bluuebunny/crossref_metadata_2025 huggingface dataset:
Chlorhexidine and Mupirocin Susceptibility of Methicillin-Resistant Staphylococcus aureus Isolates in the REDUCE-MRSA Trial
Authors: Hayden Mary K. , Lolans Karen , Haffenreffer Katherine , Avery Taliser R. , Kleinman Ken , Li Haiying , Kaganov Rebecca E. , Lankiewicz Julie , Moody Julia , Septimus Edward , Weinstein Robert A. , Hickok Jason , Jernigan John , Perlin Jonathan B. , Platt Richard , Huang Susan S.
Published: August 2016

Whether targeted or universal decolonization strategies for the control of methicillin-resistant
Staphylococcus aureus
(MRSA) select for resistance to decolonizing agents is unresolved. The REDUCE-MRSA trial (ClinicalTrials registration no. NCT00980980) provided an opportunity to investigate this question. REDUCE-MRSA was a 3-arm, cluster-randomized trial of either screening and isolation without decolonization, targeted decolonization with chlorhexidine and mupirocin, or universal decolonization without screening to prevent MRSA infection in intensive-care unit (ICU) patients. Isolates from the baseline and intervention periods were collected and tested for susceptibility to chlorhexidine gluconate (CHG) by microtiter dilution; mupirocin susceptibility was tested by Etest. The presence of the
qacA
or
qacB
gene was determined by PCR and DNA sequence analysis. A total of 3,173 isolates were analyzed; 2 were nonsusceptible to CHG (MICs, 8 μg/ml), and 5/814 (0.6%) carried
qacA
or
qacB
. At baseline, 7.1% of MRSA isolates expressed low-level mupirocin resistance, and 7.5% expressed high-level mupirocin resistance. In a mixed-effects generalized logistic regression model, the odds of mupirocin resistance among clinical MRSA isolates or MRSA isolates acquired in an ICU in intervention versus baseline periods did not differ across arms, although estimates were imprecise due to small numbers. Reduced susceptibility to chlorhexidine and carriage of
qacA
or
qacB
were rare among MRSA isolates in the REDUCE-MRSA trial. The odds of mupirocin resistance were no different in the intervention versus baseline periods across arms, but the confidence limits were broad, and the results should be interpreted with caution.
An Essential Role of INI1/hSNF5 Chromatin Remodeling Protein in HIV-1 Posttranscriptional Events and Gag/Gag-Pol Stability
Authors: La Porte Annalena , Cano Jennifer , Wu Xuhong , Mitra Doyel , Kalpana Ganjam V.
Published: August 2016

INI1/hSNF5/SMARCB1/BAF47 is an HIV-specific integrase (IN)-binding protein that influences HIV-1 transcription and particle production. INI1 binds to SAP18 (Sin3a-associated protein, 18 kDa), and both INI1 and SAP18 are incorporated into HIV-1 virions. To determine the significance of INI1 and the INI1-SAP18 interaction during HIV-1 replication, we isolated a panel of
S
AP18-
i
nteraction-
d
efective (SID)-INI1 mutants using a yeast reverse two-hybrid screen. The SID-INI1 mutants, which retained the ability to bind to IN, cMYC, and INI1 but were impaired for binding to SAP18, were tested for their effects on HIV-1 particle production. SID-INI1 dramatically reduced the intracellular Gag/Gag-Pol protein levels and, in addition, decreased viral particle production. The SID-INI1-mediated effects were less dramatic in
trans
complementation assays using IN deletion mutant viruses with Vpr-reverse transcriptase (RT)-IN. SID-INI1 did not inhibit long-terminal-repeat (LTR)-mediated transcription, but it marginally decreased the steady-state
gag
RNA levels, suggesting a posttranscriptional effect. Pulse-chase analysis indicated that in SID-INI1-expressing cells, the pr55Gag levels decreased rapidly. RNA interference analysis indicated that small hairpin RNA (shRNA)-mediated knockdown of
INI1
reduced the intracellular Gag/Gag-Pol levels and further inhibited HIV-1 particle production. These results suggest that SID-INI1 mutants inhibit multiple stages of posttranscriptional events of HIV-1 replication, including intracellular Gag/Gag-Pol RNA and protein levels, which in turn inhibits assembly and particle production. Interfering INI1 leads to a decrease in particle production and Gag/Gag-Pol protein levels. Understanding the role of INI1 and SAP18 in HIV-1 replication is likely to provide novel insight into the stability of Gag/Gag-Pol, which may lead to the development of novel therapeutic strategies to inhibit HIV-1 late events.

IMPORTANCE
Significant gaps exist in our current understanding of the mechanisms and host factors that influence HIV-1 posttranscriptional events, including
gag
RNA levels, Gag/Gag-Pol protein levels, assembly, and particle production. Our previous studies suggested that the IN-binding host factor INI1 plays a role in HIV-1 assembly. An ectopically expressed minimal IN-binding domain of INI1, S6, potently and selectively inhibited HIV-1 Gag/Gag-Pol trafficking and particle production. However, whether or not endogenous INI1 and its interacting partners, such as SAP18, are required for late events was unknown. Here, we report that endogenous INI1 and its interaction with SAP18 are necessary to maintain intracellular levels of Gag/Gag-Pol and for particle production. Interfering INI1 or the INI1-SAP18 interaction leads to the impairment of these processes, suggesting a novel strategy for inhibiting posttranscriptional events of HIV-1 replication.
Protein Primary Structure of the Vaccinia Virion at Increased Resolution
Authors: Ngo Tuan , Mirzakhanyan Yeva , Moussatche Nissin , Gershon Paul David
Published: August 2016

