bluuebunny/crossref_metadata_2025 huggingface dataset:
A Protein (ORF2) Encoded by the Latency-Related Gene of Bovine Herpesvirus 1 Interacts with DNA
Authors: Pittayakhajonwut Daraporn , Sinani Devis , Jones Clinton
Published: March 2013

Bovine herpesvirus 1 (BHV-1), like other members of theAlphaherpesvirinaesubfamily, establishes latency in sensory neurons. The virally encoded latency-related RNA (LR-RNA) is expressed abundantly in latently infected sensory neurons and encodes several proteins, including ORF2. An LR mutant virus with stop codons at the amino terminus of ORF2 does not reactivate from latency after treatment with the synthetic corticosteroid dexamethasone, in part because it induces higher levels of apoptosis during the establishment of latency. ORF2 inhibits apoptosis, interacts with three cellular transcription factors (Notch1, Notch3, and C/EBP-α), and interferes with Notch-mediated signaling. Consequently, we predict that ORF2 expression is crucial for the latency reactivation cycle in cattle. In this study, we tested whether ORF2 interacts with nucleic acids, because it contains 18% basic amino acids and localizes to the nucleus. A subset of ORF2 proteins was associated with chromatin and preferentially associated with single-stranded DNA in transfected neuroblastoma cells (Neuro-2A). Alanine substitution of serine, threonine, and tyrosine residues in ORF2 increased the steady-state protein levels in Neuro-2A cells, and this protein preferentially interacted with double-stranded DNA. Certain in-frame transposon insertion mutants did not interact with DNA as efficiently as wild-type (wt) ORF2 did. ORF2 purified from bacteria under denaturing conditions preferentially interacted with double-stranded DNA, suggesting that the interaction between ORF2 and DNA was direct. In contrast, ORF2 purified under native conditions preferentially interacted with single-stranded DNA. We suggest that interactions between ORF2 and DNA mediate certain aspects of the latency reactivation cycle.
Conformational Epitope Consisting of the V3 and V4 Loops as a Target for Potent and Broad Neutralization of Simian Immunodeficiency Viruses
Authors: Kuwata Takeo , Takaki Kaori , Yoshimura Kazuhisa , Enomoto Ikumi , Wu Fan , Ourmanov Ilnour , Hirsch Vanessa M. , Yokoyama Masaru , Sato Hironori , Matsushita Shuzo
Published: March 2013

Inducing neutralizing antibodies (NAb) is the key to developing a protective vaccine against human immunodeficiency virus type 1 (HIV-1). To clarify the neutralization mechanism of simian immunodeficiency virus (SIV), we analyzed NAb B404, which showed potent and broad neutralizing activity against various SIV strains. In 4 SIVsmH635FC-infected macaques, B404-like antibodies using the specific VH3 gene with a long complementarity-determining region 3 loop and λ light chain were the major NAbs in terms of the number and neutralizing potency. This biased NAb induction was observed in all 4 SIVsmH635FC-infected macaques but not in 2 macaques infected with a SIV mix, suggesting that induction of B404-like NAbs depended on the inoculated virus. Analysis using Env mutants revealed that the V3 and V4 loops were critical for B404 binding. The reactivity to the B404 epitope on trimeric, but not monomeric, Env was enhanced by CD4 ligation. The B404-resistant variant, which was induced by passages with increasing concentrations of B404, accumulated amino acid substitutions in the C2 region of gp120. Molecular dynamics simulations of the gp120 outer domains indicated that the C2 mutations could effectively alter the structural dynamics of the V3/V4 loops and their neighboring regions. These results suggest that a conformational epitope consisting of the V3 and V4 loops is the target for potent and broad neutralization of SIV. Identifying the new neutralizing epitope, as well as specifying the VH3 gene used for epitope recognition, will help to develop HIV-1 vaccines.
Ebola Virus Does Not Block Apoptotic Signaling Pathways
Authors: Olejnik Judith , Alonso Jesus , Schmidt Kristina M. , Yan Zhen , Wang Wei , Marzi Andrea , Ebihara Hideki , Yang Jinghua , Patterson Jean L. , Ryabchikova Elena , Mühlberger Elke
Published: March 2013

