bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibrio cholerae ToxR Downregulates Virulence Factor Production in Response to Cyclo(Phe-Pro)
Authors: Bina X. Renee , Taylor Dawn L. , Vikram Amit , Ante Vanessa M. , Bina James E.
Published: August 2013

Vibrio cholerae
is an aquatic organism that causes the severe acute diarrheal disease cholera. The ability of
V. cholerae
to cause disease is dependent upon the production of two critical virulence determinants, cholera toxin (CT) and the toxin-coregulated pilus (TCP). The expression of the genes that encode for CT and TCP production is under the control of a hierarchical regulatory system called the ToxR regulon, which functions to activate virulence gene expression in response to
in vivo
stimuli. Cyclic dipeptides have been found to be produced by numerous bacteria, yet their biological function remains unknown.
V. cholerae
has been shown to produce cyclo(Phe-Pro). Previous studies in our laboratory demonstrated that cyclo(Phe-Pro) inhibited
V. cholerae
virulence factor production. For this study, we report on the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We have demonstrated that exogenous cyclo(Phe-Pro) activated the expression of
leuO
, a LysR-family regulator that had not been previously associated with
V. cholerae
virulence. Increased
leuO
expression repressed
aphA
transcription, which resulted in downregulation of the ToxR regulon and attenuated CT and TCP production. The cyclo(Phe-Pro)-dependent induction of
leuO
expression was found to be dependent upon the virulence regulator ToxR. Cyclo(Phe-Pro) did not affect
toxR
transcription or ToxR protein levels but appeared to enhance the ToxR-dependent transcription of
leuO
. These results have identified
leuO
as a new component of the ToxR regulon and demonstrate for the first time that ToxR is capable of downregulating virulence gene expression in response to an environmental cue.

IMPORTANCE
The ToxR regulon has been a focus of cholera research for more than three decades. During this time, a model has emerged wherein ToxR functions to activate the expression of
Vibrio cholerae
virulence factors upon host entry.
V. cholerae
and other enteric bacteria produce cyclo(Phe-Pro), a cyclic dipeptide that we identified as an inhibitor of
V. cholerae
virulence factor production. This finding suggested that cyclo(Phe-Pro) was a negative effector of virulence factor production and represented a molecule that could potentially be exploited for therapeutic development. In this work, we investigated the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We found that cyclo(Phe-Pro) signaled through ToxR to activate the expression of
leuO
, a new virulence regulator that functioned to repress virulence factor production. Our results have identified a new arm of the ToxR regulon and suggest that ToxR may play a broader role in pathogenesis than previously known.
The Molecular Mechanisms of Allosteric Mutations Impairing MepR Repressor Function in Multidrug-Resistant Strains of Staphylococcus aureus
Authors: Birukou Ivan , Tonthat Nam K. , Seo Susan M. , Schindler Bryan D. , Kaatz Glenn W. , Brennan Richard G.
Published: August 2013

Overexpression of the
Staphylococcus aureus
multidrug efflux pump MepA confers resistance to a wide variety of antimicrobials.
mepA
expression is controlled by MarR family member MepR, which represses
mepA
and autorepresses its own production. Mutations in
mepR
are a primary cause of
mepA
overexpression in clinical isolates of multidrug-resistant
S. aureus
. Here, we report crystal structures of three multidrug-resistant MepR variants, which contain the single-amino-acid substitution A103V, F27L, or Q18P, and wild-type MepR in its DNA-bound conformation. Although each mutation impairs MepR function by decreasing its DNA binding affinity, none is located in the DNA binding domain. Rather, all are found in the linker region connecting the dimerization and DNA binding domains. Specifically, the A103V substitution impinges on F27, which resolves potential steric clashes via displacement of the DNA binding winged-helix-turn-helix motifs that lead to a 27-fold reduction in DNA binding affinity. The F27L substitution forces F104 into an alternative rotamer, which kinks helix 5, thereby interfering with the positioning of the DNA binding domains and decreasing
mepR
operator affinity by 35-fold. The Q18P mutation affects the MepR structure and function most significantly by either creating kinks in the middle of helix 1 or completely unfolding its C terminus. In addition, helix 5 of Q18P is either bent or completely dissected into two smaller helices. Consequently, DNA binding is diminished by 2,000-fold. Our structural studies reveal heretofore-unobserved allosteric mechanisms that affect repressor function of a MarR family member and result in multidrug-resistant
Staphylococcus aureus
.