Here we examine the protein covalent structure of the vaccinia virus virion. Within two virion preparations, >88% of the theoretical vaccinia virus-encoded proteome was detected with high confidence, including the first detection of products from 27 open reading frames (ORFs) previously designated “predicted,” “uncharacterized,” “inferred,” or “hypothetical” polypeptides containing as few as 39 amino acids (aa) and six proteins whose detection required nontryptic proteolysis. We also detected the expression of four short ORFs, each of which was located within an ORF (“ORF-within-ORF”), including one not previously recognized or known to be expressed. Using quantitative mass spectrometry (MS), between 58 and 74 proteins were determined to be packaged. A total of 63 host proteins were also identified as candidates for packaging. Evidence is provided that some portion of virion proteins are “nicked” via a combination of endoproteolysis and concerted exoproteolysis in a manner, and at sites, independent of virus origin or laboratory procedures. The size of the characterized virion phosphoproteome was doubled from 189 (J. Matson, W. Chou, T. Ngo, and P. D. Gershon, Virology 452-453:310–323, 2014, doi:http://dx.doi.org/10.1016/j.virol.2014.01.012) to 396 confident, unique phosphorylation sites, 268 of which were within the packaged proteome. This included the unambiguous identification of phosphorylation “hot spots” within virion proteins. Using isotopically enriched ATP, 23 sites of intravirion kinase phosphorylation were detected within nine virion proteins, all at sites already partially occupied within the virion preparations. The clear phosphorylation of proteins RAP94 and RP19 was consistent with the roles of these proteins in intravirion early gene transcription. In a blind search for protein modifications, cysteine glutathionylation and O-linked glycosylation featured prominently. We provide evidence for the phosphoglycosylation of vaccinia virus proteins.

IMPORTANCE
Poxviruses are among the most complex and irregular virions, about whose internal structure little is known. To better understand poxvirus virion structure, imaging should be supplemented with other tools. Here, we provide a deep study of the covalent structure of the vaccinia virus virion using the various tools of contemporary mass spectrometry.
Affinity Purification of the Hepatitis C Virus Replicase Identifies Valosin-Containing Protein, a Member of the ATPases Associated with Diverse Cellular Activities Family, as an Active Virus Replication Modulator
Authors: Yi Zhigang , Fang Caiyun , Zou Jingyi , Xu Jun , Song Wuhui , Du Xiaoting , Pan Tingting , Lu Haojie , Yuan Zhenghong
Published: August 2016

Like almost all of the positive-strand RNA viruses, hepatitis C virus (HCV) induces host intracellular membrane modification to form the membrane-bound viral replication complex (RC), within which viral replicases amplify the viral RNA genome. Despite accumulated information about how HCV co-opts host factors for viral replication, our knowledge of the molecular mechanisms by which viral proteins hijack host factors for replicase assembly has only begun to emerge. Purification of the viral replicase and identification of the replicase-associated host factors to dissect their roles in RC biogenesis will shed light on the molecular mechanisms of RC assembly. To purify the viral replicase in the context of genuine viral replication, we developed an HCV subgenomic replicon system in which two different affinity tags were simultaneously inserted in frame into HCV NS5A and NS5B. After solubilizing the replicon cells, we purified the viral replicase by two-step affinity purification and identified the associated host factors by mass spectrometry. We identified valosin-containing protein (VCP), a member of the ATPases associated with diverse cellular activities (AAA+ATPase) family, as an active viral replication modulator whose ATPase activity is required for viral replication. A transient replication assay indicated that VCP is involved mainly in viral genome amplification. VCP associated with viral replicase and colocalized with a viral RC marker. Further, in an HCV replicase formation surrogate system, abolishing VCP function resulted in aberrant distribution of HCV NS5A. We propose that HCV may co-opt a host AAA+ATPase for its replicase assembly.

IMPORTANCE
Almost all of the positive-strand RNA viruses share a replication strategy in which viral proteins modify host membranes to form the membrane-associated viral replicase. Viruses hijack host factors to facilitate this energy-unfavorable process. Understanding of this fundamental process is hampered by the challenges of purifying the replicase because of the technical difficulties involved. In this study, we developed an HCV subgenomic replicon system in which two different affinity tags were simultaneously inserted in frame into two replicase components. Using this dual-affinity-tagged replicon system, we purified the viral replicase and identified valosin-containing protein (VCP) AAA+ATPase as a pivotal viral replicase-associated host factor that is required for viral genome replication. Abolishing VCP function resulted in aberrant viral protein distribution. We propose that HCV hijacks a host AAA+ATPase for its replicase assembly. Understanding the molecular mechanism of VCP regulates viral replicase assembly may lead to novel antiviral strategies targeting the most conserved viral replication step.
LFA-1 Engagement Triggers T Cell Polarization at the HIV-1 Virological Synapse
Authors: Starling Shimona , Jolly Clare
Published: August 2016

HIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS), where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically, however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill defined. Here, we use a reductionist bead-coupled antibody assay as a model of the VS and show that cross-linking the integrin LFA-1 alone is sufficient to induce active T cell polarization and recruitment of the microtubule organizing center (MTOC) in HIV-1-infected cells. Mutant cell lines coupled with inhibitors demonstrated that LFA-1-induced polarization was dependent on the T cell kinase ZAP70. Notably, immunofluorescent staining of viral proteins revealed an accumulation of surface Env at sites of LFA-1 engagement, with intracellular Env localized to a Golgi compartment proximal to the polarized MTOC. Furthermore, blocking LFA-1-induced MTOC polarization through ZAP70 inhibition prevented intracellular Env polarization. Taken together, these data reveal that LFA-1 is a key determinant in inducing dynamic T cell remodeling to the VS and suggest a model in which LFA-1 engagement triggers active polarization of the MTOC and the associated Env-containing secretory apparatus to sites of cell-cell contact to support polarized viral assembly and egress for efficient cell-cell spread.

