bluuebunny/crossref_metadata_2025 huggingface dataset:
Discordant minimum inhibitory concentration analysis: A new path to licensure for anti-infective drugs
Authors: Follmann Dean , Brittain Erica , Powers John H
Published: November 2013

Background

Evaluation of anti-infective drugs for licensure often relies on a noninferiority (NI) design where new drug B is noninferior to comparator drug A if the difference in success rates is reliably not worse than some fixed margin. The margin must be based on historical studies that estimate the magnitude of the benefit of drug A over placebo. This approach hampers drug development because the obligatory evidence for margin determination is often nonexistent.

Purpose

To develop a new method for licensure of anti-infective drugs when there is no historical evidence for reliable construction of the NI margin.

Methods

The minimum inhibitory concentration (MIC) measures the minimum amount of drug that it takes to inhibit growth of bacteria in vitro. Patients who are infected with bacteria that have a low MIC to a given drug are expected to have good outcomes when treated with that drug. Thus, a differential effect of drug B versus drug A, if it exists, is likely to occur in patients whose pathogens have discordant MICs (e.g., low MIC for drug B, high MIC for drug A, or vice versa). A new paradigm for licensure of anti-infective drugs is proposed where a clinically acceptable NI margin is selected and licensure supported if the NI margin is met and B is reliably demonstrated superior to A in a subset of patients whose paired MICs favor B. The requirement for some evidence of superiority encourages a study that is carefully designed and executed.

Results

Simulations indicate that the approach shows promise in realistic settings, provided adequate data are available. A simulated example illustrates use of the methods.

Limitations

If the data have small sample size, weak MIC/success relationship, or high correlation between MIC-A, MIC-B, this procedure will have poor power.

Conclusion

Discordant MIC analysis may offer a novel path to licensure for certain anti-infective drugs.
Promoting stories about terrorism to the international news media: A study of public diplomacy
Authors: Yarchi Moran , Wolfsfeld Gadi , Sheafer Tamir , Shenhav Shaul R
Published: November 2013

Antagonists’ images in the international news media can play a significant role in determining their level of political success in the international arena, which explains why so many political actors invest considerable resources in public diplomacy. The goal of the present study is to explain the level of success that various actors (countries and non-state actors) have in promoting their preferred frames about terror to the international news media. Four types of explanatory variables are proposed, divided into context and focal event factors. Context factors include the political values and policy proximity between the country attacked (the victimized country) and a country whose news media have been targeted for influence (the target country), as well as the target country’s experience in dealing with terror. Focal event factors refer to the nature of the trigger events that generate news coverage of terrorism. Apart from one exception (the policy proximity), all of the hypotheses were confirmed. The findings indicated that focal event factors have the most significant effect on the way foreign media covers conflicts and that, when it comes to coverage of terrorism, journalists are more interested in constructing a dramatic story than putting the events into a more general political context.
Being a terrorist: Video game simulations of the other side of the War on Terror
Authors: Schulzke Marcus
Published: November 2013

Some of the most theoretically significant moments of video games set in the War on Terror occur in the rare instances when these games allow players to assume a terrorist’s point of view. This perspectival shift raises the possibility that games might offer a humanizing look at the enemies in the War on Terror and that they might give players greater insight into terrorists’ motives and ideologies. This article examines three popular video games that allow players to become terrorists: America’s Army, Modern Warfare 2, and Medal of Honor: Warfighter. The author argues that the simulated experience of being a terrorist holds the potential to deepen players’ understanding of terrorism, but that popular games ultimately deliver experiences of terrorist subjectivities that have virtually no content and that leave terrorists almost indistinguishable from the games’ heroes. The terrorists whose viewpoints are shown are portrayed as people who engage in senseless acts of violence that are disconnected from motives or grievances. This leads the games to confirm the overarching War on Terror narrative that terrorists are irrational and evil enemies who are unworthy of respect.
News narratives of terrorism: Assessing source diversity and source use in UK news coverage of alleged Islamist plots
Authors: Matthews Jamie
Published: November 2013

During the later years of Tony Blair’s premiership it was suggested that information provided by ‘well-placed sources’ to journalists concerning a series of alleged Islamist plots was unreliable, with this material leaked to the media in an attempt to maintain or accentuate public awareness of terrorism. This article seeks to assess these claims by identifying the prominence and role of official sources and elucidating the characteristics of source use in news reporting on alleged terrorist plots. Through a content analysis of UK national newspaper coverage, the article presents a complex picture of source use and influence. The findings reveal that anonymous sources and veiled references to public institutions were predominant within coverage. Contrary to ideological theories of political discourse, however, government sources were not influential in presenting details about a specific threat. The analysis shows that journalists’ use of sources was pragmatic and that source use was indicative of a broader shift in the media discourse of terrorism during the period of study, with more recent coverage addressing public concerns over the way official or government sources communicated information about the threat from terrorism.
Ceramic particulate filled ZA-27 metal matrix composites: Comparative analysis
Authors: Mishra S. K. , Satapathy A.
Published: November 2013