Since viruses rely on functional cellular machinery for efficient propagation, apoptosis is an important mechanism to fight viral infections. In this study, we sought to determine the mechanism of cell death caused by Ebola virus (EBOV) infection by assaying for multiple stages of apoptosis and hallmarks of necrosis. Our data indicate that EBOV does not induce apoptosis in infected cells but rather leads to a nonapoptotic form of cell death. Ultrastructural analysis confirmed necrotic cell death of EBOV-infected cells. To investigate if EBOV blocks the induction of apoptosis, infected cells were treated with different apoptosis-inducing agents. Surprisingly, EBOV-infected cells remained sensitive to apoptosis induced by external stimuli. Neither receptor- nor mitochondrion-mediated apoptosis signaling was inhibited in EBOV infection. Although double-stranded RNA (dsRNA)-induced activation of protein kinase R (PKR) was blocked in EBOV-infected cells, induction of apoptosis mediated by dsRNA was not suppressed. When EBOV-infected cells were treated with dsRNA-dependent caspase recruiter (dsCARE), an antiviral protein that selectively induces apoptosis in cells containing dsRNA, virus titers were strongly reduced. These data show that the inability of EBOV to block apoptotic pathways may open up new strategies toward the development of antiviral therapeutics.
Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes
Authors: Hoffenberg Simon , Powell Rebecca , Carpov Alexei , Wagner Denise , Wilson Aaron , Kosakovsky Pond Sergei , Lindsay Ross , Arendt Heather , DeStefano Joanne , Phogat Sanjay , Poignard Pascal , Fling Steven P. , Simek Melissa , LaBranche Celia , Montefiori David , Wrin Terri , Phung Pham , Burton Dennis , Koff Wayne , King C. Richter , Parks Christopher L. , Caulfield Michael J.
Published: March 2013

Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.
The Source of the PB1 Gene in Influenza Vaccine Reassortants Selectively Alters the Hemagglutinin Content of the Resulting Seed Virus
Authors: Cobbin Joanna C. A. , Verity Erin E. , Gilbertson Brad P. , Rockman Steven P. , Brown Lorena E.
Published: March 2013

The yields of egg-grown influenza vaccines are maximized by the production of a seed strain using a reassortment of the seasonal influenza virus isolate with a highly egg-adapted strain. The seed virus is selected based on high yields of viral hemagglutinin (HA) and expression of the surface antigens from the seasonal isolate. The remaining proteins are usually derived from the high-growth parent. However, a retrospective analysis of vaccine seeds revealed that the seasonal PB1 gene was selected in more than 50% of reassortment events. Using the model seasonal H3N2 virus A/Udorn/307/72 (Udorn) virus and the high-growth A/Puerto Rico/8/34 (PR8) virus, we assessed the influence of the source of the PB1 gene on virus growth and vaccine yield. Classical reassortment of these two strains led to the selection of viruses that predominantly had the Udorn PB1 gene. The presence of Udorn PB1 in the seed virus, however, did not result in higher yields of virus or HA compared to the yields in the corresponding seed virus with PR8 PB1. The 8-fold-fewer virions produced with the seed virus containing the Udorn PB1 were somewhat compensated for by a 4-fold increase in HA per virion. A higher HA/nucleoprotein (NP) ratio was found in past vaccine preparations when the seasonal PB1 was present, also indicative of a higher HA density in these vaccine viruses. As the HA viral RNA (vRNA) and mRNA levels in infected cells were similar, we propose that PB1 selectively alters the translation of viral mRNA. This study helps to explain the variability of vaccine seeds with respect to HA yield.
Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells
Authors: Zaitseva Marina , Shotwell Elisabeth , Scott John , Cruz Stephanie , King Lisa R. , Manischewitz Jody , Diaz Claudia G. , Jordan Robert A. , Grosenbach Douglas W. , Golding Hana
Published: March 2013

Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (
nu
−
/nu
−
) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4
+
or CD8
+
T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge.
Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger
Authors: Römling Ute , Galperin Michael Y. , Gomelsky Mark
Published: March 2013

Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.
Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense
Authors: Vasu Kommireddy , Nagaraja Valakunja
Published: March 2013

Restriction-modification (R-M) systems are ubiquitous and are often considered primitive immune systems in bacteria. Their diversity and prevalence across the prokaryotic kingdom are an indication of their success as a defense mechanism against invading genomes. However, their cellular defense function does not adequately explain the basis for their immaculate specificity in sequence recognition and nonuniform distribution, ranging from none to too many, in diverse species. The present review deals with new developments which provide insights into the roles of these enzymes in other aspects of cellular function. In this review, emphasis is placed on novel hypotheses and various findings that have not yet been dealt with in a critical review. Emerging studies indicate their role in various cellular processes other than host defense, virulence, and even controlling the rate of evolution of the organism. We also discuss how R-M systems could have successfully evolved and be involved in additional cellular portfolios, thereby increasing the relative fitness of their hosts in the population.
Exploiting Quorum Sensing To Confuse Bacterial Pathogens
Authors: LaSarre Breah , Federle Michael J.
Published: March 2013

Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.
Molecular Regulation of Antibiotic Biosynthesis in Streptomyces
Authors: Liu Gang , Chater Keith F. , Chandra Govind , Niu Guoqing , Tan Huarong
Published: March 2013

Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific.Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis inS. coelicolorand other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerousStreptomycesgenomes.
Ocular Tropism of Respiratory Viruses
Authors: Belser Jessica A. , Rota Paul A. , Tumpey Terrence M.
Published: March 2013

Respiratory viruses (including adenovirus, influenza virus, respiratory syncytial virus, coronavirus, and rhinovirus) cause a broad spectrum of disease in humans, ranging from mild influenza-like symptoms to acute respiratory failure. While species D adenoviruses and subtype H7 influenza viruses are known to possess an ocular tropism, documented human ocular disease has been reported following infection with all principal respiratory viruses. In this review, we describe the anatomical proximity and cellular receptor distribution between ocular and respiratory tissues. All major respiratory viruses and their association with human ocular disease are discussed. Research utilizingin vitroandin vivomodels to study the ability of respiratory viruses to use the eye as a portal of entry as well as a primary site of virus replication is highlighted. Identification of shared receptor-binding preferences, host responses, and laboratory modeling protocols among these viruses provides a needed bridge between clinical and laboratory studies of virus tropism.
Coexistent widespread small intestinal and colonic diverticular disease
Authors: Duff Gerald P , Chang Kah Hoong , Peirce Colin , Coffey J Calvin
Published: March 2013

A 73-year-old woman with a history of multiple abdominal surgery and sigmoid diverticulosis presented with severe constipation refractory to conservative management. As a result, she had developed food aversion and cachexia. Patient opted for laparotomy and defunctioning ileostomy to improve quality of life. At laparotomy, extensive diverticulae involving the small and large bowels were identified. Defunctioning ileostomy was performed. The patient regained her quality of life and reinstituted normal diet. Histology revealed marked serosal fibrosis and pulsion diverticulae.
Non-ketotic hyperglycaemia hemichorea–hemiballismus and acute ischaemic stroke
Authors: Carrion Diego M , Carrion Andres F
Published: March 2013

Here we describe a patient with a rare movement disorder, hemichorea–hemiballismus, which is described as a complication of non-ketotic hyperglycaemia. This complication may be seen in individuals with poorly controlled long-standing diabetes mellitus. Proper diagnosis is established with CT and MRI of the brain, which typically show classic findings in the basal ganglia. Treatment focuses on improvement of glycaemic control and usually results in rapid resolution of the movement disorder. Nevertheless, recurrent episodes of hemichorea–hemiballismus, and even more ominous complications such as ischaemic stroke may occur.
Blind drunk
Authors: Dholakia Shamik , Hashimi Yasmin , Chawla Bhavneet
Published: March 2013

Purtscher's retinopathy is a haemorrhagic and vaso-occlusive retinal vasculopathy, caused by microembolisation occluding retinal and choroidal arterioles. This leads to retinal haemorrhages and ischaemia. The usual cause is severe trauma. 1 However, a variety of conditions including acute pancreatitis, childbirth, long bone fracture, chest trauma and systemic inflammatory vasculitides may cause similar retinal presentations. 1–4 This highlights Purtscher's retinopathy as a clinically important differential diagnosis of visual loss. We present a case report of a 43-year-old man who was diagnosed with acute pancreatitis. While in hospital he developed sudden onset unilateral loss of vision. This case highlights the need to ensure prompt diagnosis and initiation of appropriate multidisciplinary management.
Successful experimental treatment of congenital ichthyosis in an infant
Authors: Deffenbacher Brandy
Published: March 2013

Ichthyosis is a rare genetic disease that causes defects in skin keratinisation. Infants born with this disease have tight shiny skin that inhibits limb and ear mobilities, eyelid and lip deformities and poor hair and nail growths. In addition, the barrier properties of the skin are disrupted, which leads to dehydration, body temperature regulation difficulties and increased susceptibility to infection. The treatments currently available include topical keratolytics, emollients, and for severe disease systemic retinoids. Given the increased permeability of the skin and increased body surface area infants are particularly susceptible to accidental overdose from the topical keratolytic treatments currently available. An experimental emollient of 10%N-acetylcysteine (NAC) and 5% urea was recently used with success in Argentina. A newborn with congenital ichthyosis cared for in our clinic failed his initial treatment of topical emollients. He was subsequently treated successfully with off-label use of a topical 5% NAC and 5% urea emollient.
Physical exercise and executive functions in preadolescent children, adolescents and young adults: a meta-analysis
Authors: Verburgh Lot , Königs Marsh , Scherder Erik J A , Oosterlaan Jaap
Published: March 2013

Purpose

The goal of this meta-analysis was to aggregate available empirical studies on the effects of physical exercise on executive functions in preadolescent children (6–12 years of age), adolescents (13–17 years of age) and young adults (18–35 years of age).