IMPORTANCEHIV-1 causes AIDS by spreading within immune cells and depletion of CD4 T lymphocytes. Rapid spread between these cells occurs by highly efficient cell-cell transmission that takes place at virological synapses (VS). VS are characterized by striking T cell remodeling that is spatially associated with polarized virus assembly and budding at sites of cell contact. Here, we show that the integrin LFA-1 triggers organelle polarization and viral protein recruitment, facilitating formation of the VS, and that this requires the T cell kinase ZAP70. Taken together, these data suggest a mechanism by which HIV-1-infected T cells sense and respond to cell contact to polarize viral egress and promote cell-cell spread. Understanding how cell-cell spread is regulated may help reveal therapeutic targets to specifically block this mode of HIV-1 dissemination.
Antagonism of RNase L Is Required for Murine Coronavirus Replication in Kupffer Cells and Liver Sinusoidal Endothelial Cells but Not in Hepatocytes
Authors: Li Yize , Weiss Susan R.
Published: August 2016

Mouse hepatitis virus strain A59 infection of mice is a useful tool for studying virus-host interaction during hepatitis development. The NS2
H126R
mutant is attenuated in liver replication due to loss of phosphodiesterase activity, which the wild-type (WT) virus uses to block the 2′,5′-oligoadenylate synthetase (OAS)-RNase L (RNase L) antiviral pathway. The activation of RNase L by NS2
H126R
is cell type dependent and correlates with high basal expression levels of OAS, as found in myeloid cells. We tested the hypothesis that the resident liver macrophages, Kupffer cells (KC), represent the cell type most likely to restrict NS2
H126R
and prevent hepatitis. As found previously, A59 and NS2
H126R
replicate similarly in hepatocytes and neither activates RNase L, as assessed by an rRNA degradation assay. In contrast, in KC, A59 exhibited a 100-fold-higher titer than NS2
H126R
and NS2
H126R
induced rRNA degradation. Interestingly, in liver sinusoidal endothelial cells (LSEC), the cells that form a barrier between blood and liver parenchymal cells, NS2
H126R
activates RNase L, which limits viral replication. Similar growth kinetics were observed for the two viruses in KC and LSEC from RNase L
−/−
mice, demonstrating that both use RNase L to limit NS2
H126R
replication. Depletion of KC by gadolinium(III) chloride or of LSEC by cyclophosphamide partially restores liver replication of NS2
H126R
, leading to hepatitis. Thus, during mouse hepatitis virus (MHV) infection, hepatitis, which damages the parenchyma, is prevented by RNase L activity in both KC and LSEC but not in hepatocytes. This may be explained by the undetectable levels of RNase L as well as by the OASs expressed in hepatocytes.

IMPORTANCE
Mouse hepatitis virus infection of mice provides a useful tool for studying virus-host interactions during hepatitis development. The NS2
H126R
mutant is attenuated in liver replication due to loss of phosphodiesterase activity, by which the wild-type virus blocks the potent OAS-RNase L antiviral pathway. RNase L activation by NS2
H126R
is cell type dependent and correlates with high basal expression levels of OAS, as found in myeloid cells. We showed that the hepatocytes that comprise the liver parenchyma do not activate RNase L when infected with NS2
H126R
or restrict replication. However, both Kupffer cells (KC) (i.e., the liver-resident macrophages) and the liver sinusoidal endothelial cells (LSEC) which line the sinusoids activate RNase L in response to NS2
H126R
. These data suggest that KC and LSEC prevent viral spread into the parenchyma, preventing hepatitis. Furthermore, hepatocytes express undetectable levels of OASs and RNase L, which likely explains the lack of RNase L activation during NS2
H126R
infection.
Is the incidence of heart attack still decreasing in Australia? Developing reliable methods for monitoring trends in myocardial infarction and coronary heart disease (AUS-MOCHA): a study protocol
Authors: Nedkoff Lee , Knuiman Matthew , Hobbs Michael S T , Hung Joseph , Mathur Sushma , Beilby John , Reynolds Anna , Briffa Tom G , Lopez Derrick , Sanfilippo Frank M
Published: August 2016

Introduction

Accurate monitoring of acute coronary heart disease (CHD) is essential for understanding the effects of primary and secondary prevention and for planning of healthcare services. The ability to reliably monitor acute CHD has been affected by new diagnostic tests for myocardial infarction (MI) and changing clinical classifications and management of CHD. Our study will develop new and reliable methods for monitoring population trends in incidence, outcomes and health service usage for acute CHD and chest pain.

Methods and analysis

The study cohort of all CHD will be identified from the Western Australian Data Linkage System using state-wide data sets for emergency department presentation, hospitalisations and mortality data for 2002–2014. This core linked data set will be supplemented with data from hospital medical record reviews, pathology data and hospital pharmacy dispensing databases. The consistency over time of the coding of the different subgroups of CHD/chest pain (ST-elevation MI, non-ST elevation MI, unstable angina, stable angina, other CHD, non-CHD chest pain) in linked data will be assessed using these data sources, and an algorithm developed detailing groups in which temporal trends can be reliably measured. This algorithm will be used for measurement of trends in incidence and outcomes of acute CHD, and to develop further methods for monitoring acute CHD using unlinked and linked data with varying availability of hospitalisation history.