In the present article, processing and characterisation of ZA-27 alloy reinforced with two commonly used and easily available hard ceramic particulate filler (i.e. alumina and silicon carbide) are taken into consideration. In the present work, ZA-27 metal matrix composites reinforced with ceramic particles are prepared by stir casting method. Pretreated ceramic particles are reinforced into the molten ZA-27 in different weight proportions (0, 3, 6 and 9 wt-) with a continuous stirring action. Some of the major properties of these two different types of composites are compared in the present analysis. These composites possess a very low amount of porosity and improved microhardness, tensile strength and impact strength. However, they exhibit slightly inferior flexural strengths than those of the pure ZA-27 alloy. It also reveals that SiC possesses better filler characteristics compared to Al2O3 as it shows more improvement in most of the properties of the composites.
Phylogenetic and transcriptional analysis of an expanded bZIP transcription factor family in Phytophthora sojae
Authors: Ye Wenwu , Wang Yang , Dong Suomeng , Tyler Brett M , Wang Yuanchao
Published: November 2013

Background

Basic leucine zipper (bZIP) transcription factors are present exclusively in eukaryotes and constitute one of the largest and most diverse transcription factor families. The proteins are responsible for central developmental and physiological processes in plants, animals, and fungi, including the pathogenicity of fungal plant pathogens. However, there is limited understanding of bZIPs in oomycetes, which are fungus-like organisms in the kingdom Stramenopila. Oomycetes include many destructive plant pathogens, including the well-studied species Phytophthora sojae, which causes soybean stem and root rot.

Results

Candidate bZIPs encoded in the genomes of P. sojae and four other oomycetes, two diatoms, and two fungal species were predicted using bioinformatic methods. Comparative analysis revealed expanded numbers of bZIP candidates in oomycetes, especially the Phytophthora species, due to the expansion of several novel bZIP classes whose highly conserved asparagines in basic DNA-binding regions were substituted by other residues such as cysteine. The majority of these novel bZIP classes were mostly restricted to oomycetes. The large number of novel bZIPs appears to be the result of widespread gene duplications during oomycete evolution. The majority of P. sojae bZIP candidates, including both conventional and novel bZIP classes, were predicted to contain canonical protein secondary structures. Detection of gene transcripts using digital gene expression profiling and qRT-PCR suggested that most of the candidates were not pseudogenes. The major transcriptional shifts of bZIPs occurred during the zoosporangia/zoospore/cyst and host infection stages. Several infection-associated bZIP genes were identified that were positively regulated by H2O2 exposure.

Conclusions

The identification of large classes of bZIP proteins in oomycetes with novel bZIP motif variants, that are conserved and developmentally regulated and thus presumably functional, extends our knowledge of this important family of eukaryotic transcription factors. It also lays the foundation for detailed studies of the roles of these proteins in development and infection in P. sojae and other oomycetes.
Family history of cancer, personal history of medical conditions and risk of oral cavity cancer in France: the ICARE study
Authors: Radoï Loredana , Paget-Bailly Sophie , Guida Florence , Cyr Diane , Menvielle Gwenn , Schmaus Annie , Carton Matthieu , Cénée Sylvie , Sanchez Marie , Guizard Anne-Valérie , Trétarre Brigitte , Stücker Isabelle , Luce Danièle
Published: November 2013

Background

The aim of this study was to evaluate the role of family history of cancer and personal history of other medical conditions in the aetiology of the oral cavity cancer in France.

Methods

We used data from 689 cases of oral cavity squamous cell carcinoma and 3481 controls included in a population-based case–control study, the ICARE study. Odds-ratios (ORs) associated with family history of cancer and personal medical conditions and their 95% confidence intervals (95% CI) were estimated by unconditional logistic regression and were adjusted for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking.

Results

Personal history of oral candidiasis was related to a significantly increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). History of head and neck cancers among the first-degree relatives was associated with an OR of 1.9 (95% CI 1.2-2.8). The risk increased with the number of first-degree relatives with head and neck cancer.

Conclusion

A family history of head and neck cancer is a marker of an increased risk of oral cavity cancer and should be taken into account to target prevention efforts and screening. Further studies are needed to clarify the association between oral cavity cancer and personal history of candidiasis.
Surface-exposed proteins of pathogenic mycobacteria and the role of cu-zn superoxide dismutase in macrophages and neutrophil survival
Authors: McNamara Michael , Tzeng Shin-Cheng , Maier Claudia , Wu Martin , Bermudez Luiz E
Published: November 2013