Method

The electronic databases PubMed, EMBASE and SPORTDiscus were searched for relevant studies reporting on the effects of physical exercise on executive functions. Nineteen studies were selected.

Results

There was a significant overall effect ofacutephysical exercise on executive functions (d=0.52, 95% CI 0.29 to 0.76, p<0.001). There were no significant differences between the three age groups (Q (2)=0.13, p=0.94). Furthermore, no significant overall effect ofchronicphysical exercise (d=0.14, 95%CI −0.04 to 0.32, p=0.19) on executive functions (Q (1)=5.08, p<0.05) was found. Meta-analytic effect sizes were calculated for the effects of acute physical exercise on the domain's inhibition/interference control (d=0.46, 95% CI 0.33 to 0.60, p<0.001) and working memory (d=0.05, 95% CI  −0.51 to 0.61, p=0.86) as well as for the effects ofchronicphysical exercise on planning (d=0.16, 95% CI 0.18 to 0.89, p=0.18).

Conclusions

Results suggest thatacutephysical exercise enhances executive functioning. The number of studies onchronicphysical exercise is limited and it should be investigated whetherchronicphysical exercise shows effects on executive functions comparable toacutephysical exercise. This is highly relevant in preadolescent children and adolescents, given the importance of well-developed executive functions for daily life functioning and the current increase in sedentary behaviour in these age groups.
A novel model-based meta-analysis to indirectly estimate the comparative efficacy of two medications: an example using DPP-4 inhibitors, sitagliptin and linagliptin, in treatment of type 2 diabetes mellitus
Authors: Gross Jorge Luiz , Rogers James , Polhamus Daniel , Gillespie William , Friedrich Christian , Gong Yan , Monz Brigitta Ursula , Patel Sanjay , Staab Alexander , Retlich Silke
Published: March 2013

Objectives

To develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example.

Design

Systematic review with MBMA.

Data sources

MEDLINE, EMBASE,http://www.ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer.

Eligibility criteria for selecting studies

Double-blind, randomised controlled clinical trials, ≥12 weeks’ duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication.

Model development and application

A Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%.

Results

The model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were −0.88 to −0.75 (linagliptin) and −0.89 to −0.73 (sitagliptin), and for those with washout, −0.91 to −0.76 (linagliptin) and −0.91 to −0.75 (sitagliptin).

Conclusions

This study demonstrates the use of longitudinal MBMA in the field of diabetes treatment. Based on an example evaluating HbA1c reduction with linagliptin versus sitagliptin, the model used seems a valid approach for indirect drug comparisons.
The two-step Fagan's nomogram: ad hoc interpretation of a diagnostic test result without calculation
Authors: Caraguel Charles G B , Vanderstichel Raphaël
Published: March 2013

In 1975, Fagan published a nomogram to help practitioners determine, without the use of a calculator or computer, the probability of a patient truly having a condition of interest given a particular test result. Nomograms are very useful for bedside interpretations of test results, as no test is perfect. However, the practicality of Fagan's nomogram is limited by its use of the likelihood ratio (LR), a parameter not commonly reported in the evaluation studies of diagnostic tests. The LR reflects the direction and strength of evidence provided by a test result and can be computed from the conventional diagnostic sensitivity (DSe) and specificity (DSp) of the test. This initial computation is absent in Fagan's nomogram, making it impractical for routine use. We have seamlessly integrated the initial step to compute the LR and the resulting two-step nomogram allows the user to quickly interpret the outcome of a test. With the addition of the DSe and DSp, the nomogram, for the purposes of interpreting a dichotomous test result, is now complete. This tool is more accessible and flexible than the original, which will facilitate its use in routine evidence-based practice. The nomogram can be downloaded at: www.adelaide.edu.au/vetsci/research/pub_pop/2step-nomogram/.
Postconcussion syndrome (PCS) in the emergency department: predicting and pre-empting persistent symptoms following a mild traumatic brain injury
Authors: Reuben Adam , Sampson Paul , Harris Adrian Ralph , Williams Huw , Yates Phil
Published: March 2013