Ethics and dissemination

Ethics approval has been obtained from the Human Research Ethics Committees of the WA Department of Health (#2016/23) and The University of Western Australia (RA/4/1/7230). Findings will be disseminated via publication in peer-reviewed journals, and presentation at national and international conferences. There will also be a strong platform for dissemination of new monitoring methods via collaboration with the Australian Institute of Health and Welfare which will assist with promotion of these methods at state and national levels.
Impact of area regeneration policies: performing integral interventions, changing opportunity structures and reducing health inequalities
Authors: Zapata Moya Angel R , Navarro Yáñez Clemente J
Published: August 2016

Background

Urban regeneration policies are area-based interventions addressing multidimensional problems. In this study, we analyse the impact of urban regeneration processes on the evolution of inequalities in mortality from certain causes. On the basis of Fundamental Cause Theory (FCT), our main hypothesis is that the impact of urban regeneration programmes will be more clearly observed on the causes of preventable deaths, as these programmes imply a direct or indirect improvement to a whole range of ‘flexible resources’ that residents in relevant areas have access to, and which ultimately may influence the inverse relationship between socioeconomic status and health.

Methods

Using a quasi-experimental design and data from Longitudinal Statistics on Survival and Longevity of Andalusia (Spain), we analyse differences in the evolution of standard mortality ratios for preventable and less-preventable causes of premature death. This encompasses 59 neighbourhoods in 37 municipalities where urban regeneration projects were implemented in the last decade within the framework of three different programmes and in 59 counterparts where these policies were not implemented.

Results

As expected in line with FCT, there are no significant patterns in the evolution of internal differences in terms of less-preventable mortality. However, excessive preventable mortality strongly decreases in the neighbourhoods with intervention programmes, specifically in those where two or more projects were in force. This is even more apparent for women.

Conclusions

The urban regeneration policies studied seem to contribute to reducing health inequity when the interventions are more integral in nature.
I too, am America: a review of research on systemic lupus erythematosus in African-Americans
Authors: Williams Edith M , Bruner Larisa , Adkins Alyssa , Vrana Caroline , Logan Ayaba , Kamen Diane , Oates James C
Published: August 2016

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder that can cause significant morbidity and mortality. A large body of evidence has shown that African-Americans experience the disease more severely than other racial-ethnic groups. Relevant literature for the years 2000 to August 2015 were obtained from systematic searches of PubMed, Scopus, and the EBSCOHost platform that includes MEDLINE, CINAHL, etc. to evaluate research focused on SLE in African-Americans. Thirty-six of the 1502 articles were classified according to their level of evidence. The systematic review of the literature reported a wide range of adverse outcomes in African-American SLE patients and risk factors observed in other mono and multi-ethnic investigations. Studies limited to African-Americans with SLE identified novel methods for more precise ascertainment of risk and observed novel findings that hadn't been previously reported in African-Americans with SLE. Both environmental and genetic studies included in this review have highlighted unique African-American populations in an attempt to isolate risk attributable to African ancestry and observed increased genetic influence on overall disease in this cohort. The review also revealed emerging research in areas of quality of life, race-tailored interventions, and self-management. This review reemphasizes the importance of additional studies to better elucidate the natural history of SLE in African-Americans and optimize therapeutic strategies for those who are identified as being at high risk.
Pregnancy as protest in interwar British women's writing: an antecedent alternative to Aldous Huxley'sBrave New World
Authors: Bigman Fran
Published: August 2016

Accounts that take Aldous Huxley'sBrave New World(1932) as representative of interwar reproductive dystopia fail to recognise that the novel expresses both an interest and an anxiety about the possibility of new reproductive technologies to transform sex, gender, and the family that were widely shared by writers in different genres and perhaps expressed best by those likely to be most affected: women. This article explores three earlier works—Charlotte Haldane'sMan's World(1926), Vera Brittain'sHalcyon, or the Future of Monogamy(1929), and Naomi Mitchison'sComments on Birth Control(1930)—in which pregnancy, instead of figuring as illness or debility, becomes a form of resistance to the status quo. These works engage with biomedicine, however, rather than abjuring it. Through a reading of these works, this article argues that the intersection of medical humanities and science fiction (SF) can enrich both: medical humanities can push SF to go beyond the canon, and SF can challenge any characterisation of literature in the medical humanities as purely fantastical by demonstrating how it responds to the hopes and anxieties of a particular time.
Impact of non-contrast enhanced volumetric MRI-based feeder localization in the treatment of spinal dural arteriovenous fistula
Authors: Kannath Santhosh Kumar , Thomas Bejoy , Sankara Sarma P , Enakshy Rajan Jayadevan
Published: August 2016

Background

The preoperative localization of the feeder of spinal dural arteriovenous fistula (SDAVF) could simplify the diagnostic spinal angiographic procedure. Localization by non-contrast-enhanced MRI-based techniques is an attractive option. However, the usefulness of such an approach for evaluation of SDAVF has not yet been reported.

Objective

To study the impact of non-contrast MRI-based feeder localization, followed by targeted spinal angiography, in the evaluation of SDAVF before endovascular intervention.