IMPORTANCE
Staphylococcus aureus
is a major health threat to immunocompromised patients.
S. aureus
multidrug-resistant variants that overexpress the multidrug efflux pump
mepA
emerge frequently due to point mutations in MarR family member MepR, the
mepA
transcription repressor. Significantly, the majority of MepR mutations identified in these
S. aureus
clinical isolates are found not in the DNA binding domain but rather in a linker region, connecting the dimerization and DNA binding domains. The location of these mutants underscores the critical importance of a properly functioning allosteric mechanism that regulates MepR function. Understanding the dysregulation of such allosteric MepR mutants underlies this study. The high-resolution structures of three such allosteric MepR mutants reveal unpredictable conformational consequences, all of which preclude cognate DNA binding, while biochemical studies emphasize their debilitating effects on DNA binding affinity. Hence, mutations in the linker region of MepR and their structural consequences are key generators of multidrug-resistant
Staphylococcus aureus
.
Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
Authors: Rohatgi Soma , Gohil Shruti , Kuniholm Mark H. , Schultz Hannah , Dufaud Chad , Armour Kathryn L. , Badri Sheila , Mailliard Robbie B. , Pirofski Liise-anne
Published: August 2013

Cryptococcus neoformans
is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4
+
T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1;
P
= 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4
+
T cell decline, and nadir CD4
+
T cell count (OR, 21;
P
= 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-
C. neoformans
complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more
C. neoformans
-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote
C. neoformans
pathogenesis via increased binding of
C. neoformans
immune complexes, resulting in increased phagocyte cargo and/or immune activation.

IMPORTANCE
HIV-associated CD4
+
T cell deficiency is a sine qua non for HIV-associated cryptococcal disease (CD), but not all patients with CD4
+
T cell deficiency develop CD despite serological evidence of previous infection. At present, there are no biomarkers that predict HIV-associated CD risk. The goal of our study was to understand whether Fc gamma receptor (FCGR) polymorphisms that have been shown to portend CD risk in HIV-uninfected people are associated with CD risk in HIV-infected people. Such biomarkers could identify those who would benefit most from targeted prophylaxis and/or earlier treatment, particularly in sub-Saharan Africa, where there are nearly a million cases of HIV-associated CD annually. A biomarker of risk could also identify potential candidates for immunization, should there be a vaccine for
Cryptococcus neoformans
.
Illustrating the relevance of updated diagnostic criteria for sporadic Creutzfeldt-Jakob disease: a teaching neurocase
Authors: Kamtchum Tatuene Joseph , Vargas Maria Isabel , Burkhardt Karim , Chofflon Michel
Published: August 2013

A 75-year-old woman with unremarkable medical history, consulted for a 5-month history of involuntary shaking of left upper limb. Clinical examination revealed polyminimyoclonus of the upper limbs with cogwheel-like rigidity, hyperreflexia, bradykinesia, inconstant spastic-like rigidity in the lower limbs and a stiff and cautious gait. These symptoms, together with the memory impairment found on neuropsychological assessment yielded suspicion for a subacute encephalopathy probably due to a non-conventional infectious agent. There was no 14-3-3 protein found in the cerebrospinal fluid and no periodic sharp wave complexes on EEG. These findings made the diagnosis of Creutzfeldt-Jakob disease (CJD) rather unlikely according to the current WHO diagnostic criteria. However, typical isolated cortical hyperintensity of right temporal, parietal and occipital lobes on MRI suggested a probable CJD and prompted cerebral biopsy which confirmed the diagnosis. This article emphasises the need to update the current WHO criteria by including radiological findings.
Clinical and histological resolution of collagenous sprue following gluten-free diet and discontinuation of non-steroidal anti-inflammatory drugs (NSAIDs)
Authors: Vasant D H , Hayes S , Bucknall R , Lal S
Published: August 2013

Collagenous sprue is a rare small bowel enteropathy that has overlapping clinical features with coeliac disease; it is commonly associated with arthritic autoimmune conditions, which often require non-steroidal anti-inflammatory drugs (NSAIDs). In the limited published literature available, there are putative suggestions of a link between NSAID use and collagen deposition in intestinal subepithelia in such patients. The authors present a case of a 43-year-old woman with long-standing NSAID use for autoimmune polyarthropathy and positive coeliac antibodies. However, distal duodenal biopsies revealed a thickened band of subepithelial collagen with villous atrophic appearances consistent with collagenous sprue. The patient was treated with a gluten-free diet and her NSAIDs were discontinued. After 6 months, her gastrointestinal symptoms had resolved with complete histological resolution of the collagenous subepithelial bands and villous atrophy on duodenal biopsy.
Within-tree patterns of wood stiffness for white spruce (Picea glauca) and trembling aspen (Populus tremuloides)
Authors: Sattler Derek F. , Comeau Philip G. , Achim Alexis
Published: August 2013

