bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel
cis
-Acting Regulatory Sequence
Authors: Cavallari Ilaria , Rende Francesca , Bona Marion K. , Sztuba-Solinska Joanna , Silic-Benussi Micol , Tognon Martina , LeGrice Stuart F. J. , Franchini Genoveffa , D'Agostino Donna M. , Ciminale Vincenzo
Published: November 2015

Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex–wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the
p21rex
mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the
p30tof
,
p13
, and
p12/8
mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system.

IMPORTANCE
HTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel
cis
-acting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system.
RNA Replication and Membrane Modification Require the Same Functions of Alphavirus Nonstructural Proteins
Authors: Kallio Katri , Hellström Kirsi , Jokitalo Eija , Ahola Tero
Published: November 2015

The alphaviruses induce membrane invaginations known as spherules as their RNA replication sites. Here, we show that inactivation of any function (polymerase, helicase, protease, or membrane association) essential for RNA synthesis also prevents the generation of spherule structures in a Semliki Forest virus
trans
-replication system. Mutants capable of negative-strand synthesis, including those defective in RNA capping, gave rise to spherules. Recruitment of RNA to membranes in the absence of spherule formation was not detected.
Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice
Authors: Xie Guorui , Luo Huanle , Pang Lan , Peng Bi-hung , Winkelmann Evandro , McGruder Brenna , Hesse Joseph , Whiteman Melissa , Campbell Gerald , Milligan Gregg N. , Cong Yingzi , Barrett Alan D. , Wang Tian
Published: November 2015

The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito-borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6- to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21- to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B-P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed γδ T cell expansion, and lower antibody and WNV-specific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced γδ T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing γδ T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant.

IMPORTANCE
The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals.
Generation of an Avian-Mammalian Rotavirus Reassortant by Using a Helper Virus-Dependent Reverse Genetics System
Authors: Johne Reimar , Reetz Jochen , Kaufer Benedikt B. , Trojnar Eva
Published: November 2015

The genetic diversity of rotavirus A (RVA) strains is facilitated in part by genetic reassortment. Although this process of genome segment exchange has been reported frequently among mammalian RVAs, it remained unknown if mammalian RVAs also could package genome segments from avian RVA strains. We generated a simian RVA strain SA11 reassortant containing the VP4 gene of chicken RVA strain 02V0002G3. To achieve this, we transfected BSR5/T7 cells with a T7 polymerase-driven VP4-encoding plasmid, infected the cells with a temperature-sensitive SA11 VP4 mutant, and selected the recombinant virus by increasing the temperature. The reassortant virus could be stably passaged and exhibited cytopathic effects in MA-104 cells, but it replicated less efficiently than both parental viruses. Our results show that avian and mammalian rotaviruses can exchange genome segments, resulting in replication-competent reassortants with new genomic and antigenic features.

IMPORTANCE
This study shows that rotaviruses of mammals can package genome segments from rotaviruses of birds. The genetic diversity of rotaviruses could be broadened by this process, which might be important for their antigenic variability. The reverse genetics system applied in the study could be useful for targeted generation and subsequent characterization of distinct rotavirus reassortant strains.
Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a
Authors: Grauwet K. , Vitale M. , De Pelsmaeker S. , Jacob T. , Laval K. , Moretta L. , Parodi M. , Parolini S. , Cantoni C. , Favoreel H. W.
Published: November 2015

Several reports have indicated that natural killer (NK) cells are of particular importance in the innate response against herpesvirus infections. As a consequence, herpesviruses have developed diverse mechanisms for evading NK cells, although few such mechanisms have been identified for the largest herpesvirus subfamily, the alphaherpesviruses. The antiviral activity of NK cells is regulated by a complex array of interactions between activating/inhibitory receptors on the NK cell surface and the corresponding ligands on the surfaces of virus-infected cells. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) displays previously uncharacterized immune evasion properties: it triggers the binding of the inhibitory NK cell receptor CD300a to the surface of the infected cell, thereby providing increased CD300a-mediated protection of infected cells against NK cell-mediated lysis. US3-mediated CD300a binding was found to depend on aminophospholipid ligands of CD300a and on group I p21-activated kinases. These data identify a novel alphaherpesvirus strategy for evading NK cells and demonstrate, for the first time, a role for CD300a in regulating NK cell activity upon contact with virus-infected target cells.

IMPORTANCEHerpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, contributing to their ability to cause lifelong infections with recurrent reactivation events. Natural killer (NK) cells are central in the innate antiviral response. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus displays a previously uncharacterized capacity for evasion of NK cells. Expression of US3 protects infected cells from NK cell-mediated lysis via increased binding of the inhibitory NK cell receptor CD300a. We show that this US3-mediated increase in CD300a binding depends on aminophospholipids and on cellular p21-activated kinases (PAKs). The identification of this novel NK cell evasion strategy may contribute to the design of improved herpesvirus vaccines and may also have significance for other PAK- and CD300a-modulating viruses and cancer cells.
Large aortic arch mural thrombus in non-atherosclerotic thoracic aorta—a rare cause of stroke in the young
Authors: Aldaher Moutaz Khaled , El-Fayed Hani M , Malouka Saber A , Gad Fady Safwat
Published: November 2015

A 43-year-old Indian woman was admitted to the intensive care unit, with large cerebellar infarction. A brain CT scan showed a large non-haemorrhagic infarct involving the vermis and cerebellar hemispheres. Transesophageal echocardiography and CT angiography demonstrated a large mural aortic thrombus. No evidence of cardiac or vascular pathology was present. The patient had a high risk for surgical intervention and was treated with anticoagulation. Follow-up imaging 2 weeks later showed complete resolution of the thoracic aortic thrombus. This case report emphasises that imaging of the great vessels of the neck and transesophageal echocardiography should be included in ischaemic stroke work up. A thoracic aortic thrombus should always be considered in young patients with unexplained stroke or peripheral embolism; the condition can be treated effectively with anticoagulation.
Effectiveness and safety of 1 vs 4 h blood pressure profile with clinical and laboratory assessment for the exclusion of gestational hypertension and pre-eclampsia: a retrospective study in a university affiliated maternity hospital
Authors: McCarthy Elizabeth Anne , Carins Thomas A , Hannigan Yolanda , Bardien Nadia , Shub Alexis , Walker Susan P
Published: November 2015

Objective

We asked whether 60 compared with 240 min observation is sufficiently informative and safe for pregnancy day assessment (PDAC) of suspected pre-eclampsia (PE).

Design

A retrospective study of 209 pregnant women (475 PDAC assessments, 6 months) with routinely collected blood pressure (BP), symptom and laboratory information. We proposed a 60 min screening algorithm comprising: absence of symptoms, normal laboratory parameters and ≤1high-BP reading (systolic blood pressure, SBP 140 mm Hg or higher or diastolic blood pressure, DBP 90 mm Hg or higher). We also evaluated two less inclusive screening algorithms. We determined short-term outcomes (within 4 h): severe hypertension, proteinuric hypertension and pregnancy-induced hypertension, as well as long-term outcome: PE-related diagnoses up to the early puerperium. We assessed performance of alternate screening algorithms performance using 2×2 tables.

Results

1 in 3 women met all screen negative criteria at 1 h. Their risk of hypertension requiring treatment in the next 3 h was 1.8% and of failing to diagnose proteinuric hypertensive PE at 4 h was 5.1%. If BP triggers were 5 mm Hg lower, 1 in 6 women would be screen-negative of whom 1.1% subsequently develops treatment-requiring hypertension and 4.5% demonstrate short-term proteinuric hypertension. We present sensitivity, specificity, negative and positive likelihood ratios for alternate screening algorithms.