Materials and methods

Prospectively collected data were analyzed and the level of the feeder was localized preoperatively. The procedural time for targeted spinal angiography was calculated and compared with that of a historical cohort, who underwent routine spinal angiographic examination before the study period. Follow-up MRI was carried out to assess the reliability of this model for detection of occasional metachronous lesions that might be missed with this approach.

Results

Seven patients underwent targeted spinal angiography during the study. The feeder level was accurately identified in five patients and was localized to one vertebral level in six patients. The correlation between MRI and DSA was statistically significant. The number of spinal levels assessed was fewer and overall procedure time was significantly shorter compared to historical cohort (58 min vs 162 min, respectively; p<0.001). Intervention was coupled with targeted angiography in two patients. Follow-up MRI demonstrated flow voids in one patient, who had recurrent fistula at one vertebral level below the previously embolized feeder.

Conclusions

The non-contrast MRI-based localization technique can reliably detect the level of feeder and help in therapeutic planning of SDAVF. The localization techniques potentially shorten the angiographic procedure and may facilitate simultaneous endovascular definitive treatment. Inclusion of follow-up MRI may be useful for detection of synchronous or metachronous lesions if a targeted approach is adopted. Additionally, this helps to identify failed endovascular therapy.
Outcomes of patients with spontaneous coronary artery dissection
Authors: McGrath-Cadell Lucy , McKenzie Pamela , Emmanuel Sam , Muller David W M , Graham Robert M , Holloway Cameron J
Published: August 2016

Background

Spontaneous coronary artery dissection (SCAD) is an uncommon but serious condition presenting as an acute coronary syndrome (ACS) or cardiac arrest. The pathophysiology and outcomes are poorly understood. We investigated the characteristics and outcomes of patients presenting with SCAD.

Methods

In a retrospective study of a large cohort of patients with SCAD, data were collected regarding clinical presentation, patient characteristics, vascular screening, coronary artery involvement and clinical outcomes.

Results

40 patients with SCAD (95% women, mean age 45±10 years) were included. At least 1 traditional cardiovascular risk factor was present in 40% of patients. Migraine was reported in 43% of patients. Events preceding SCAD included parturition (8%), physical stress (13%), emotional stress (10%) and vasoconstrictor substance-use (8%). 65% of patients had a non-ST elevation ACS (NSTEACS) at presentation, 30% had an ST elevation myocardial infarction (STEMI) and 13% had a cardiac arrest. The left anterior descending artery was most frequently involved (68% of patients), and 13% had involvement of multiple coronary territories. Fibromuscular dysplasia (FMD) was identified in 7 (37%) of 19 patients screened. 68% of patients were managed medically, 30% had percutaneous coronary intervention and 5% had coronary artery bypass grafting. Over a median 16-month follow-up period, 8% of patients had at least 1 recurrent SCAD event. There were no deaths.

Conclusions

Patients with SCAD in this study often had multiple coronary territories involved (13%) and extracardiac vascular abnormalities, suggesting a systemic vascular process, which may explain the high incidence of migraine. All patients with SCAD should be screened for FMD and followed closely due to the possibility of recurrence.
Influence of cytokine gene polymorphisms on proinflammatory/anti-inflammatory cytokine imbalance in premature coronary artery disease
Authors: Ansari Wafa Munir , Humphries Steve E , Naveed Abdul Khaliq , Khan Omer Jamshed , Khan Dilshad Ahmed
Published: August 2016

Background

Genetic information has the potential to create a more personalised, prompt, early and accurate risk evaluation. The effect of these genetic variants on the serum biomarker levels (phenotype) needs to be studied to assess their potential causal role in the pathogenesis of premature coronary artery disease (PCAD). Objectives were to determine the genotypic distribution of interleukin (IL) 18, tumour necrosis factor-α (TNFA), IL6 and IL10 single nucleotide polymorphisms (SNPs) in Pakistani PCAD cases and disease free controls and to study the effect of these gene polymorphisms on the serum cytokine levels (IL18, TNFA, IL6 and IL10) and cytokine imbalance (IL18:IL10 and TNFA:IL10).

Material and methods

The case–control study was carried out in National University of Sciences and Technology, Islamabad in collaboration with the Cardiovascular Genetics Institute, University College London, UK. Subjects (n=340) with >70% stenosis in at least a single major coronary artery on angiography were taken as PCAD cases along with 310 angiographically verified controls. ELISA was performed for measuring the concentrations of serum IL18, TNFA, IL6 and IL10. Genotyping was done using TAQMAN assay.

Results

The risk allele frequencies (RAFs) of rs1800795 (IL6) and rs187238 (IL18) cytokine gene promoter SNPs were significantly higher in the PCAD cases as compared with the controls. Serum IL18 and IL10 levels were significantly greater in the IL18 rs187238 GG genotype patients while serum IL18 and IL6 levels were significantly higher in patients having the IL6 rs1800795 CC genotype. IL18 SNP rs1946519 significantly altered the IL18, TNFA, IL6, IL18/IL10 and TNFA/IL10 ratio levels followed by TNFA SNP rs1800629 which significantly altered the serum levels of IL18, IL18:IL-0 and TNFA:IL10 ratios.