Radial patterns of modulus of elasticity (MOE) were examined for white spruce (Picea glauca (Moench) Voss) and trembling aspen (Populus tremuoides Michx.) from 19 mature, uneven-aged stands in the boreal mixedwood region of northern Alberta, Canada. The main objectives were to (1) evaluate the relationship between pith-to-bark changes in MOE and cambial age or distance from pith; (2) develop species-specific models to predict pith-to-bark changes in MOE; and (3) to test the influences of radial growth, relative vertical height, and tree slenderness (tree height/DBH) on MOE. For both species, cambial age was selected as the best explanatory variable with which to build pith-to-bark models of MOE. For white spruce and trembling aspen, the final nonlinear mixed-effect models indicated that an augmented rate of increase in MOE occurred with increasing vertical position within the tree. For white spruce trees, radial growth and slenderness were found to positively influence maximum estimated MOE. For trembling aspen, there was no apparent effect of vertical position or radial growth on maximum MOE. The results shed light on potential drivers of radial patterns of MOE and will be useful in guiding silvicultural prescriptions.
ONE-DIMENSIONAL QUASI-RELATIVISTIC PARTICLE IN THE BOX
Authors: KALETA KAMIL , KWAŚNICKI MATEUSZ , MAŁECKI JACEK
Published: August 2013

The eigenvalues and eigenfunctions of the one-dimensional quasi-relativistic Hamiltonian (-ℏ2c2d2/dx2 + m2c4)1/2 + V well (x) (the Klein–Gordon square-root operator with electrostatic potential) with the infinite square well potential V well (x) are studied. Eigenvalues represent energies of a "massive particle in the box" quasi-relativistic model. Approximations to eigenvalues λn are given, uniformly in n, ℏ, m, c and a, with error less than C1ℏca-1 exp (-C2ℏ-1mca)n-1. Here 2a is the width of the potential well. As a consequence, the spectrum is simple and the nth eigenvalue is equal to (nπ/2 - π/8)ℏc/a + O(1/n) as n → ∞. Non-relativistic, zero mass and semi-classical asymptotic expansions are included as special cases. In the final part, some L2 and L∞ properties of eigenfunctions are studied.
ON CUSTOMERS ACTING AS SERVERS
Authors: PEREL EFRAT , YECHIALI URI
Published: August 2013

We consider systems comprised of two interlacing M/M/ • /• type queues, where customers of each queue are the servers of the other queue. Such systems can be found for example in file sharing programs, SETI@home project, and other applications [Arazi, A, E Ben-Jacob and U Yechiali (2005). Controlling an oscillating Jackson-type network having state-dependant service rates. Mathematical Methods of Operations Research, 62, 453–466]. Denoting by Li the number of customers in queue i(Qi), i = 1, 2, we assume that Q1 is a multi-server finite-buffer system with an overall capacity of size N, where the customers there are served by the L2 customers present in Q2. Regarding Q2, we study two different scenarios described as follows: (i) All customers present in Q1 join hands together to form a single server for the customers in Q2, with service time exponentially distributed with an overall intensity μ2L1. That is, the service rate of the customers in Q2 changes dynamically, following the state of Q1. (ii) Each of the customers present in Q1individually acts as a server for the customers in Q2, with service time exponentially distributed with mean 1/μ2. In other words, the number of servers at Q2 changes according to the queue size fluctuations of Q1.

We present a probabilistic analysis of such systems, applying both Matrix Geometric method and Probability Generating Functions (PGFs) approach, and derive the stability condition for each model, along with its two-dimensional stationary distribution function. We reveal a relationship between the roots of a given matrix, related to the PGFs, and the stability condition of the systems. In addition, we calculate the means of Li, i = 1, 2, along with their correlation coefficient, and obtain the probability of blocking at Q1. Finally, we present numerical examples and compare between the two models.
PHOTOACTIVE GOLD NANOPARTICLE SOFTOXOMETALATES (SOM) USING A KEPLERATE FOR SYNTHESIS OF POLYSTYRENE LATEX MICROSPHERES BY PHOTOPOLYMERIZATION
Authors: SAHASRABUDHE ATHARVA , ROY SOUMYAJIT
Published: August 2013

In this paper, a green and facile synthetic protocol for the preparation of photoactive gold nanoparticle-soft oxometalates ( AuNP-SOM ) using a unique keplarate type oxomolybdate cluster viz. { Mo 132}, is reported. The as-synthesized AuNP-SOMs are fully characterized by electronic absorption spectroscopy, Raman spectroscopy and high resolution transmission electron microscopy (HR-TEM). We further demonstrate that by merely tuning the ratio of the precursors in solution it is possible to control the morphology of AuNP-SOM nanostructures. Moreover, these photoactive AuNP-SOMs are employed as photocatalysts for the photopolymerization of styrene to generate colloidal monodisperse polystyrene microspheres in a controllable way in the absence of any external co-initiator or inert atmosphere. Effect of styrene concentration on the size of microspheres is studied using DLS and optical microscopy. Finally, the role of AuNP-SOMs as efficient photocatalyst is established through several control experiments and a reaction pathway is proposed.
The Politics and Poetics of Infrastructure
Authors: Larkin Brian
Published: August 2013