Conclusions

We endorse further research into the safest screening test where women are considered for discharge after 60 min. Safety, patient and staff satisfaction should be assessed prospectively. Any screening test should be used in conjunction with good clinical care to minimise maternal and perinatal hazards of PE.
Acupuncture for postoperative pain following total knee arthroplasty: a systematic review protocol
Authors: Jung Jae-Young , Cho Jae-Heung , Chung Seok-hee
Published: November 2015

Introduction

Total knee arthroplasty (TKA) is a common surgical method in orthopaedics; however, pain management after TKA remains a significant challenge. This review provides a comprehensive evaluation of the effects of acupuncture for postoperative pain after TKA.

Methods and analysis

The following 10 databases will be searched until August 2015: MEDLINE, EMBASE, CENTRAL, AMED, CINAHL, three Chinese databases (the China National Knowledge Infrastructure Database, the Chongqing VIP Chinese Science and Technology Periodical Database, and Wanfang Database) and five Korean databases (the Korean Medical Database, the Korean Studies Information Service System, the National Discovery for Science Leaders, the Database Periodical Information Academic, and the Oriental Medicine Advanced Searching Integrated System). All eligible randomised controlled trials related to the use of acupuncture for postoperative pain after TKA will be included. Assessment of risk of bias will be performed with the Cochrane risk-of-bias method. Mean differences or standardised mean differences will be calculated with 95% CIs for continuous data; the risk ratio will be used with 95% CIs for dichotomous data.

Dissemination

This systematic review will be presented in a peer-reviewed journal. The result of this review will also be disseminated at a relevant conference presentation.

Trial registration number

PROSPERO 2015: CRD42015020924.
Discontinuation rates of biologics in patients with rheumatoid arthritis: are TNF inhibitors different from non-TNF inhibitors?
Authors: Ramiro Sofia , Landewé Robert , van der Heijde Désirée , Harrison David , Collier David , Michaud Kaleb
Published: November 2015

Objective

To compare discontinuation rates of first and second biologics in rheumatoid arthritis (RA) by tumour-necrosis factor inhibitor (TNFi) status and identify predictors and reasons for discontinuation.

Methods

From 1998 to 2011, self-reported medication use for RA was assessed every 6 months via questionnaire in a longitudinal study in the USA. Time-on-drug analyses were conducted for individual biologics and groups, and annual rates reported. Time to discontinuation of TNFi and non-TNFi was compared, unadjusted and adjusted using propensity score analyses. Baseline and time-varying predictors of biologic discontinuation were derived through Cox regression.

Results

Of 2281 patients initiating their first biologic, 1100 (48%) discontinued and of 1097 initiating a second biologic, 537 (49%) discontinued. The annual discontinuation rate was 17% (median 4 years) for first biologic and 20% (median 3.3 years) for second biologic. TNFi had lower discontinuation rates than non-TNFi after propensity score adjustment: HR for first biologic 0.49 (0.34 to 0.71) and 0.68 (0.51 to 0.90) for second biologic. The annual discontinuation rate was significantly lower in patients starting their first biologic before January 2005 vs after (16 vs 25%, p=0.005). Predictors of discontinuation for the first biologic included smoking, higher comorbidity index, worse overall health and not using concomitant methotrexate.

Conclusions

In this large cohort, patients with RA tended to remain on their first and second biologics for relatively long periods suggesting the drugs’ effectiveness. Discontinuation rates were lower in patients using TNFi, and all rates increased after January 2005 when the number of biologics available increased.
Retrospective forecasting — evaluating performance of stock projections for New England groundfish stocks
Authors: Brooks Elizabeth N. , Legault Christopher M.
Published: November 2015