Conclusions

The association of the selected SNPs with differential serum cytokine levels especially the cytokine imbalance points towards their potential causal role in the immune inflammatory pathogenic pathway of PCAD.
Alkali metal ion catalysis and inhibition in alkaline ethanolysis of O-Y-substituted-phenyl O-phenyl thionocarbonates: contrasting M+ ion effects upon changing electrophilic centre from C=O to C=S
Authors: Um Ik-Hwan , Kang Ji-Sun , Dust Julian M.
Published: August 2016

Pseudo-first-order rate constants (kobsd) were measured for nucleophilic substitution reactions of O-Y-substituted-phenyl O-phenyl thionocarbonates (4a–4h) with alkali metal ethoxides (EtOM, M = Li, Na, or K) in anhydrous ethanol at 25.0 ± 0.1 °C. Plots of kobsd vs. [EtOM] exhibited upward curvature for the reaction of O-4-nitrophenyl O-phenyl thionocarbonate (4a) with EtOK in the presence of 18-crown-6-ether (18C6), but showed downward curvature for the reaction with EtOLi, indicating that the reaction is catalyzed by the 18C6-crowned K+ ion, but is inhibited by Li+ ion. The kobsd values were dissected into kEtO− and kEtOM, the second-order rate constant for the reaction with dissociated EtO− and ion-paired EtOM, respectively. The reactivity of EtOM toward 4a increases in the order EtOLi < EtONa < EtO− < EtOK < EtOK/18C6, which is in contrast to that reported previously for the corresponding reaction of 4-nitrophenyl phenyl carbonate (a C=O analogue of 4a), e.g., EtO− ≈ EtOK/18C6 < EtOLi < EtONa < EtOK. The reaction mechanism, including the transition-state model and the origin of the contrasting reactivity patterns found for the reactions of the C=O and C=S compounds, are discussed.
Optimum winter road maintenance: effect of pavement types on snow melting performance of road salts
Authors: Hossain S.M. Kamal , Fu Liping , Hosseini Faranak , Muresan Matthew , Donnelly Thomas , Kabir Shahriar
Published: August 2016

This paper presents the results of an extensive field study of the comparative performance of road salt on different pavement types for snow and ice control in transportation facilities. Approximately 400 tests were conducted in a real-world environment, covering three different pavement types and 27 snow events. The performance is compared on asphalt concrete (AC), portland cement concrete (PCC), and interlocked concrete (IC) pavements in terms of pavement clearing speed. The study suggests that on average, salt performs better on AC than PCC or ICC pavement, with the latter two having similar performance. The results were confirmed with a paired t-test analysis and then used to develop a performance model, the results of which were used to develop an adjustment factor for each of the different pavement types. The results from this research can be applied by pavement maintenance personnel to optimize salt usage and improve safety in transportation facilities.
A new class of anisotropic solutions of the generalized TOV equation
Authors: Riazi Nematollah , Hashemi S. Sedigheh , Sajadi S. Naseh , Assyyaee Shahrokh
Published: August 2016

We present gravitating relativistic spheres composed of an anisotropic, barotropic fluid. We assume a bi-polytropic equation of state that has both linear and power-law terms. The generalized Tolman–Oppenheimer–Volkoff (TOV) equation, which describes the hydrostatic equilibrium, is used and the full system of equations is solved for solutions that are regular at the origin and asymptotically flat. Conditions for the appearance of horizon and a basic treatment of stability are also presented.
TUNNEL POSITIONING IN REMNANT SPARING DOUBLE BUNDLE ACL RECONSTRUCTION — A 2-YEAR STUDY OF MRI TUNNEL POSITIONS, CLINICAL OUTCOMES AND TUNNEL CONFLUENCE
Authors: Falconer Travis M. , Gohil Satyen , Tusak Louise , Breidahl William H. , Annear Peter T.
Published: August 2016

Purpose: The purpose of this study is to examine the outcomes of a cohort of patients who have undergone a new surgical technique for anterior cruciate ligament (ACL) tunnel targeting using the footprint of the torn ACL as soft tissue markers. This is in the setting of anatomical ACLR with remnant preservation. Methods: This retrospective single center cohort study was conducted on patients undergoing a primary ACLR between August 2008 and February 2013. A total of 103 patients underwent ACLR with a remnant sparing technique with non-radiological soft tissue targeting of femoral and tibial tunnels. Exclusion criteria included skeletal immaturity, concomitant meniscal repair or ligament surgery, knee malalignment, delayed presentation ([Formula: see text]6 months post injury) and incomplete medical insurance. At 2 years all patients had gadolinium MRI scan, plain film X-ray, and a clinical assessment including KT-1000 arthrometry, and the following outcome scores; Tegner, IKDC (subjective/objective), Lysholm, Cincinnati and ACL Quality of Life. Results: A total of 44 patients (18 males, 26 females; mean age 30.9 years [Formula: see text]/[Formula: see text]11.8) were enrolled within the study. About 93.2% of the participants achieved an IKDC objective rating of A or B. The mean scores for outcome measures were; IKDC Subjective (84.9[Formula: see text][Formula: see text]/[Formula: see text][Formula: see text]11), Tegner (6.1[Formula: see text][Formula: see text]/[Formula: see text][Formula: see text]2), Lysholm (87.2[Formula: see text][Formula: see text]/[Formula: see text][Formula: see text]11.3), Cincinnati (358.1[Formula: see text][Formula: see text]/[Formula: see text][Formula: see text]40.8) and ACL Quality of Life (75.4[Formula: see text][Formula: see text]/[Formula: see text][Formula: see text]19). There were no graft failures at follow up. No patients had a loss of full extension [Formula: see text]. All tunnels were positioned satisfactorily. Almost half of all femoral tunnels (47.8%) and 30.4% of tibial tunnels were confluent at the joint surface. Conclusions: This series demonstrates that anatomical double tunnel ACLR using non-radiological guided remnant retention technique, provides satisfactory 2-year clinical outcomes and is a safe and effective option. Targeting tunnels to be within the native remnant leads to high rates of tunnel confluence.
Calabi quasimorphisms for monotone coadjoint orbits
Authors: Castro Alexander Caviedes
Published: August 2016