Pathogenic mycobacteria are important agents causing human disease.Mycobacterium aviumsubsp.hominissuis(M. avium) is a species of recalcitrant environmental pathogen. The bacterium forms robust biofilms that allow it to colonize and persist in austere environments, such as residential and commercial water systems.M. aviumis also an opportunistic pathogen that is a significant source of mortality for immune-compromised individuals. Proteins exposed at the bacterial surface play a central role in mediating the relationship between the bacterium and its environment. The processes underlying both biofilm formation and pathogenesis are directly dependent on this essential subset of the bacterial proteome. Therefore, the characterization of the surface-exposed proteome is an important step towards an improved understanding of the mycobacterial biology and pathogenesis. Here we examined the complement of surface exposed proteins fromMycobacterium avium 104, a clinical isolate and reference strain ofMycobacterium aviumsubsp.hominissuis.To profile the surface-exposed proteins of viableM. avium 104,bacteria were covalently labeled with a membrane impermeable biotinylation reagent and labeled proteins were affinity purified via the biotin-streptavidin interaction. The results provide a helpful snapshot of the surface-exposed proteome of this frequently utilized reference strain ofM. avium.A Cu-Zn SOD knockout mutant, MAV_2043, a surface identified protein, was evaluated regarding its role in the survival in both macrophages and neutrophils.
Anaplasma phagocytophilum strains from voles and shrews exhibit specific ankA gene sequences
Authors: Majazki Juliana , Wüppenhorst Nicole , Hartelt Kathrin , Birtles Richard , von Loewenich Friederike D
Published: November 2013

Background

Anaplasma phagocytophilum is a Gram-negative bacterium that replicates obligate intracellularly in neutrophils. It is transmitted by Ixodes spp. ticks and causes acute febrile disease in humans, dogs, horses, cats, and livestock. Because A. phagocytophilum is not transmitted transovarially in Ixodes spp., it is thought to depend on reservoir hosts to complete its life cycle. In Europe, A. phagocytophilum was detected in roe deer, red deer, wild boars, and small mammals. In contrast to roe deer, red deer and wild boars have been considered as reservoir hosts for granulocytic anaplasmosis in humans, dogs, and horses according to groESL- and ankA-based genotyping. A. phagocytophilum variants infecting small mammals in Europe have not been characterized extensively to date.

Results

We amplified the total ankA open reading frames of 27 strains from voles and shrews. The analysis revealed that they harboured A. phagocytophilum strains that belonged to a distinct newly described ankA gene cluster. Further, we provide evidence that the heterogeneity of ankA gene sequences might have arisen via recombination.

Conclusions

Based on ankA-based genotyping voles and shrews are unlikely reservoir hosts for granulocytic anaplasmosis in humans, dogs, horses, and livestock in Europe.
B cells tell scleroderma fibroblasts to produce collagen
Authors: Daoussis Dimitrios , Liossis Stamatis-Nick C
Published: November 2013

In fibrosis fibroblasts are activated and overproduce collagen in a process with unknown drivers and equally unknown brakes that recently implicated a novel and surprising player, the B cell. B cells may be crucially involved in fibrosis in several ways: B cells may produce autoantibodies that can directly stimulate fibroblasts; B cells can produce profibrotic cytokines such as IL-6 or transforming growth factor beta; and, finally, B cells could directly stimulate fibroblasts by a contact-dependent mechanism. Recent experimental evidence suggests that B cells can enhance collagen production by fibroblasts, by a contact-dependent mechanism, and therefore are profibrotic ex vivo. These data strengthen the rationale of pursuing B-cell targeting therapies in systemic sclerosis.
Lower Expression of the TWIK-Related Acid-Sensitive K+ Channel 2 (TASK-2) Gene Is a Hallmark of Aldosterone-Producing Adenoma Causing Human Primary Aldosteronism
Authors: Lenzini Livia , Caroccia Brasilina , Campos Abril González , Fassina Ambrogio , Belloni Anna S. , Seccia Teresa M. , Kuppusamy Maniselvan , Ferraro Silvia , Skander Ghizlane , Bader Michael , Rainey William E. , Rossi Gian Paolo
Published: November 2013

Context:

The molecular mechanisms of primary aldosteronism, a common cause of human hypertension, are unknown, but alterations of K+ channels can play a key role.

Objective:

The objective of the study was to investigate the following: 1) the expression of the Twik-related acid-sensitive K+ channels (TASK) in aldosterone producing adenomas (APAs); 2) the role of TASK-2 in aldosterone synthesis; and 3) the determinants of TASK-2-blunted expression in APAs.

Design:

We analyzed the transcriptome and the microRNA profiles of 32 consecutive APAs and investigated the protein expression and localization of TASK-2 in APA and adrenocortical cell lines (H295R and HAC15) using immunoblotting and confocal microscopy. The functional effect of TASK-2 blunted activity caused by a dominant-negative mutation on steroidogenic enzymes, and aldosterone production was also assessed. TASK-2 regulation by selected microRNA was studied by a luciferase assay.

Results:

TASK-2 was consistently less expressed at the transcript and protein levels in APAs than in the normal human adrenal cortex. H295R cell transfection with a TASK-2 dominant-negative mutant construct significantly increased the aldosterone production by 153% and the gene expression of aldosterone synthase (CYP11B2, gene expression fold change 3.1 vs control, P < .05) and the steroidogenic acute regulatory protein (gene expression fold change 1.8 vs control, P < .05). Two microRNAs, hsa-miR-23 and hsa-miR-34, were found to decrease the TASK-2 expression by binding to the 3′ untranslated region of the TASK-2 gene.