Infrastructures are material forms that allow for the possibility of exchange over space. They are the physical networks through which goods, ideas, waste, power, people, and finance are trafficked. In this article I trace the range of anthropological literature that seeks to theorize infrastructure by drawing on biopolitics, science and technology studies, and theories of technopolitics. I also examine other dimensions of infrastructures that release different meanings and structure politics in various ways: through the aesthetic and the sensorial, desire and promise.
Geographic Mode of Speciation and Genomic Divergence
Authors: Feder Jeffrey L. , Flaxman Samuel M. , Egan Scott P. , Comeault Aaron A. , Nosil Patrik
Published: August 2013

Understanding speciation requires determining how inherent barriers to gene flow (reproductive isolation, RI) evolve between populations. The field of population genomics attempts to address this question by characterizing genome-wide patterns of divergence between taxa, often utilizing next-generation sequencing. Here, we focus on a central assumption of such “genome scans”: regions displaying high levels of differentiation contain loci contributing to RI. Three major issues are discussed concerning the relationship between gene flow, genomic divergence, and speciation: (a) patterns expected in the presence versus absence of gene flow; (b) processes, such as direct selection and genetic hitchhiking, allowing for divergence with gene flow; and (c) the consequences of the timing of when gene flow occurs during speciation (e.g., continuous gene flow versus gene flow following secondary contact after a period of initial allopatric divergence). Theory and existing data are presented for each issue, and avenues for future work are highlighted.
α-Cells are dispensable in postnatal morphogenesis and maturation of mouse pancreatic islets
Authors: Shiota Chiyo , Prasadan Krishna , Guo Ping , El-Gohary Yousef , Wiersch John , Xiao Xiangwei , Esni Farzad , Gittes George K.
Published: August 2013

Glucagon-producing α-cells are the second-most abundant cell type in the islet. Whereas α-cells make up less than 20% of the cells in a mature mouse islet, they occupy a much larger proportion of the pancreatic endocrine cell population during the early postnatal period, the time when morphological and functional maturation occurs to form adult islets. To determine whether α-cells have a role in postnatal islet development, a diphtheria toxin-mediated α-cell ablation mouse model was established. Rapid and persistant depletion of α-cells was achieved by daily injection of the toxin for 2 wk starting at postnatal day 1 (P1). Total pancreatic glucagon content in the α-cell-ablated mice was undetectable at P14 and still less than 0.3% of that of the control mice at 4 mo of age. Histological analyses revealed that formation of spherical islets occurred normally, and the islet size distribution was not changed despite the near-total lack of α-cells. Furthermore, there were no differences in expression of β-cell maturation marker proteins, including urocortin 3 and glucose transporter 2, in the α-cell-ablated islets at P14. Mice lacking α-cells grew normally and appeared healthy. Both glucose and insulin tolerance tests demonstrated that the α-cell-ablated mice had normal glucose homeostasis. These results indicate that α-cells do not play a critical role in postnatal islet morphogenesis or functional maturation of β-cells.
Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice
Authors: Sheng Liang , Jiang Bijie , Rui Liangyou
Published: August 2013

The liver is an essential metabolic organ. In addition to metabolizing glucose and lipids, hepatocytes also secrete various cytokines that modulate both hepatocyte metabolism and liver inflammation. Hepatocyte injury and death and liver inflammation are the major contributors to liver diseases, including nonalcoholic steatohepatitis (NASH). Anatomic locations have a profound effect on hepatocyte metabolism, and liver zonation describes the metabolic heterogeneity of hepatocytes along the portovenous axis. However, it is unclear whether hepatocyte heterogeneity is affected by intrinsic factors and whether dietary fat, a risk factor for NASH, has distinct detrimental effects on different hepatocyte subpopulations. Here, we showed that mouse livers contained both high-lipid and low-lipid subpopulations of hepatocytes. The high-lipid subpopulation was more susceptible to injury and apoptosis and produced more proinflamatrory cytokines after treatment with endotoxin and saturated fatty acids. Dietary fat consumption further increased fatty acid uptake, intracellular lipid levels, hepatocyte injury and death, and the expression of proinflammatory cytokines in the high-lipid subpopulation. In contrast, dietary fat slightly increased lipid levels, cell death, and expression of proinflammatory cytokines in the low-lipid subpopulation. The low-lipid subpopulation produced more glucose. Fat consumption further activated the gluconeogenic program in the low-lipid, but not the high-lipid, subpopulations. These data suggest that intracellular lipid content is a key intrinsic determinant for hepatocyte heterogeneity of metabolic, inflammatory, and survival states.
Unilateral once daily milking locally induces differential gene expression in both mammary tissue and milk epithelial cells revealing mammary remodeling
Authors: Boutinaud Marion , Galio Laurent , Lollivier Vanessa , Finot Laurence , Wiart Sandra , Esquerré Diane , Devinoy Eve
Published: August 2013