We show the existence of Calabi quasimorphisms on the universal covering of the group of Hamiltonian diffeomorphisms of a monotone coadjoint orbit of a compact Lie group with Kostant–Kirillov–Souriau form. We show that this result follows from positivity results of Gromov–Witten invariants and the fact that the quantum product of Schubert classes is never zero.
Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation
Authors: Gomez Angela C. , Holford Timothy W. , Yamaguchi Naohiro
Published: August 2016

Channel activities of skeletal muscle ryanodine receptor (RyR1) are activated by micromolar Ca2+ and inactivated by higher (∼1 mM) Ca2+. To gain insight into a mechanism underlying Ca2+-dependent inactivation of RyR1 and its relationship with skeletal muscle diseases, we constructed nine recombinant RyR1 mutants carrying malignant hyperthermia or centronuclear myopathy-associated mutations and determined RyR1 channel activities by [3H]ryanodine binding assay. These mutations are localized in or near the RyR1 domains which are responsible for Ca2+-dependent inactivation of RyR1. Four RyR1 mutations (F4732D, G4733E, R4736W, and R4736Q) in the cytoplasmic loop between the S2 and S3 transmembrane segments (S2–S3 loop) greatly reduced Ca2+-dependent channel inactivation. Activities of these mutant channels were suppressed at 10–100 μM Ca2+, and the suppressions were relieved by 1 mM Mg2+. The Ca2+- and Mg2+-dependent regulation of S2–S3 loop RyR1 mutants are similar to those of the cardiac isoform of RyR (RyR2) rather than wild-type RyR1. Two mutations (T4825I and H4832Y) in the S4–S5 cytoplasmic loop increased Ca2+ affinities for channel activation and decreased Ca2+ affinities for inactivation, but impairment of Ca2+-dependent inactivation was not as prominent as those of S2–S3 loop mutants. Three mutations (T4082M, S4113L, and N4120Y) in the EF-hand domain showed essentially the same Ca2+-dependent channel regulation as that of wild-type RyR1. The results suggest that nine RyR1 mutants associated with skeletal muscle diseases were differently regulated by Ca2+ and Mg2+. Four malignant hyperthermia-associated RyR1 mutations in the S2–S3 loop conferred RyR2-type Ca2+- and Mg2+-dependent channel regulation.
The myonuclear domain is not maintained in skeletal muscle during either atrophy or programmed cell death
Authors: Schwartz Lawrence M. , Brown Christine , McLaughlin Kevin , Smith Wendy , Bigelow Carol
Published: August 2016

Skeletal muscle mass can increase during hypertrophy or decline dramatically in response to normal or pathological signals that trigger atrophy. Many reports have documented that the number of nuclei within these cells is also plastic. It has been proposed that a yet-to-be-defined regulatory mechanism functions to maintain a relatively stable relationship between the cytoplasmic volume and nuclear number within the cell, a phenomenon known as the “myonuclear domain” hypothesis. While it is accepted that hypertrophy is typically associated with the addition of new nuclei to the muscle fiber from stem cells such as satellite cells, the loss of myonuclei during atrophy has been controversial. The intersegmental muscles from the tobacco hawkmoth Manduca sexta are composed of giant syncytial cells that undergo sequential developmental programs of atrophy and programmed cell death at the end of metamorphosis. Since the intersegmental muscles lack satellite cells or regenerative capacity, the tissue is not “contaminated” by these nonmuscle nuclei. Consequently, we monitored muscle mass, cross-sectional area, nuclear number, and cellular DNA content during atrophy and the early phases of cell death. Despite a ∼75–80% decline in muscle mass and cross-sectional area during the period under investigation, there were no reductions in nuclear number or DNA content, and the myonuclear domain was reduced by ∼85%. These data suggest that the myonuclear domain is not an intrinsic property of skeletal muscle and that nuclei persist through atrophy and programmed cell death.
Dual effects of a high-protein diet on DSS-treated mice during colitis resolution phase
Authors: Lan Annaïg , Blais Anne , Coelho Desire , Capron Juliette , Maarouf Manar , Benamouzig Robert , Lancha Antonio H. , Walker Francine , Tomé Daniel , Blachier François
Published: August 2016

The impact of the dietary protein level on the process of colonic mucosal inflammation and subsequent recovery remains largely unknown. In this study, we fed DSS-treated mice with either a normoproteic (NP) or a high-protein (HP) isocaloric diet from the beginning of the 5-day dextran sulfate sodium (DSS) treatment to 14 days later. Measurements of colitis indicators (colon weight:length ratio, myeloperoxidase activity, cytokine expressions) showed a similar level of colonic inflammation in both DSS groups during the colitis induction phase. However, during the colitis resolution phase, inflammation intensity was higher in the DSS-HP group than in the DSS-NP group as evidenced by higher inflammatory score and body weight loss. This coincided with a higher mortality rate. In surviving animals, an increase in colonic crypt height associated with a higher number of colon epithelial cells per crypt, and TGF-β3 content was observed in the DSS-HP vs. DSS-NP group. Moreover, colonic expression patterns of tight junction proteins and E-cadherin were also different according to the diet. Altogether, our results indicate that the HP diet, when given during both the induction and resolution periods of DSS-induced colitis, showed deleterious effects during the post-induction phase. However, HP diet ingestion was also associated with morphological and biochemical differences compatible with higher colonic epithelium restoration in surviving animals, indicating an effect of the dietary protein level on colonic crypt repair after acute inflammation. These data highlight the potential impact of the dietary protein amount during the colitis course.
Age-dependent shifts in renal response to injury relate to altered BMP6/CTGF expression and signaling
Authors: Falke Lucas L. , Kinashi Hiroshi , Dendooven Amelie , Broekhuizen Roel , Stoop Reinout , Joles Jaap A. , Nguyen Tri Q. , Goldschmeding Roel
Published: August 2016