Conclusions:

The TASK-2 channel lower expression represents a hallmark of APA and is associated with a higher expression of hsa-miR-23 and hsa-miR-34. The ensuing blunted TASK-2 activity increased the production of aldosterone in vitro and the expression of steroidogenic acute regulatory protein and CYP11B2. Hence, the lower expression of TASK-2 channel in APA cells can explain high aldosterone secretion in human primary aldosteronism despite the suppression of angiotensin II, hypertension, and hypokalemia.
Pyroglutamylated RF-amide Peptide (QRFP) Gene Is Regulated by Metabolic Endotoxemia
Authors: Jossart Christian , Mulumba Mukandila , Granata Riccarda , Gallo Davide , Ghigo Ezio , Marleau Sylvie , Servant Marc J. , Ong Huy
Published: November 2013

Pyroglutamylated RF-amide peptide (QRFP) is involved in the regulation of food intake, thermogenesis, adipogenesis, and lipolysis. The expression of QRFP in adipose tissue is reduced in diet-induced obesity, a mouse model in which plasma concentrations of endotoxins are slightly elevated. The present study investigated the role of metabolic endotoxemia (ME) on QRFP gene regulation. Our results uncovered the expression of QRFP in murine macrophages and cell lines. This expression has been found to be decreased in mice with ME. Low doses of lipopolysaccharide (LPS) transiently down-regulated QRFP by 59% in RAW264.7 macrophages but not in 3T3-L1 adipocytes. The effect of LPS on QRFP expression in macrophages was dependent on the inhibitor of kB kinase and TIR-domain-containing adapter-inducing interferon (IFN)-β (TRIF) but not myeloid differentiation primary response gene 88. IFN-β was induced by ME in macrophages. IFN-β sustainably reduced QRFP expression in macrophages (64%) and adipocytes (49%). IFN-γ down-regulated QRFP (74%) in macrophages only. Both IFNs inhibited QRFP secretion from macrophages. LPS-stimulated macrophage-conditioned medium reduced QRFP expression in adipocytes, an effect blocked by IFN-β neutralizing antibody. The effect of IFN-β on QRFP expression was dependent on phosphoinositide 3-kinase, p38 MAPK, and histone deacetylases. The effect of IFN-γ was dependent on MAPK/ERK kinase 1/2 and histone deacetylases. Macrophage-conditioned medium containing increased amounts of QRFP preserved adipogenesis in adipocytes. In conclusion, LPS induces IFN-β release from macrophages, which reduces QRFP expression in both macrophages and adipocytes in an autocrine/paracrine-dependent manner, suggesting QRFP as a potential biomarker in ME.
Both Estrogen Receptor α and β Stimulate Pituitary GH Gene Expression
Authors: Avtanski Dimiter , Novaira Horacio J. , Wu Sheng , Romero Christopher J. , Kineman Rhonda , Luque Raul M. , Wondisford Fredric , Radovick Sally
Published: November 2013

Although sex steroids have been implicated in the control of mammalian growth, their direct effect on GH synthesis is less clear. The aim of this study was to establish whether estradiol (E2) directly affects GH synthesis in somatotrophs. Somatotroph GH3 and MtT/S cells were used as in vitro models. At physiological doses of E2 stimulation, GH mRNA levels were increased and the ER antagonist ICI 182,780 completely abolished this effect. Estrogen receptor (ER) α– and ERβ-selective agonists, propylpyrazole triol (PPT), and 2,3-bis(4-hydroxyphenyl) propionitrile (DPN), respectively, augmented GH mRNA expression and secretion, whereas E2 and PPT, but not DPN increased prolactin (PRL) mRNA levels. E2, PPT, and DPN stimulated expression of the pituitary transcription factor Pou1f1 and increased its binding to the GH promoter. In vivo evidence of E2 effects on GH synthesis was obtained from the generation of the somatotroph-specific ERα knockout (sERα-KO) mouse model. Basal pituitary GH, PRL, POU1F1, and ERα mRNA expression levels were lower in sERα-KO mice compared with those in controls; whereas ERβ mRNA levels remained unchanged. E2 and DPN stimulated pituitary GH mRNA expression and serum GH levels in control and sERα-KO ovariectomized mice; however, serum GH levels were unchanged in PPT-treated ovariectomized sERα-KO mice. In these animal models, PRL mRNA levels increased after either E2 or PPT, but an increase was not seen after DPN treatment. Thus, we propose a mechanism by which estrogen directly regulates somatotroph GH synthesis at a pretranslational level. In contrast to the predominant effect of ERα in the lactotroph, these results support a role for both ERα and ERβ in the transcriptional control of Gh in the somatotroph and illustrate important differences in ER isoform specificity in the anterior pituitary gland.
GATA Factors Promote ER Integrity and β-Cell Survival and Contribute to Type 1 Diabetes Risk
Authors: Sartori Daniel J. , Wilbur Christopher J. , Long Simon Y. , Rankin Matthew M. , Li Changhong , Bradfield Jonathan P. , Hakonarson Hakon , Grant Struan F. A. , Pu William T. , Kushner Jake A.
Published: November 2013