Once daily milking reduces milk yield, but the underlying mechanisms are not yet fully understood. Local regulation due to milk stasis in the tissue may contribute to this effect, but such mechanisms have not yet been fully described. To challenge this hypothesis, one udder half of six Holstein dairy cows was milked once a day (ODM), and the other twice a day (TDM). On the 8th day of unilateral ODM, mammary epithelial cells (MEC) were purified from the milk using immunomagnetic separation. Mammary biopsies were harvested from both udder halves. The differences in transcript profiles between biopsies from ODM and TDM udder halves were analyzed by a 22k bovine oligonucleotide array, revealing 490 transcripts that were differentially expressed. The principal category of upregulated transcripts concerned mechanisms involved in cell proliferation and death. We further confirmed remodeling of the mammary tissue by immunohistochemistry, which showed less cell proliferation and more apoptosis in ODM udder halves. Gene expression analyzed by RT-qPCR in MEC purified from milk and mammary biopsies showed a common downregulation of six transcripts ( ABCG2, FABP3, NUCB2, RNASE1 and 5, and SLC34A2) but also some discrepancies. First, none of the upregulated transcripts in biopsies varied in milk-purified MEC. Second, only milk-purified MEC showed significant LALBA downregulation, which suggests therefore that they correspond to a mammary epithelial cell subpopulation. Our results, obtained after unilateral milking, suggest that cell remodeling during ODM is due to a local effect, which may be triggered by milk accumulation.
Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer
Authors: Naro Chiara , Sette Claudio
Published: August 2013

Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted bycis-acting RNA sequence elements andtrans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation.
Approaching Cave Level Identification with GIS: A Case Study of Carter Caves
Authors: Jacoby Brianne S. , Peterson Eric W. , Kostelnick John C. , Dogwiler Toby
Published: August 2013

Cave passages that are found at similar elevations are grouped together and called levels. The current understanding is that passages within a level are speleogenetically linked to a common static baselevel or stratigraphic control. Cave levels have provided an interpretive framework for deciphering cave development, landscape evolution, and climatic changes. Cosmogenic dating has been successfully used to interpret levels in Mammoth Cave and the Cumberland Plateau; however, this technique is expensive and there are limited funding resources available. Geographic information systems may be used as preliminary procedures to identify cave levels and constrain the timing of level development. A GIS method is applied to the Carter Cave system in northeastern Kentucky. Cave entrance elevations along stream valleys were found by extracting elevation values from a  m digital elevation model. Using a histogram generated from the frequency of cave elevations and a natural breaks classifier, four cave levels were identified in the Carter Cave system. This work improves the understanding of the Carter Cave system evolution and contributes toa methodology that can be used to ascertain an erosion history of karst systems.
Bone-Targeted Therapies in Metastatic Castration-Resistant Prostate Cancer: Evolving Paradigms
Authors: El-Amm Joelle , Freeman Ashley , Patel Nihar , Aragon-Ching Jeanny B.
Published: August 2013

Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases.
Detection of Severe Respiratory Disease Epidemic Outbreaks by CUSUM-Based Overcrowd-Severe-Respiratory-Disease-Index Model
Authors: Polanco Carlos , Castañón-González Jorge Alberto , Macías Alejandro E. , Samaniego José Lino , Buhse Thomas , Villanueva-Martínez Sebastián
Published: August 2013

A severe respiratory disease epidemic outbreak correlates with a high demand of specific supplies and specialized personnel to hold it back in a wide region or set of regions; these supplies would be beds, storage areas, hemodynamic monitors, and mechanical ventilators, as well as physicians, respiratory technicians, and specialized nurses. We describe an online cumulative sum based model named Overcrowd-Severe-Respiratory-Disease-Index based on the Modified Overcrowd Index that simultaneously monitors and informs the demand of those supplies and personnel in a healthcare network generating early warnings of severe respiratory disease epidemic outbreaks through the interpretation of such variables. Apost hochistorical archive is generated, helping physicians in charge to improve the transit and future allocation of supplies in the entire hospital network during the outbreak. The model was thoroughly verified in a virtual scenario, generating multiple epidemic outbreaks in a 6-year span for a 13-hospital network. When it was superimposed over the H1N1 influenza outbreak census (2008–2010) taken by the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City, it showed that it is an effective algorithm to notify early warnings of severe respiratory disease epidemic outbreaks with a minimal rate of false alerts.
Development of Transgenic Papaya throughAgrobacterium-Mediated Transformation
Authors: Azad Md. Abul Kalam , Rabbani Md. Golam , Amin Latifah , Sidik Nik Marzuki
Published: August 2013