Head injuries across all age groups represent an extremely common emergency department (ED) presentation. The main focus of initial assessment and management rightly concentrates on the need to exclude significant pathology, that may or may not require neurosurgical intervention. Relatively little focus, however, is given to the potential for development of post-concussion syndrome (PCS), a constellation of symptoms of varying severity, which may bear little correlation to the nature or magnitude of the precipitating insult. This review aims to clarify the aetiology and terminology surrounding PCS and to examine the mechanisms for diagnosing and treating.
Addressing challenges in 4 F and 5 F arterial access for neurointerventional procedures in infants and young children
Authors: Gross Bradley A , Orbach Darren B
Published: March 2013

Background

Among the technical challenges involved in safely performing neuroendovascular procedures in infants are limitations on the size of femoral arterial access catheters. Restricting groin access to 4 F and 5 F systems constrains the range of procedures that can potentially be performed.

Methods and Results

We present here a consecutive series of transfemoral angiographic procedures in children with no permanent and one transient case of groin morbidity related to femoral access. We illustrate two strategies for using 4 F and 5 F systems for interventions in a manner that enables such techniques as balloon assisted coil embolization and the deployment of triaxial catheter systems to be used.

Conclusions

Extremely low groin morbidity is achievable using rigorous parameters around femoral catheterization in children. With creative approaches to working within the limitations of the access vessel size, complex endovascular neurointerventions are possible, even in the youngest infants.
Predictive value of flat-panel CT for haemorrhagic transformations in patients with acute stroke treated with thrombectomy
Authors: Rouchaud Aymeric , Pistocchi Silvia , Blanc Raphaël , Engrand Nicolas , Bartolini Bruno , Piotin Michel
Published: March 2013

Introduction

Haemorrhagic transformations are pejorative for patients with acute ischaemic stroke (AIS). We estimated flat-panel CT performances to detect brain parenchymal hyperdense lesions immediately after mechanical thrombectomy directly on the angiography table in patients with AIS, and its ability to predict haemorrhagic transformation. We also evaluated an easy-reading protocol for post-procedure flat-panel CT evaluation by clinicians to enable them to determine the potential risk of haemorrhage.

Methods

Two neuroradiologists retrospectively reviewed post-procedural flat-panel CT and 24 h follow-up imaging. We evaluated hyperdense lesions on flat-panel CT to predict the occurrence of haemorrhagic transformation within 24 h detected with conventional imaging.

Results

Of 63 patients, 60.3% presented post-procedural parenchymal hyperdensity and 54.0% had haemorrhagic transformation. Significantly more patients with hyperdense lesions on post-thrombectomy flat-panel CT presented haemorrhagic transformation (84.2% vs 8.0%; p<0.0001). No significant haemorrhagic transformations were detected for patients without parenchymal hyperdensity. Sensitivity and specificity of hyperdense lesions on flat-panel CT for the prediction of haemorrhagic transformation were 94.1% (80.3–99.3%) and 79.3% (60.3–92.0%), respectively. The positive and negative predictive values for the occurrence of haemorrhage were 84.2% (68.8–94.0%) and 92.0% (74.0–99.0%), respectively. For significant parenchymal haemorrhage type 2, sensitivity and negative predictive values were 100%. We observed good homogeneity between the different readers. Hyperdensity on post-procedural flat-panel CT was associated with a tendency for higher risk of death and lower risk of good clinical outcome.

Conclusions

Flat-panel CT appears to be a good tool to detect brain parenchymal hyperdensities after mechanical thrombectomy in patients with AIS and to predict haemorrhagic transformation.
Proteomics based detection of differentially expressed proteins in human osteoblasts subjected to mechanical stress
Authors: Li Fei-Fei , Chen Fu-Lin , Wang Huan , Yu Shi-Bin , Cui Ji-Hong , Ding Yin , Feng Xue
Published: March 2013