Pancreatic β-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult β-cells remains undefined. To investigate the role of GATA factors in adult β-cells, we derived β-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. β-Cell Gata4 deletion modestly increased the proportion of dying β-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in β-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored β-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such β-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and β-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.
Minireview: Dynamic Structures of Nuclear Hormone Receptors: New Promises and Challenges
Authors: Simons S. Stoney , Edwards Dean P. , Kumar Raj
Published: November 2013

Therapeutic targeting of nuclear receptors (NRs) is presently restricted due to 2 constraints: 1) a limited knowledge of the structural dynamics of intact receptor when complexed to DNA and coregulatory proteins; and 2) the inability to more selectively modulate NR actions at specific organ/gene targets. A major obstacle has been the current lack of understanding about the function and structure of the intrinsically disordered N-terminal domain that contains a major regulatory transcriptional activation function (AF1). Current studies of both mechanism of action and small molecule-selective receptor modulators for clinical uses target the structured pocket of the ligand-binding domain to modulate coregulatory protein interactions with the other activation function AF2. However, these approaches overlook AF1 activity. Recent studies have shown that highly flexible intrinsically disordered regions of transcription factors, including that of the N-terminal domain AF1 of NRs, not only are critical for several aspects of NR action but also can be exploited as drug targets, thereby opening unique opportunities for endocrine-based therapies. In this review article, we discuss the role of structural flexibilities in the allosteric modulation of NR activity and future perspectives for therapeutic interventions.
Retinoic acid controls proper head-to-trunk linkage in zebrafish by regulating an anteroposterior somitogenetic rate difference
Authors: Retnoaji Bambang , Akiyama Ryutaro , Matta Tatsuro , Bessho Yasumasa , Matsui Takaaki
Published: November 2013

During vertebrate development, the primary body axis elongates towards the posterior and is periodically divided into somites, which give rise to the vertebrae, skeletal muscles and dermis. Somites form periodically from anterior to posterior, and the anterior somites form in a more rapid cycle than the posterior somites. However, how this anteroposterior (AP) difference in somitogenesis is generated and how it contributes to the vertebrate body plan remain unclear. Here, we show that the AP difference in zebrafish somitogenesis originates from a variable overlapping segmentation period between one somite and the next. The AP difference is attributable to spatiotemporal inhibition of the clock gene her1 via retinoic acid (RA) regulation of the transcriptional repressor ripply1. RA depletion thus disrupts timely somite formation at the transition, eventually leading to the loss of one somite and the resultant cervical vertebra. Overall, our results indicate that RA regulation of the AP difference is crucial for proper linkage between the head and trunk in the vertebrate body plan.
CCAAT/enhancer binding protein-mediated regulation of TGFβ receptor 2 expression determines the hepatoblast fate decision
Authors: Takayama Kazuo , Kawabata Kenji , Nagamoto Yasuhito , Inamura Mitsuru , Ohashi Kazuo , Okuno Hiroko , Yamaguchi Tomoko , Tashiro Katsuhisa , Sakurai Fuminori , Hayakawa Takao , Okano Teruo , Furue Miho Kusada , Mizuguchi Hiroyuki
Published: November 2013

Human embryonic stem cells (hESCs) and their derivatives are expected to be used in drug discovery, regenerative medicine and the study of human embryogenesis. Because hepatocyte differentiation from hESCs has the potential to recapitulate human liver development in vivo, we employed this differentiation method to investigate the molecular mechanisms underlying human hepatocyte differentiation. A previous study has shown that a gradient of transforming growth factor beta (TGFβ) signaling is required to segregate hepatocyte and cholangiocyte lineages from hepatoblasts. Although CCAAT/enhancer binding proteins (c/EBPs) are known to be important transcription factors in liver development, the relationship between TGFβ signaling and c/EBP-mediated transcriptional regulation in the hepatoblast fate decision is not well known. To clarify this relationship, we examined whether c/EBPs could determine the hepatoblast fate decision via regulation of TGFβ receptor 2 (TGFBR2) expression in the hepatoblast-like cells differentiated from hESCs. We found that TGFBR2 promoter activity was negatively regulated by c/EBPα and positively regulated by c/EBPβ. Moreover, c/EBPα overexpression could promote hepatocyte differentiation by suppressing TGFBR2 expression, whereas c/EBPβ overexpression could promote cholangiocyte differentiation by enhancing TGFBR2 expression. Our findings demonstrated that c/EBPα and c/EBPβ determine the lineage commitment of hepatoblasts by negatively and positively regulating the expression of a common target gene, TGFBR2, respectively.
PTP-PEST targets a novel tyrosine site in p120-catenin to control epithelial cell motility and Rho GTPase activity
Authors: Espejo Rosario , Jeng Yowjiun , Paulucci-Holthauzen Adriana , Rengifo-Cam William , Honkus Krysta , Anastasiadis Panos Z. , Sastry Sarita K.
Published: November 2013

