozialisation sind, so schwierig ist es, ihre Konstitution in der Erfahrungswelt von kleinen Kindern zu erklären. In diesem Beitrag wird mit dem philosophischen Pragmatismus (James, Mead, Dewey) die Dingkonstitution wie auch die emotionale Qualität der Dingerfahrung reflektiert. Anhand der Kindheitserinnerungen von Literaten und Literatinnen aus der Türkei und Deutschland werden diese theoretischen Einsichten exemplarisch vertieft. Deutlich wird dabei die hohe Relevanz von materiellen Dingen für die emotionale Grundierung des eigenen Weltbezugs.
Nostalgia Overdose. Homesickness in Wedding Ceremonies of the Turkish-German Community in Berlin
Authors: Ergun Köken
Published: February 2012

Having a focus on wedding rituals of the Turkish communities in Berlin, this research is based on the ways in which rituals strengthen community bonding within immigrants away from their homeland. When done periodically, such rituals reassure social connections within immigrant communities, while creating borders to keep others outside. Unlike weddings in Turkey, those in Germany are performed in purpose-built indoor spaces, isolated from the German community. This voluntary isolation enables the restaging of cultural codes and forms of the homeland, which often results in excess of emotions related to nostalgia. This in turn mutates cultural symbols for younger members of the immigrant community and paves the way to confused identities.
Unzählbare Schönheit. Für eine Poetik des Interkulturellen
Authors: Wahbi Hassan
Published: February 2012

In diesem Beitrag möchte ich zurückkommen auf die Frage nach der Erweiterung des Ich im Laufe eines Lebens, welches mehrfältig ist oder wird; es ist dies eine Variante dessen, was ich schon in früheren Texten vorschlug (L’art dialogique, Alexandria 2006; L’apprentissage négatif, Tunis 2008; Hybride toi-même, Casablanca 2009) bezüglich der notwendigen Labilität des Ich, d. h., dass der mehrfältige Mensch nicht mehrfältig ist in seiner Dispersion, sondern im Erarbeiten seiner Redefinition. Alles neu Erworbene bedingt, was er ist und stellt ihn vor etwas Weiteres. Eine Art der Vervollkommnungsmöglichkeit auf persönlichem Niveau, nicht moralisch, sondern eher als Vision der Dinge und des Selbst. Dieses Mal gehe ich von einer weniger verdeckten Subjektivität aus, falls ich das je zu tun versäumte, denn Erfahrung speist sich ja ununterbrochen aus einer interkulturellen Wunde, die sich als Sollbruchstelle träumt.
Emotionen, Selbstachtung und Zusammenleben
Authors: Bencherki Benmeziane
Published: February 2012

Der Beitrag befasst sich mit dem Phänomen des Lachens und seiner Spielarten im Zusammenhang mit der Gestaltung des öffentlichen Lebens im Kontext von Individuation und individueller Expressivität einerseits, Sozialisierung und gemeinschaftlicher Expressivität bzw. Kommunikation andererseits. Abgehoben wird insbesondere auf die Rolle, die das Lachen als Indiz für die Gesundheit der künstlerischen Sphäre und des politischen Systems spielt.
Effect of Silicon on the Cast Macrostructure of Fe-Si Alloys
Authors: García H. J. A. , Cruz M. H. , Balandra A. A. , González F. G. , Houbaert Y
Published: February 2012

In this work was studied the effect of silicon content from 0.5 to 3 wt.% Si on the macrostructure of casting ingots. Fe-Si alloys with low contents of impurities were produced in electric induction furnace under inert atmosphere. Castings of 12.5 cm thick, 25 cm long and 30 cm high were obtained of each alloy poured into metallic mould. The ingots obtained were sectioned in slices of 12 cm wide, 25 cm high and 2 cm thick, the central slice of each ingot was prepared metallographically to reveal the macrostructure of the six cast alloys. The results indicate that alloys with low silicon levels (0.5 and 1.0% Si) and with small solidification intervals have relatively fine equiaxed grains, while alloys with higher silicon content and a higher solidification intervals present predominantly columnar grains. These macrostructures are not the usually structures linked to short and long freezing range. Another important result is the absence of dendritic structure usually present in cast alloys.
Dislocation Density Based Crystal Plasticity Finite Element Simulation of Alpha-Iron
Authors: Leng Zhe , Field David P.
Published: February 2012

Ferritic/martensitic steels such as HT9 steel, is used for structural components in nuclear power plants because of its high strength and good swelling resistance. Understanding the mechanical behavior of these steels is quite important, since it will affect the strength and the life of the component. In this study, a dislocation density based crystal plasticity finite element model is developed in which different types of dislocation evolves on the activated 12 slip systems in alpha-iron. The dislocation evolves in the form of closed loop and the dislocation density is tracked as internal state variable, the generation and annihilation of dislocations are modeled based on the dislocation interaction laws. The plastic flow is calculated based on the dislocation densities and a generalized Taylor equation is used as the hardening law, and the hardening is assumed to be isotropic in this study. The evolution of polycrystal texture of alpha-iron is presented in the form of pole figures, which indicate the orientation spread and agree with the experimental result. The model also indicates the inhomogeneous dislocation distribution and stress concentration at the grain boundaries.
Copper photoelectrodeposition onto boron doped diamond electrodes at different doping level to enhance nitrate electroreduction.
Authors: Couto A. B. , Baldan M. R. , Ferreira N. G.
Published: February 2012