Mechanical stress is essential for bone development. Mechanical stimuli are transduced to biochemical signals that regulate proliferation, differentiation, and cytoskeletal reorganization in osteoblasts. In this study, we used proteomics to evaluate differences in the protein expression profiles of untreated Saos-2 osteoblast cells and Saos-2 cells subjected to mechanical stress loading. Using 2-D electrophoresis, MALDI–TOF mass spectroscopy, and bioinformatics, we identified a total of 26 proteins differentially expressed in stress loaded cells compared with control cells. Stress loaded Saos-2 cells exhibited significant upregulation of 17 proteins and significant downregulation of 9 proteins compared with control cells. Proteins that were most significantly upregulated in mechanically loaded cells included those regulating osteogenesis, energy metabolism, and the stress response, such as eukaryotic initiation factor 2 (12-fold), mitochondrial ATP synthase (8-fold), and peptidylprolyl isomerase A (cyclophilin A)-like 3 (6.5-fold). Among the proteins that were significantly downregulated were those involved in specific signaling pathways and cell proliferation, such as protein phosphatase regulatory (inhibitor) subunit 12B (13.8-fold), l-lactate dehydrogenase B (9.4-fold), Chain B proteasome activator Reg (Alpha) PA28 (7.7-fold), and ubiquitin carboxyl-terminal esterase L1 (6.9-fold). Our results provide a platform to understand the molecular mechanisms underlying mechanotransduction.
The quantum entanglement between colorful dark energy universes in a colorful multiverse
Authors: Sepehri Alireza , Shoorvazi Somayyeh , Zomorrodian Mohammad Ebrahim
Published: March 2013

Recently, a model for colorful black hole production and decay in proton–proton collisions has been constructed. These results can be extended to a multiverse, because it is obvious that there is enough energy in cosmic rays to produce a baby Universe. It is observed that these Universes are defined by their gauge charges. Notably, Universes can have a color charge. This is not in contradiction with confinement because the typical length scale of QCD (i.e., a Fermi) is much larger than the size of a baby Universe at its birth. These colorful Universes can interact with each other, annihilate, and form a color singlet Universe. Next, it is argued that color confinement may generate an entanglement between colorful dark energy Universes to form a color singlet binary system. Finally, the production cross section for entangled colorful dark energy Universes in a multiverse is obtained. It is found that the cross section of a Friedmann–Robertson–Walker Universe is much larger for smaller values of the Hubble parameter. Also, this cross section is greater for entangled open Universes and smaller for entangled closed Universes.
THE CORRELATION FRACTAL DIMENSION OF COMPLEX NETWORKS
Authors: WANG XINGYUAN , LIU ZHENZHEN , WANG MOGEI
Published: March 2013

The fractality of complex networks is studied by estimating the correlation dimensions of the networks. Comparing with the previous algorithms of estimating the box dimension, our algorithm achieves a significant reduction in time complexity. For four benchmark cases tested, that is, the Escherichia coli (E. Coli) metabolic network, the Homo sapiens protein interaction network (H. Sapiens PIN), the Saccharomyces cerevisiae protein interaction network (S. Cerevisiae PIN) and the World Wide Web (WWW), experiments are provided to demonstrate the validity of our algorithm.
MODE I STRESS INTENSITY FACTOR OF CENTER-CRACKED TENSILE STEEL PLATES WITH CFRP REINFORCEMENT
Authors: WU CHAO , ZHAO XIAO LING , AL-MAHAIDI RIADH , DUAN WEN HUI
Published: March 2013

Advanced carbon fiber reinforced polymer (CFRP) demonstrates promise for the fatigue strengthening of steel structures. By decreasing the stress field at the crack tip, the stress intensity factors (SIFs) can be effectively reduced by CFRP reinforcement. In this paper, the mode I SIF of CFRP-reinforced center-cracked tensile (CCT) steel plate is proposed based on a series of fatigue tests. The selected fatigue tests include experiments conducted by the authors as well as fatigue tests reported in the literature, covering different CFRP systems (low/high modulus, CFRP sheeting/plate) with various CFRP strengthening dimensions. The classical mode I SIF of CCT steel plate without CFRP strengthening is selected as the basis of the proposed solution. Then two reduction factors, similar to the correction factors given in the Japanese Society of Steel Construction (JSSC) standard, are introduced to study the effects of the mechanical properties of CFRP composites and the geometries of the CFRP reinforcement, respectively. Modified SIFs for both single-side CFRP-reinforced and double-side CFRP-reinforced CCT steel plates are proposed. It is found that the experimental SIFs of CFRP-reinforced CCT steel plates can be reasonably captured by the proposed mode I SIF formula. Finally, parametric studies for investigating the sensitivity of SIF to various mechanical and geometric factors are presented.
NONLINEAR STABILITY ANALYSIS OF HYBRID GRID SHELLS
Authors: CAI JIANGUO , GU LEMING , XU YIXIANG , FENG JIAN , ZHANG JIN
Published: March 2013