Tyrosine phosphorylation is implicated in regulating the adherens junction protein, p120 catenin (p120), however the mechanisms are not well defined. Here, we show using substrate trapping that p120 is a direct target of the protein tyrosine phosphatase, PTP-PEST, in epithelial cells. Stable shRNA knockdown of PTP-PEST in colon carcinoma cells results in an increased cytosolic pool of p120 concomitant with its enhanced tyrosine phosphorylation and decreased association with E-cadherin. Consistent with this, PTP-PEST knockdown cells exhibit increased motility, enhanced Rac1 and decreased RhoA activity on a collagen substrate. Further, p120 shows an enhanced localization at actin-rich protrusions and lamellipodia and an enhanced association with the guanine nucleotide exchange factor, VAV2 and cortactin. Exchange factor activity of VAV2 is enhanced by PTP-PEST knockdown while overexpression of a VAV2 C-terminal domain or DH domain mutant block cell motility. Point mutation analysis identified tyrosine 335 in the N-terminal domain of p120 as the site of PTP-PEST dephosphorylation. A Y335F mutant of p120 failed to induce the “p120 phenotype”, interact with VAV2, stimulate cell motility or activate Rac1. Together, these data suggest that PTP-PEST affects epithelial cell motility by controlling the distribution and phosphorylation of p120 and its availability to control Rho GTPase activity.
Slp2-a controls renal epithelial cell size through regulation of Rap–ezrin signaling independently of Rab27
Authors: Yasuda Takao , Fukuda Mitsunori
Published: November 2013

Slp2-a is a Rab27 effector protein that regulates transport of Rab27-bearing vesicles/organelles via its N-terminal Rab27-binding domain and a phospholipid-binding C2A domain. Here we demonstrate a Rab27-independent function of Slp2-a in the control of renal cell size via a previously uncharacterized C2B domain. We found that by recruiting Rap1GAPs to the plasma membrane of MDCK II cells via the C2B domain Slp2-a inactivates Rap signaling and modulates the size of the cells. Functional ablation of Slp2-a resulted in an increase in the size of MDCK II cells. Drosophila Slp bitesize was found to compensate for the function of Slp2-a in MDCK II cells, thereby indicating that the mechanism of the cell size control by Slps has been evolutionarily conserved. Interestingly, blockade of the activity of ezrin, a downstream target of Rap, with the glucosylceramide synthase inhibitor miglustat effectively inhibited cell spreading of Slp2-a-knockdown cells. We also discovered aberrant expression of Slp2-a and increased activity of ezrin in pcy mice, a model of polycystic kidney disease that is characterized by renal cell spreading. Our findings indicate that Slp2-a controls renal cell size through regulation of Rap–ezrin signaling independently of Rab27.
Src-Like Adaptor Protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling
Authors: Kazi Julhash U. , Agarwal Shruti , Sun Jianmin , Bracco Enrico , Rönnstrand Lars
Published: November 2013

The Src-Like Adaptor Protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in variety of cells regulating receptor tyrosine kinase signaling by direct association. In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitination which, in turn, is followed by receptor degradation. Although SLAP depletion potentiates c-Kit downstream signaling by stabilizing the receptor, it remains non-functional in c-Kit-D816V signaling. Ligand-stimulated c-Kit or c-Kit-D816V did not alter membrane localization of SLAP. Interestingly oncogenic c-Kit-D816V, but not wild-type c-Kit, phosphorylates SLAP on Y120, Y258 and Y273 residues. Physical interaction between c-Kit-D816V and SLAP is mandatory for the phosphorylation to take place. Although tyrosine phosphorylated SLAP does not affect c-Kit-D816V signaling, mutation of these tyrosine sites to phenylalanine can restore SLAP activity. Taken together the data demonstrate that SLAP negatively regulates wild-type c-Kit signaling, but not its oncogenic counterpart, indicating a possible mechanism by which the oncogenic c-Kit bypasses the normal cellular negative feedback control.
Transitory expression of Dlx5 and Dlx6 in maxillary arch precursors is essential for upper jaw morphogenesis
Authors: Gitton Yorick , Narboux-Nême Nicolas , Levi Giovanni
Published: November 2013

Asymmetric, articulated jaws support active predation in vertebrates; they derive from the first pharyngeal arch (PA1) which generates both maxillary and mandibular components. PA1 is colonized by cranial neural crest cells (CNCCs) which give rise to most bones and tendons of the jaws. The elements formed by different CNCCs contingents are specified by the combinatorial expression ofDlxgenes.Dlx5andDlx6are predominantly expressed by mandibular CNCCs. Analysis of the phenotype ofDlx5andDlx6double mutant mice has suggested that they are necessary and sufficient to specify mandibular identity. Here, using 3D reconstruction, we show that inactivation ofDlx5andDlx6does not only affect the mandibular arch, but results in the simultaneous transformation of mandibular and maxillary skeletal elements which assume a similar morphology with gain of symmetry. AsDlx5-andDlx6-expressing cells are not found in the maxillary bud, we have examined the lineage ofDlx5-expressing progenitors using anin vivogenetic approach. We find that a contingent of cells deriving from precursors transiently expressingDlx5participate in the formation of the maxillary arch. These cells are mostly located in the distal part of the maxillary arch and might derive from its lambdoidal junction with the olfactory pit. Our findings extend current models of jaw morphogenesis and provide an explanation for the maxillary defects ofDlx5andDlx6mutants. Our results imply that Dlx5 and Dlx6 model the upper and the lower PA1 components through different morphogenetic mechanisms which are, however, coordinated as they give rise to functional, articulated jaws.
Lectures on discipline "Motivation and stimultion of labour activity"
Authors: Митрофанова  , Mitrofanova Elena
Published: November 2013