Transgenic papaya plants were regenerated from hypocotyls and immature zygotic embryo after cocultivation withAgrobacterium tumefaciensLBA-4404 carrying a binary plasmid vector system containing neomycin phosphotransferase (nptII) gene as the selectable marker andβ-glucuronidase (GUS) as the reporter gene. The explants were co-cultivated withAgrobacterium tumefacienson regeneration medium containing 500 mg/L carbenicillin + 200 mg/L cefotaxime for one week. The cocultivated explants were transferred into the final selection medium containing 500 mg/L carbenicillin + 200 mg/L cefotaxime + 50 mg/L kanamycin for callus induction as well as plant regeneration. The callus derived from the hypocotyls ofCarica papayacv. Shahi showed the highest positive GUS activities compared toCarica papayacv. Ranchi. The transformed callus grew vigorously and formed embryos followed by transgenic plantlets successfully. The result of this study showed that the hypocotyls ofC. papayacv. Shahi andC. papayacv. Ranchi are better explants for genetic transformation compared to immature embryos. The transformedC. papayacv. Shahi also showed the maximum number of plant regeneration compared to that ofC. papayacv. Ranchi.
Parent and Peer Influence on Recreational Use of Pain Medication: Are Their Influences Similar to That of Marijuana Use?
Authors: Fleary Sasha , Taylor Aaron , Heffer Robert W. , McKyer E. Lisako
Published: August 2013

Parent and peer disapproval were examined as potential predictors of recreational use of over-the-counter (OTC) and prescription pain medication. Risk perception was studied as a potential mediator of the effects of parent and peer disapproval. Four hundred and sixty-five college students (, ) were recruited between September 2009 and September 2010. Participants completed an online survey about their recreational medication use, other substance use, and correlates of use. Path analyses showed that predictors of OTC and prescription pain medication recreational use are largely similar to predictors of marijuana use in college students such that risk perception mediated both the effect of parent and peer disapproval on dichotomous misuse, and peer disapproval had a significant direct effect on dichotomous misuse. Prevention interventions for recreational use of pain medication should target risk perception and peer disapproval.
The Role of Changes in Extracellular Matrix of Cartilage in the Presence of Inflammation on the Pathology of Osteoarthritis
Authors: Maldonado Maricela , Nam Jin
Published: August 2013

Osteoarthritis (OA) is a degenerative disease that affects various tissues surrounding joints such as articular cartilage, subchondral bone, synovial membrane, and ligaments. No therapy is currently available to completely prevent the initiation or progression of the disease partly due to poor understanding of the mechanisms of the disease pathology. Cartilage is the main tissue afflicted by OA, and chondrocytes, the sole cellular component in the tissue, actively participate in the degeneration process. Multiple factors affect the development and progression of OA including inflammation that is sustained during the progression of the disease and alteration in biomechanical conditions due to wear and tear or trauma in cartilage. During the progression of OA, extracellular matrix (ECM) of cartilage is actively remodeled by chondrocytes under inflammatory conditions. This alteration of ECM, in turn, changes the biomechanical environment of chondrocytes, which further drives the progression of the disease in the presence of inflammation. The changes in ECM composition and structure also prevent participation of mesenchymal stem cells in the repair process by inhibiting their chondrogenic differentiation. This review focuses on how inflammation-induced ECM remodeling disturbs cellular activities to prevent self-regeneration of cartilage in the pathology of OA.
Improved Rao-Blackwellized Particle Filter by Particle Swarm Optimization
Authors: Zhao Zeng-Shun , Feng Xiang , Lin Yan-yan , Wei Fang , Wang Shi-Ku , Xiao Tong-Lu , Cao Mao-Yong , Hou Zeng-Guang , Tan Min
Published: August 2013

The Rao-Blackwellized particle filter (RBPF) algorithm usually has better performance than the traditional particle filter (PF) by utilizing conditional dependency relationships between parts of the state variables to estimate. By doing so, RBPF could not only improve the estimation precision but also reduce the overall computational complexity. However, the computational burden is still too high for many real-time applications. To improve the efficiency of RBPF, the particle swarm optimization (PSO) is applied to drive all the particles to the regions where their likelihoods are high in the nonlinear area. So only a small number of particles are needed to participate in the required computation. The experimental results demonstrate that this novel algorithm is more efficient than the standard RBPF.
Improved Reception of In-Body Signals by Means of a Wearable Multi-Antenna System
Authors: Castel Thijs , Van Torre Patrick , Tanghe Emmeric , Agneessens Sam , Vermeeren Günter , Joseph Wout , Rogier Hendrik
Published: August 2013

High data-rate wireless communication for in-body human implants is mainly performed in the 402–405 MHz Medical Implant Communication System band and the 2.45 GHz Industrial, Scientific and Medical band. The latter band offers larger bandwidth, enabling high-resolution live video transmission. Although in-body signal attenuation is larger, at least 29 dB more power may be transmitted in this band and the antenna efficiency for compact antennas at 2.45 GHz is also up to 10 times higher. Moreover, at the receive side, one can exploit the large surface provided by a garment by deploying multiple compact highly efficient wearable antennas, capturing the signals transmitted by the implant directly at the body surface, yielding stronger signals and reducing interference. In this paper, we implement a reliable 3.5 Mbps wearable textile multi-antenna system suitable for integration into a jacket worn by a patient, and evaluate its potential to improve the In-to-Out Body wireless link reliability by means of spatial receive diversity in a standardized measurement setup. We derive the optimal distribution and the minimum number of on-body antennas required to ensure signal levels that are large enough for real-time wireless endoscopy-capsule applications, at varying positions and orientations of the implant in the human body.
The Role of Vaginal Mesh Procedures in Pelvic Organ Prolapse Surgery in View of Complication Risk
Authors: Ellington David R. , Richter Holly E.
Published: August 2013