In this paper, we investigate the buckling capacity of a hybrid grid shell, which is made of quadrangular meshes diagonally stiffened by pre-tensioned thin cables. The eigenvalue buckling, geometrical nonlinear elastic buckling and elasto-plastic buckling analyses of the hybrid structure were carried out. Then the influences of the shape and scale of imperfections on the elasto-plastic buckling loads were discussed. Also, the effects of different structural parameters, such as the rise-to-span ratio, cross-section of beams, area and pre-stress of cables and boundary conditions, on the failure load were investigated. The results show that the buckling capacity is reduced when taking into account the material nonlinearity. Furthermore, the hybrid structure is highly imperfection sensitive and the reduction of the failure load due to imperfections can be considerable. The proper shape and scale of the imperfection are also important. It is also shown that there exists an optimal rise-to-span ratio resulting in a relatively high buckling capacity for a specific span. Moreover, the enlarging of the cross-section of steel beams notably improves the stability performance of the structure. However, the area and pre-stress of cables pose small effect on the structural stability.
USING WEIGHTED-SUM FUNCTIONS TO COMPUTE NONSUPPORTED EFFICIENT SOLUTIONS IN MULTIOBJECTIVE COMBINATORIAL-{0,1} PROBLEMS
Authors: GOMES DA SILVA CARLOS , CLÍMACO JOÃO
Published: March 2013

In multiobjective linear programming, the weighted-sum functions can be used to characterize the entire set of efficient solutions, but in multiobjective combinatorial-{0,1} problems these functions can only determine a small subset of efficient solutions, called supported efficient solutions. In this paper, we show how the entire set of efficient solutions can be found with the same technique by modifying the original problem. An algorithm is proposed. Some results are presented and the effect of some parameters of the proposed algorithm is illustrated with the multiobjective {0,1}-knapsack problem.
The Secretion, Components, and Properties of Saliva
Authors: Carpenter Guy H.
Published: March 2013

Saliva has one of the most difficult roles to perform in the body. It must facilitate the taste and detection of foods nutritious to the body but also defend the mucosa from infection by the ever-present microbiota present in the mouth. It achieves these roles by having a complex composition and versatile physical properties. The protein and ion components make a solution that is 99% water into a viscoelastic solution capable of many roles, such as acting as a lubricant and an antimicrobial, preventing the dissolution of teeth, aiding digestion, and facilitating taste. This review describes the neural regulation of salivary secretion in terms of fluid, protein, and ion secretion. It then describes some of the components and physical properties of saliva and attempts to relate them to the functions that saliva must perform.
Wine Matrix Compounds Affect Perception of Wine Aromas
Authors: Villamor Remedios R. , Ross Carolyn F.
Published: March 2013

Wine is a complex alcoholic beverage. The wine matrix or the components that are present in the wine play an important role in the perceived aroma and flavor of the wine. The wine matrix is composed of two fractions, the nonvolatile fraction, which includes ethanol (in liquid phase), polyphenolic compounds, proteins, and carbohydrates, and the volatile fraction, which incorporates flavor and aroma compounds. Interactions among these compounds may arise through various mechanisms, thus affecting the sensory and chemical properties of the wine. The main focus of this review is to highlight recent research on wine component interactions and their effects on perceived aroma in the wine. An overview of the wine impact odorants and their determination using sensory and chemical methods is also provided in this paper.
The force-frequency relationship: insights from mathematical modeling
Authors: Puglisi Jose L. , Negroni Jorge A. , Chen-Izu Ye , Bers Donald M.
Published: March 2013

The force-frequency relationship has intrigued researchers since its discovery by Bowditch in 1871. Many attempts have been made to construct mathematical descriptions of this phenomenon, beginning with the simple formulation of Koch-Wesser and Blinks in 1963 to the most sophisticated ones of today. This property of cardiac muscle is amplified by β-adrenergic stimulation, and, in a coordinated way, the neurohumoral state alters both frequency (acting on the sinoatrial node) as well as force generation (modifying ventricular myocytes). This synchronized tuning is needed to meet new metabolic demands. Cardiac modelers have already linked mechanical and electrical activity in their formulations and showed how those activities feedback on each other. However, now it is necessary to include neurological control to have a complete description of heart performance, especially when changes in frequency are involved. Study of arrhythmias (or antiarrhythmic drugs) based on mathematical models should incorporate this effect to make useful predictions or point out potential pharmaceutical targets.
International Union of Physiological Sciences Physiology Teaching Workshop, March 31–April 1, 2012, Arabian Gulf University, Kingdom of Bahrain
Authors: Subhan M. M. F.
Published: March 2013