Given article opens a series of the publications shining prospects

of development of educative and methodical maintenance (textbooks,

abstracts of lectures and so forth) preparations of bachelors and masters

in a direction «Human resource management». The author brings to attention

of readers the abstract of lectures on discipline «Motivation and

stimulation of labor activity» under the program of preparation of bachelors.
Theory and practice of management staff turnover
Authors: Печатникова  , Pechatnikova Anastasiya
Published: November 2013

Dismissal of staff is a natural phenomenon, while staff turnover

is not transformed into a chronic, and turns into a real threat to business.

The author says how to identify and assess the problem and prevent its

negative consequences.
Scaling-up or going viral? Comparing self-help housing and community land trust facilitation
Authors: Moore Tom , Mullins David
Published: November 2013

Community-led housing organisations innovate in the resolution of local housing issues by adopting a specialised local focus and emphasising community leadership and engagement. In order to meet their objectives they require access to finance, skills and legitimacy; resources that are often secured through frameworks of intermediary support and external partnerships. This article uses two sector-based case studies of community land trusts (CLTs) and self-help housing to explore the importance and effect of intermediary support in securing access to these resources. These sectors have grown in size and importance in recent years through different forms of intermediation that replicate community-led housing in different locations. The article compares the ‘scaling-up’ of CLTs and the viral spread of self-help housing, highlighting differences in the emphasis that each approach places on community leadership and links with technical experts. We then discuss the implications of this for future housing initiatives and wider relevance for facilitating community-led innovation.
Indução de micronúcleos e toxicidade por efluente doméstico em duas populações de Bathygobius soporator (Valenciennes, 1837) (Teleostei, Gobbidae) no litoral de Salvador (BA), Brasil
Authors: Galindo Toni , Da Silva Eduardo , Rosário Igor
Published: November 2013

Fish micronuclei tests were used to evaluate the potential of municipal wastewater sewage to cause genetic change in Bathygobius soporator. The levels of toxicity of municipal wastewater sewage were evaluated in populations of B. soporator originating from metal-contaminated and metal-free areas. Blood samples were taken from ten fish caught in sites with low anthropogenic influence to measure the levels of spontaneous micronucleated erythrocytes. An additional 30 fish specimens were captured to conduct laboratory testing. After a 30-day acclimation period, blood samples were collected under controlled conditions, while fish that were not sampled from blood were exposed to concentration of 10 % of the urban effluents for 10 days. Acute toxicity experiments were also carried out at different concentrations (0, 1, 3, 7, 10, and 30%) of urban effluent for 48-h in using fish specimens of the two sampled populations of B. soporator. The results of this study showed that mortality was threefold higher for fish exposed to the urban effluents in the population of metal-free area compared with fish from the metal-contaminated area. There were micronucleus inductions in fish after 10 days of exposures to the urban effluents and significant differences (p< 0.01) after only 10 days when comparing to spontaneous micronucleus levels. We concluded that were microncleus inductions from urban effluents leading to higher mortality of individuals from the population of metal-free area, and this was higher than for individuals of the population exposed to metal contaminants.
Comparison of restricted mean survival times between treatments based on a stratified Cox model
Authors: Zhang Xu
Published: November 2013

Causal inference in survival analysis has been centered on treatment effect assessment with adjustment of covariates. The direct adjustment method is usually employed to find the survival function of a treatment. A Cox model that stratifies the cumulative hazard by treatment is an ideal choice for performing direct adjustment because the treatment effects are allowed to vary over time. A SAS macro was developed to implement comparison of direct adjusted survivals between treatments at a selected time point. The restricted mean survival time can be derived from a direct adjusted survival function. This statistic summarizes the survival outcome of a treatment. Comparison of restricted means provides assessment of treatment effect over a time interval. The first aim of this article was to provide an overview of the restricted mean survival time. The second aim was to introduce a SAS macro that computes the restricted mean survival times from direct adjusted survivals based on a stratified Cox model. Data preparation and macro invocation are illustrated in an analysis of survival data involving three types of stem cell transplants.
Digital endocasts of the cranial surface generated by the 3D vision system
Authors: Skrzat Janusz , Sioma Andrzej
Published: November 2013

This article demonstrates a technique of generating digital endocasts of the cranial interior using the three-dimensional (3D) vision system. Obtained digital endocasts reflected the shape and size of the brain, pattern of dural vascularization, position, and interlocking of the cranial sutures. Hence, some minor anatomical structures (granulations faveole, digital impressions) were recorded by the 3D vision system and were revealed on the digital endocasts.
The identification and the elimination of clashes in the structure of an early-stage intermediate in the protein folding process
Authors: Baster Zbigniew
Published: November 2013