Age is associated with an increased prevalence of chronic kidney disease (CKD), which, through progressive tissue damage and fibrosis, ultimately leads to loss of kidney function. Although much effort is put into studying CKD development experimentally, age has rarely been taken into account. Therefore, we investigated the effect of age on the development of renal tissue damage and fibrosis in a mouse model of obstructive nephropathy (i.e., unilateral ureter obstruction; UUO). We observed that after 14 days, obstructed kidneys of old mice had more tubulointerstitial atrophic damage but less fibrosis than those of young mice. This was associated with reduced connective tissue growth factor (CTGF), and higher bone morphogenetic protein 6 (BMP6) expression and pSMAD1/5/8 signaling, while transforming growth factor-β expression and transcriptional activity were no different in obstructed kidneys of old and young mice. In vitro, CTGF bound to and inhibited BMP6 activity. In summary, our data suggest that in obstructive nephropathy atrophy increases and fibrosis decreases with age and that this relates to increased BMP signaling, most likely due to higher BMP6 and lower CTGF expression.
Effect of irradiation on Akt signaling in atrophying skeletal muscle
Authors: Fix Dennis K. , Hardee Justin P. , Bateman Ted A. , Carson James A.
Published: August 2016

Muscle irradiation (IRR) exposure can accompany unloading during spaceflight or cancer treatment, and this has been shown to be sufficient by itself to induce skeletal muscle signaling associated with a remodeling response. Although protein kinase B/Akt has an established role in the regulation of muscle growth and metabolism, there is a limited understanding of how Akt signaling in unloaded skeletal muscle is affected by IRR. Therefore, we examined the combined effects of acute IRR and short-term unloading on muscle Akt signaling. Female C57BL/6 mice were subjected to load bearing or hindlimb suspension (HS) for 5 days ( n = 6/group). A single, unilateral hindlimb IRR dose (0.5 Gy X-ray) was administered on day 3. Gastrocnemius muscle protein expression was examined. HS resulted in decreased AktT308 phosphorylation, whereas HS+IRR resulted in increased AktT308 phosphorylation above baseline. HS resulted in reduced AktS473 phosphorylation, which was rescued by HS+IRR. Interestingly, IRR alone resulted in increased phosphorylation of AktS473, but not that of AktT308. HS resulted in decreased mTORC1 signaling, and this suppression was not altered by IRR. Both IRR and HS resulted in increased MuRF-1 expression, whereas atrogin-1 expression was not affected by either condition. These results demonstrate that either IRR alone or when combined with HS can differentially affect Akt phosphorylation, but IRR did not disrupt suppressed mTORC1 signaling by HS. Collectively, these findings highlight that a single IRR dose is sufficient to disrupt the regulation of Akt signaling in atrophying skeletal muscle.
Existence of Nonoscillatory Solutions of Higher-Order Neutral Differential Equations with Distributed Coefficients and Delays
Authors: Liu Youjun , Zhao Huanhuan , Yan Jurang
Published: August 2016

We consider the existence of nonoscillatory solutions of higher-order neutral differential equations with distributed coefficients. We use theBanachcontraction principle to obtain new sufficient condition for the existence of nonoscillatory solutions.
Application of Response Surface Methodology for Optimization of Urea Grafted Multiwalled Carbon Nanotubes in Enhancing Nitrogen Use Efficiency and Nitrogen Uptake by Paddy Plants
Authors: Mohamad Yatim Norazlina , Shaaban Azizah , Dimin Mohd Fairuz , Yusof Faridah , Abd Razak Jeefferie
Published: August 2016

Efficient use of urea fertilizer (UF) as important nitrogen (N) source in the world’s rice production has been a concern. Carbon-based materials developed to improve UF performance still represent a great challenge to be formulated for plant nutrition. Advanced N nanocarrier is developed based on functionalized multiwall carbon nanotubes (f-MWCNTs) grafted with UF to produce urea-multiwall carbon nanotubes (UF-MWCNTs) for enhancing the nitrogen uptake (NU) and use efficiency (NUE). The grafted N can be absorbed and utilized by rice efficiently to overcome the N loss from soil-plant systems. The individual and interaction effect between the specified factors of f-MWCNTs amount (0.10–0.60 wt%) and functionalization reflux time (12–24 hrs) with the corresponding responses (NUE, NU) were structured via the Response Surface Methodology (RSM) based on five-level CCD. The UF-MWCNTs with optimized 0.5 wt% f-MWCNTs treated at 21 hrs reflux time achieve tremendous NUE up to 96% and NU at 1180 mg/pot. Significant model terms (pvalue < 0.05) for NUE and NU responses were confirmed by the ANOVA. Homogeneous dispersion of UF-MWCNTs was observed via FESEM and TEM. The chemical changes were monitored by FT-IR and Raman spectroscopy. Hence, this UF-MWCNTs’ approach provides a promising strategy in enhancing plant nutrition for rice.