Synthetic transvaginal mesh has been employed in the treatment of pelvic organ prolapse for more than a decade. As the use of these devices increased during this period so did adverse event reporting. In 2008, the Food and Drug Administration (FDA) Public Health Notification informed physicians and patients of rising concerns with the use of synthetic transvaginal mesh. Shortly thereafter and in parallel to marked increases in adverse event reporting within the Manufacturer and User Device Experience (MAUDE), the FDA released a Safety Communication regarding urogynecologic surgical mesh use. Following this report and in the wake of increased medical industry product withdrawal, growing medicolegal concerns, patient safety, and clinical practice controversy, many gynecologists and pelvic reconstructive surgeons are left with limited long-term data, clinical guidance, and growing uncertainty regarding the role of synthetic transvaginal mesh use in pelvic organ prolapse. This paper reviews the reported complications of synthetic transvaginal mesh with an evidence-based approach as well as providing suggested guidance for the future role of its use amidst the controversy.
Activation of the ERK1/2 Signaling Pathway during the Osteogenic Differentiation of Mesenchymal Stem Cells Cultured on Substrates Modified with Various Chemical Groups
Authors: Bai Bing , He Jin , Li Yan-Shu , Wang Xiu-Mei , Ai Hong-Jun , Cui Fu-Zhai
Published: August 2013

The current study examined the influence of culture substrates modified with the functional groups –OH, –COOH, –NH2, and –CH3using SAMs technology, in conjunction with TAAB control, on the osteogenic differentiation of rabbit BMSCs. The CCK-8 assay revealed that BMSCs exhibited substrate-dependent cell viability. The cells plated on –NH2- and –OH-modified substrates were well spread and homogeneous, but those on the –COOH- and –CH3-modified substrates showed more rounded phenotype. The mRNA expression of BMSCs revealed that –NH2-modified substrate promoted the mRNA expression and osteogenic differentiation of the BMSCs. The contribution of ERK1/2 signaling pathway to the osteogenic differentiation of BMSCs cultured on the –NH2-modified substrate was investigatedin vitro. The –NH2-modified substrate promoted the expression of integrins; the activation of FAK and ERK1/2. Inhibition of ERK1/2 activation by PD98059, a specific inhibitor of the ERK signaling pathway, blocked ERK1/2 activation in a dose-dependent manner, as revealed for expression of Cbfα-1 and ALP. Blockade of ERK1/2 phosphorylation in BMSCs by PD98059 suppressed osteogenic differentiation on chemical surfaces. These findings indicate a potential role for ERK in the osteogenic differentiation of BMSCs on surfaces modified by specific chemical functional groups, indicating that the microenvironment affects the differentiation of BMSCs. This observation has important implications for bone tissue engineering.
A Hybrid Bat Algorithm with Path Relinking for Capacitated Vehicle Routing Problem
Authors: Zhou Yongquan , Xie Jian , Zheng Hongqing
Published: August 2013

The capacitated vehicle routing problem (CVRP) is an NP-hard problem with wide engineering and theoretical background. In this paper, a hybrid bat algorithm with path relinking (HBA-PR) is proposed to solve CVRP. The HBA-PR is constructed based on the framework of continuous bat algorithm; the greedy randomized adaptive search procedure (GRASP) and path relinking are effectively integrated into bat algorithm. Moreover, in order to further improve the performance, the random subsequences and single-point local search are operated with certain loudness (probability). In order to verify the validity of the method in this paper, and it's efficiency and with other existing methods, several classical CVRP instances from three classes of CVRP benchmarks are selected to tested. Experimental results and comparisons show that the HBA-PR is effective for CVRP.
Automatic Planar Optical Waveguide Devices Packaging System Based on Polynomial Fitting Algorithm
Authors: Zheng Yu , Duan Ji-an , Wang Huaming , Li Wenjuan
Published: August 2013

This paper has proposed an automatic precise alignment coupling algorithm of planar optical waveguide devices based on polynomial fitting, and the experiment shows that for 1 × 8 planar optical waveguide splitter, the time it takes for alignment is within 2.5 min and for 1 × 16 planar optical waveguide splitter, the required time is within 3 min. For 1 × 8 planar optical waveguide splitter, many repeated experiments can guarantee that the insertion loss of the device channels is less than 10.5 dB, with the maximum uniformity of 0.67 dB; for 1 × 16 planar optical waveguide splitter, many repeated experiments can guarantee that the insertion loss of the device channels is less than 13.7 dB, with the maximum uniformity of 0.66 dB. The alignment velocity, precision, and reliability of this algorithm are all greatly increased.
Iterative Method for Solving a Beam Equation with Nonlinear Boundary Conditions
Authors: Dang Quang A. , Thanh Huong Nguyen
Published: August 2013