Since 2009, the Department of Physiology had planned an International Union of Physiological Sciences Physiology Teaching Workshop at Arabian Gulf University. The date was set for March 5–6, 2011; however, due to civil unrest, the workshop was postponed to March 31–April 1, 2012. The workshop was a success, bringing together 92 speakers and participants from 23 countries. Twenty-eight participants from economically disadvantaged countries were given travel support. The workshop included plenary lectures, breakout workshops, poster sessions, dinners, and a social trip. On April 2, 2012, an AD Instruments satellite workshop on data-acquisition systems for laboratory teaching was held, with 60 participants from 12 countries.
Aldosterone induces myofibroblast EGF secretion to regulate epithelial colonic permeability
Authors: Miró Lluïsa , Pérez-Bosque Anna , Maijó Mònica , Amat Concepció , Naftalin Richard J. , Moretó Miquel
Published: March 2013

In vivo studies show that raised aldosterone (Aldo) during low-Na adaptation regulates the growth of pericryptal myofibroblasts and reduces the permeability of the colonic epithelium. The aim of this study was to reproduce in vitro the in vivo condition of increased Aldo using human CCD-18Co myofibroblasts and T84 colonic epithelial cells to measure myofibroblast and epithelial proliferation and the expression of intercellular junction proteins. Proliferation was quantified by measuring 5-bromo-2′-deoxyuridine incorporation. The myofibroblast expression of EGF, VEGFa, and transforming growth factor-β1 (TGF-β1) was measured by real-time PCR and the expression of junctional complex proteins by Western blot. Aldo stimulated the proliferation of myofibroblasts by 70% ( P < 0.05) and increased EGF mRNA expression by 30% ( P < 0.05) without affecting VEGFa and TGF-β1. EGF concentration in the incubation medium increased by 30% ( P < 0.05) 24 h after Aldo addition, and these effects were prevented by the addition of spironolactone. Myofibroblast proliferation in response to Aldo was mediated by EGF receptor (EGFR) and involved both MAPKK and phosphatidylinositol 3-kinase pathways. When T84 cells were incubated with medium from myofibroblasts stimulated with Aldo (conditioned medium), the expression of β-catenin and claudin IV was increased by 30% ( P < 0.05) and proliferation by 40% ( P < 0.05). T84 proliferation decreased when α-EGF, or the EGFR antagonist AG1478, was present. Results in vivo indicate that rats fed a low-salt diet showed an increased expression of EGF and EGFR in the colonic mucosa. These results support the view that changes in colonic permeability during low-Na adaptation are mediated by the EGF secreted by myofibroblasts in response to raised Aldo.
Hepatic steatosis development with four weeks of physical inactivity in previously active, hyperphagic OLETF rats
Authors: Linden Melissa A. , Meers Grace M. , Ruebel Meghan L. , Jenkins Nathan T. , Booth Frank W. , Laughlin M. Harold , Ibdah Jamal A. , Thyfault John P. , Rector R. Scott
Published: March 2013

Physical activity-induced prevention of hepatic steatosis is maintained during short-term (7-day) transitions to an inactive state; however, whether these protective effects are present under a longer duration of physical inactivity is largely unknown. Here, we sought to determine whether previous physical activity had protective effects on hepatic steatosis and metabolic health following 4 wk of physical inactivity. Four-week old, hyperphagic, male Otsuka Long-Evans Tokushima fatty (OLETF) rats were randomly assigned to either a sedentary group for 16 wk (OLETF-SED), given access to running wheels for 16 wk with wheels locked 5 h (OLETF-WL5hr) or given access to running wheels for 12 wk with wheels locked 4 wk (OLETF-WL4wk) prior to death. Four weeks of physical inactivity caused hepatic steatosis development, but liver triglycerides remained 60% lower than OLETF-SED ( P < 0.01), and this was associated with only a partial loss in activity-induced improvements in body composition, serum lipids, and glycemic control. Total hepatic mitochondrial palmitate oxidation, citrate synthase, and β-HAD activity returned to SED levels following 4 wk of inactivity, whereas markers of fatty acid uptake and lipogenesis remained relatively suppressed following 4 wk of inactivity. In addition, 4 wk of inactivity caused a complete loss of activity-induced increases in serum IL-6 and reductions in regulated upon activation, normal T-cell expressed, and secreted (RANTES), and a partial loss in reductions in leptin, monocyte chemoattractant protein-1, and TNF-α. In conclusion, 4 wk of physical inactivity does not result in a complete loss in physical activity-induced benefits but does cause deterioration in the liver phenotype and overall metabolic health in hyperphagic OLETF rats.