Photoelectrodeposition of copper on boron-doped diamond films (BDD) was investigated. In this work, two different doped films were analyzed. Copper particles were deposited in the potentiostat mode and under UV irradiation. The BDD film as-grown and the BDD film modifed with Cu (Cu/BDD) on the surface were characterized by Raman Spectroscopy and Scanning Electron Microscopy (SEM) respectivily. These electrodes were tested as electrocatalysts for nitrate reduction in Britton-Robinson buffer solution (pH=3). Electrochemical measurements showed that the electrode with high doping level displayed the best electrocatalytic activity.
Comorbidities associated with epilepsy and headaches
Authors: Ferreira Thalles P. , Coan Ana Carolina , Guerreiro Carlos A. M.
Published: February 2012

Comorbidities are often associated with chronic neurological diseases, such as headache and epilepsy. OBJECTIVES: To identify comorbidities associated with epilepsy and headaches, and to determine possible drug interactions. METHODS: A standardized questionnaire with information about type of epilepsy/headache, medical history, and medication was administered to 80 adult subjects (40 with epilepsy and 40 with chronic headache). RESULTS: Patients with epilepsy had an average of two comorbidities and those with headache of three. For both groups, hypertension was the most prevalent. On average, patients with epilepsy were taking two antiepileptic medications and those with headache were taking only one prophylactic medication. Regarding concomitant medications, patients with epilepsy were in use, on average, of one drug and patients with headache of two. CONCLUSIONS: Patients with chronic neurological diseases, such as epilepsy and headaches, have a high number of comorbidities and they use many medications. This may contribute to poor adherence and interactions between different medications.
Frontal assessment battery in a Brazilian sample of healthy controls: normative data
Authors: Beato Rogério , Amaral-Carvalho Viviane , Guimarães Henrique Cerqueira , Tumas Vitor , Souza Carolina Pinto , Oliveira Guiomar Nascimento de , Caramelli Paulo
Published: February 2012

OBJECTIVE: To show data on the performance of healthy subjects in the Frontal Assessment Battery (FAB), correlating with gender, age, education, and scores in the Mini-Mental State Examination (MMSE). METHODS: Two hundred and seventy-five healthy individuals with mean age of 66.4±10.6 years-old were evaluated. Mean total FAB scores were established according to the educational level. RESULTS: Mean total FAB scores according to the educational level were 10.9±2.3, for one to three years; 12.8±2.7, for four to seven years; 13.8±2.2, for eight to 11 years; and 15.3±2.3, for 12 or more years. Total FAB scores correlated significantly with education (r=0.47; p<0.0001) and MMSE scores (r=0.39; p<0.0001). No correlation emerged between FAB scores, age, and gender. CONCLUSION: In this group of healthy subjects, the Brazilian version of the FAB proved to be influenced by the education level, but not by age and gender.
Experimental encephalitis caused by Taenia crassiceps cysticerci in mice
Authors: Matos-Silva Hidelberto , Reciputti Bruno Pereira , Paula Élbio Cândido de , Oliveira André Luiz , Moura Vânia Beatriz Lopes , Vinaud Marina Clare , Oliveira Milton Adriano Pelli , Lino-Júnior Ruy de Souza
Published: February 2012

OBJECTIVES: To present the experimental model of neurocysticercosis (NCC) caused by Taenia crassiceps cysticerci, to describe the inflammatory process, susceptibility, or resistance of BALB/c and C57BL/6 mice to this infection, and to describe the host-parasite relationship. METHODS: The animals were intracranially inoculated with initial stage T. crassiceps cysticerci. They were euthanized at 7, 30, 60, and 90 days after the inoculation. Their encephala were removed for the histopathologic analysis, classification of the parasites, and inflammatory lesions. RESULTS: Experimental NCC was observed on both mice lineages. BALB/c mice presented inflammatory lesions with greater intensity, inducing necrosis on late stage parasites, and with an acute inflammation pattern, while C57BL/6 mice showed greater capability on provoking early necrosis in the cysticerci, which showed a chronic inflammation pattern. CONCLUSIONS: This experimental model induced NCC on mice with characteristic inflammation and lesions. C57BL/6 mice were able to induce precocious necrosis of the parasites presenting inflammatory lesions with lower intensity.
Psychiatric patients' return for HIV/STI test results in mental health centers
Authors: Melo Ana Paula Souto , McKinnon Karen , Wainberg Milton L , César Cibele Comini , Guimarães Mark Drew Crosland
Published: February 2012

OBJECTIVE: To assess individual and/or health service factors associated with patients returning for results of HIV or sexually transmitted infection (STI) tests in mental health centers. METHODS: Cross-sectional national multicenter study among 2,080 patients randomly selected from 26 Brazilian mental health centers in 2007. Multilevel logistic regression was used to assess the effect of individual (level 1) and mental health service characteristics (level 2) on receipt of test results. RESULTS: The rate of returning HIV/STI test results was 79.6%. Among health service characteristics examined, only condom distribution was associated with receiving HIV/STI test results, whereas several individual characteristics were independently associated including living in the same city where treatment centers are; being single; not having heard of AIDS; and not having been previously HIV tested. CONCLUSIONS: It is urgent to expand HIV/STI testing in health services which provide care for patients with potentially increased vulnerability to these conditions, and to promote better integration between mental health and health services.