In this paper, we propose an iterative method for solving a beam problem which is described by a nonlinear fourth-order equation with nonlinear boundary conditions. The method reduces this nonlinear fourth-order problem to a sequence of linear second-order problems with linear boundary conditions. The convergence of the method is proved, and some numerical examples demonstrate the efficiency of the method.
Adverse Health Effects Associated with Increased Activity at Kīlauea Volcano: A Repeated Population-Based Survey
Authors: Longo Bernadette M.
Published: August 2013

Eruptive activity at the Kīlauea volcano (Hawai`i, USA) has increased since 2008 resulting in volcanic air pollution (vog) at levels exceeding the national air quality standard for sulfur dioxide. Previous investigations during lower vog levels found adverse cardiorespiratory effects in the residents. The purpose of this 2012 survey was to reassess and compare the impact of the increased volcanic activity on population health. Prevalence of cardiorespiratory signs, symptoms, and diseases was estimated in vog exposed and unexposed communities, and descriptions of perceived health and environmental effects were collected door-to-door. Vog exposure was significantly associated with increased odds of self-reported cough, phlegm, rhinorrhea, sore/dry throat, shortness of breath, sinus congestion, continual wheezing, eye and skin irritation, and diagnosed hypertension. Field measurements identified significantly higher average systolic and diastolic blood pressures (P=0.045,0.002) and lower blood oxygen saturation (P=0.008). Half of the participants perceived that Kīlauea’s intensified eruption had negatively affected their health with reports of financial impacts from degradation of agriculture and livestock. Relatively stronger magnitudes of health effects were associated with the higher exposure to vog. Public concerns remain about attributed effects of the ongoing eruption. Enhanced public health efforts are recommended at Kīlauea and other degassing volcanoes worldwide.
Exponential Collocation Method for Solutions of Singularly Perturbed Delay Differential Equations
Authors: Yüzbaşı Şuayip , Sezer Mehmet
Published: August 2013

This paper deals with the singularly perturbed delay differential equations under boundary conditions. A numerical approximation based on the exponential functions is proposed to solve the singularly perturbed delay differential equations. By aid of the collocation points and the matrix operations, the suggested scheme converts singularly perturbed problem into a matrix equation, and this matrix equation corresponds to a system of linear algebraic equations. Also, an error analysis technique based on the residual function is introduced for the method. Four examples are considered to demonstrate the performance of the proposed scheme, and the results are discussed.
Effective Proactive and Reactive Defense Strategies against Malicious Attacks in a Virtualized Honeynet
Authors: Lin Frank Yeong-Sung , Wang Yu-Shun , Huang Ming-Yang
Published: August 2013

Virtualization plays an important role in the recent trend of cloud computing. It allows the administrator to manage and allocate hardware resources flexibly. However, it also causes some security issues. This is a critical problem for service providers, who simultaneously strive to defend against malicious attackers while providing legitimate users with high quality service. In this paper, the attack-defense scenario is formulated as a mathematical model where the defender applies both proactive and reactive defense mechanisms against attackers with different attack strategies. In order to simulate real-world conditions, the attackers are assumed to have incomplete information and imperfect knowledge of the target network. This raises the difficulty of solving the model greatly, by turning the problem nondeterministic. After examining the experiment results, effective proactive and reactive defense strategies are proposed. This paper finds that a proactive defense strategy is suitable for dealing with aggressive attackers under “winner takes all” circumstances, while a reactive defense strategy works better in defending against less aggressive attackers under “fight to win or die” circumstances.
The Outline of Prognosis and New Advances in Diagnosis of Oral Squamous Cell Carcinoma (OSCC): Review of the Literature
Authors: Omar Esam Ahmad
Published: August 2013

Objective. Oral squamous cell carcinoma (OSCC) has a remarkable incidence over the world and a fairly strenuous prognosis, encouraging further research on the prognostic factors and new techniques for diagnosis that might modify disease outcome.Data Sources. A web-based search for all types of articles published was initiated using Medline/Pub Med, with the key words such as oral cancer, prognostic factors of oral cancer, diagnostic method of oral cancer, and imaging techniques for diagnosis of oral cancer. The search was restricted to articles published in English, with no publication date restriction (last update April, 2013).Review Methods. In this paper, I approach the factors of prognosis of OSCC and the new advances in diagnostic technologies as well. I also reviewed available studies of the tissue fluorescence spectroscopy and other noninvasive diagnostic aids for OSCC.Results. The outcome is greatly influenced by the stage of the disease (especially TNM). Prognosis also depends or varies with tumour primary site, nodal involvement, tumour thickness, and the status of the surgical margins.Conclusion. Tumour diameter is not the most accurate when compared to tumour thickness or depth of invasion, which can be related directly to prognosis. There is a wide agreement on using ultrasound guided fine needle aspiration biopsies in the evaluation of lymph node metastasis.