The model (under consideration) to simulate the protein folding process assumes two steps: early stage (ES) and late stage (LS). The first is assumed to define the preliminary structure, which when applied to an optimization procedure, may produce the proper structure of the protein. However, the ES model produces the structures with clashes. This work demonstrates the possible solution to remove clashes before proceeding to the LS. Additionally, the presented solution describes mathematically the precession phenomenon, which might be useful in other fields of studies aside from protein folding such as medical imaging, quantum physics, and astronomy.
Forensic voice comparison by means of artificial neural networks
Authors: Sałapa Kinga , Trawińska Agata , Roterman-Konieczna Irena
Published: November 2013

This article examines the effectiveness of artificial neural networks (ANNs) as forensic voice comparison techniques. This study specifically considers feed-forward multilayer perceptron (MLP) and radial basic function (RBF) network models. Formant frequencies of Polish vowel e (stressed or unstressed) in selected contexts were used as predictors. This has already been confirmed in an earlier investigation that determined that dynamic formant frequencies of vowels are powerful elements in distinguishing the voice. It has been concluded that neural networks might assist in distinguishing speakers from the others with very good accuracy, reaching 100%. MLP models should be given preference. The results of the investigation have shown the influence of vowel e triads on the effectiveness of correct classification rates. In addition, the authors have determined that the accuracy of classification is greater when based on a single context than for similar input data aggregated over several different contexts.
Pressure-dependent network water quality modelling
Authors: Seyoum Alemtsehay G. , Tanyimboh Tiku T.
Published: November 2013

Water quality models are increasingly being routinely used to help ascertain the quality of water in drinking water distribution systems for design and operational management purposes. Conventional water quality models are demand driven and consequently do not incorporate the effects of any deficiency in pressure on the water quality throughout the distribution network. This paper assesses a new integrated pressure-dependent hydraulic and water quality model. The model is an extension of the well-known Epanet 2 model that has an embedded logistic pressure-dependent nodal flow function. Hydraulic and water quality analyses based on two water supply zones in the UK were conducted for a range of simulated operating conditions including normal and subnormal pressure and pipe closures. It is shown that operating conditions with subnormal pressures, if severe and protracted, can lead to spatial and temporal distributions of the water age and concentrations of chlorine and disinfection by-products that are significantly different from operating conditions in which the pressure is satisfactory. The results presented may be indicative of modelling errors that may not have been recognised explicitly hitherto.
Cimetidine Reduces Alveolar Bone Loss in Induced Periodontitis in Rat Molars
Authors: Longhini Renata , Aparecida de Oliveira Priscila , Sasso‐Cerri Estela , Cerri Paulo Sérgio
Published: November 2013

Background: There is evidence that histamine released during inflammation plays a role in bone metabolism via the H2 receptor, stimulating bone resorption. The purpose of this study is to evaluate whether cimetidine, a histamine H2‐receptor antagonist, interferes with the initiation and progression of induced periodontal disease in rat molars.

Methods: Forty male rats received 100 mg/kg body weight of cimetidine (cimetidine group [CimG]) or saline solution (sham group [SG]). Periodontal disease was induced in the maxillary left first molars (PDSG and PDCimG); maxillary right molars were used as non‐ligature controls. After 7, 15, 30, and 50 days, maxillary fragments were embedded in paraffin. The sections were stained with Masson trichrome and hematoxylin and eosin and subjected to the tartrate‐resistant acid phosphatase (TRAP) method. The distances between the cemento‐enamel junction (CEJ) and alveolar process (AP) crest, as well as between the CEJ and junctional epithelium (JE) level, were measured; the number of inflammatory cells was computed. Receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) immunohistochemistry was carried out, and the RANKL/OPG ratio was calculated.

Results: In PDSG and PDCimG, a significant increase (P ≤0.05) was observed in CEJ‐AP and CEJ‐JE distances. However, the increases in both distances were significantly less in PDCimG compared with PDSG at 15, 30, and 50 days. Numerous TRAP‐positive osteoclasts were found in the PDSG and PDCimG. In PDCimG, the volume density of inflammatory cells and the RANKL/OPG ratio were significantly lower (P ≤0.05) than in PDSG.

Conclusions: Cimetidine exerts a beneficial effect on periodontal disease in rats, decreasing the RANKL/OPG ratio in gingival connective tissue and reducing alveolar bone resorption.
Blog-Based Support for Preservice Teachers in an Afterschool Tutoring Program
Authors: Ro Jennifer Moon , Magiera Kathleen , Gradel Kathleen , Simmons Rhea
Published: November 2013

This article reports on findings from a study that explored blogging (a web-based log) as a tool for literacy graduate students to deliver support to preservice teachers who were working in an afterschool intervention program. Its effectiveness is compared to the use of an online literacy instructional module. Analyses of the discussions in nine blogs and lesson plan sets written by preservice teachers indicated that the blogging between the coaches and the preservice teachers aided their learning during the tutoring process. A content analysis of the blogs indicated disparity in both the activities and the types of support in the coach-created blogs that resulted in differences in how the blogs promoted or limited preservice teacher learning. This article concludes with possibilities for using blogs as a mediating tool for learning in field-based courses and teacher training programs.