Projections are used to explore scenarios for catch advice and rebuilding and are an important tool for sustainably managing fisheries. We tested each projection specification for 12 groundfish stocks in the Northwest Atlantic to identify sources of bias and evaluate techniques for reducing bias. Projections were made from assessments using virtual population analysis (VPA) with 1–7 years of recent data removed from the full time series and were then compared with results from a VPA assessment on the full time series of data. The main source of bias in projections was the assessment model estimates of the numbers at age in the terminal model year + 1 (Na,T+1). Recruitment was responsible for more bias in projections beyond 3 years, when population numbers begin to be dominated by cohorts that were statistically generated. Retrospective analysis was performed and several adjustment factors to reduce bias were tested. Even after adjusting for bias, the remaining bias in projections was non-negligible. The direction of bias generally resulted in projected spawning stock biomass (SSB) and catch being overestimated, and the bias in catch was nearly always larger than in SSB. Scientists need to clearly communicate the direction and magnitude of this bias, managers need to consider this additional uncertainty when specifying future catch limits, and both scientists and managers need to develop more robust control rules so that objectives are achieved.
Interannual variability in the effects of physical habitat and parentage on Chinook salmon egg-to-fry survival
Authors: Roni Philip , Johnson Christopher , De Boer Trenton , Pess George , Dittman Andrew , Sear David
Published: November 2015

Mortality during incubation is believed to be a major factor limiting the recovery of many salmon populations, though direct field measurements of egg-to-fry survival are rare or small in scale. To determine the effects of physical habitat (river reach, fine sediment intrusion, scour), parentage (mating, source of gametes) on Chinook salmon (Oncorhynchus tshawytscha) egg-to-fry survival and developmental stage at emergence across a basin, we constructed 324 artificial redds in nine reaches over 4 years in the Yakima River Basin, Washington, USA. Mean egg-to-fry survival ranged from 49% to 69% annually from 2009 to 2012 brood years. Survival was significantly different among reaches in 2010, but not in 2009, 2011, or 2012, while mating was a significant factor in all years but 2010. In contrast, developmental stage differed significantly among reaches and matings in all 4 years. Percentage of fines, days-in-gravel, and median particle size explained only small (<10%) additional amount of variation in survival or developmental stages. Our results suggest that parentage and reach within a basin are major factors influencing egg-to-fry survival, but their relative influence varies annually, presumably depending on the magnitude of high flows and scour during incubation.
Lycopene modulates cholinergic dysfunction, Bcl-2/Bax balance, and antioxidant enzymes gene transcripts in monosodium glutamate (E621) induced neurotoxicity in a rat model
Authors: Sadek Kadry , Abouzed Tarek , Nasr Sherif
Published: November 2015

The effect of monosodium glutamate (MSG) on brain tissue and the relative ability of lycopene to avert these neurotoxic effects were investigated. Thirty-two male Wistar rats were distributed into 4 groups: group I, untreated (placebo); group II, injected with MSG (5 mg·kg−1) s.c.; group III, gastrogavaged with lycopene (10 mg·kg−1) p.o.; and group IV received MSG with lycopene with the same mentioned doses for 30 days. The results showed that MSG induced elevation in lipid peroxidation marker and perturbation in the antioxidant homeostasis and increased the levels of brain and serum cholinesterase (ChE), total creatine phosphokinase (CPK), creatine phosphokinase isoenzymes BB (CPK-BB), and lactate dehydrogenase (LDH). Glutathione S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) activities and gene expression were increased and glutathione content was reduced in the MSG-challenged rats, and these effects were ameliorated by lycopene. Furthermore, MSG induced apoptosis in brain tissues reflected in upregulation of pro-apoptotic Bax while lycopene upregulated the anti-apoptotic Bcl-2. Our results indicate that lycopene appears to be highly effective in relieving the toxic effects of MSG by inhibiting lipid peroxidation and inducing modifications in the activity of cholinesterase and antioxidant pathways. Interestingly, lycopene protects brain tissue by inhibiting apoptosis signaling induced by MSG.
EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1
Authors: Yang Yan , Yang Feng , Wu Xiaojuan , Lv Xiongwen , Li Jun
Published: November 2015

Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 μmol/L acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA). Our data showed that both cAMP/PKA and cAMP/EPAC signaling pathways were involved in acetaldehyde-induced HSCs. Acetaldehyde could reduce the expression of EPAC1 while enhancing the expression of EPAC2. The cAMP analog Me-cAMP, which stimulates the EPAC/Rap1 pathway, could significantly decrease the proliferation and collagen synthesis of acetaldehyde-induced HSCs. Furthermore, depletion of EPAC2, but not EPAC1, prevented the activation of HSC measured as the production of α-SMA and collagen type I and III, indicating that EPAC1 appears to have protective effects on acetaldehyde-induced HSCs. Curiously, activation of PKA or EPAC perhaps has opposite effects on the synthesis of collagen and α-SMA: EPAC activation by Me-cAMP increased the levels of GTP-bound (activated) Rap1 while PKA activation by Phe-cAMP had no significant effects on such binding. These results suggested that EPAC activation could inhibit the activation and proliferation of acetaldehyde-induced HSCs via Rap1.
Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells
Authors: Massey Katherine J. , Li Quanwen , Rossi Noreen F. , Keezer Susan M. , Mattingly Raymond R. , Yingst Douglas R.
Published: November 2015

How angiotensin (ANG) II acutely stimulates the Na-K pump in proximal tubules is only partially understood, limiting insight into how ANG II increases blood pressure. First, we tested whether ANG II increases the number of pumps in plasma membranes of native rat proximal tubules under conditions of rapid activation. We found that exposure to 100 pM ANG II for 2 min, which was previously shown to increase affinity of the Na-K pump for Na and stimulate activity threefold, increased the amount of the Na-K pump in plasma membranes of native tubules by 33%. Second, we tested whether previously observed increases in phosphorylation of the Na-K pump at Ser938 were part of the stimulatory mechanism. These experiments were carried out in opossum kidney cells, cultured proximal tubules stably coexpressing the ANG type 1 (AT1) receptor, and either wild-type or a S938A mutant of rat kidney Na-K pump under conditions found by others to stimulate activity. We found that 10 min of incubation in 10 pM ANG II stimulated activity of wild-type pumps from 2.3 to 3.5 nmol K·mg protein−1·min−1 and increased the amount of the pump in the plasma membrane by 80% but had no effect on cells expressing the S938A mutant. We conclude that acute stimulation of Na-K pump activity in native rat proximal tubules includes increased trafficking to the plasma membrane and that phosphorylation at Ser938 is part of the mechanism by which ANG II directly stimulates activity and trafficking of the rat kidney Na-K pump in opossum kidney cells.
The cytoplasmic domain is essential for transport function of the integral membrane transport protein SLC4A11
Authors: Loganathan Sampath K. , Lukowski Chris M. , Casey Joseph R.
Published: November 2015

Large cytoplasmic domains (CD) are a common feature among integral membrane proteins. In virtually all cases, these CD have a function (e.g., binding cytoskeleton or regulatory factors) separate from that of the membrane domain (MD). Strong associations between CD and MD are rare. Here we studied SLC4A11, a membrane transport protein of corneal endothelial cells, the mutations of which cause genetic corneal blindness. SLC4A11 has a 41-kDa CD and a 57-kDa integral MD. One disease-causing mutation in the CD, R125H, manifests a catalytic defect, suggesting a role of the CD in transport function. Expressed in HEK-293 cells without the CD, MD-SLC4A11 is retained in the endoplasmic reticulum, indicating a folding defect. Replacement of CD-SLC4A11 with green fluorescent protein did not rescue MD-SLC4A11, suggesting some specific role of CD-SLC4A11. Homology modeling revealed that the structure of CD-SLC4A11 is similar to that of the Cl−/HCO3− exchange protein AE1 (SLC4A1) CD. Fusion to CD-AE1 partially rescued MD-SLC4A11 to the cell surface, suggesting that the structure of CD-AE1 is similar to that of CD-SLC4A11. The CD-AE1-MD-SLC4a11 chimera, however, had no functional activity. We conclude that CD-SLC4A11 has an indispensable role in the transport function of SLC4A11. CD-SLC4A11 forms insoluble precipitates when expressed in bacteria, suggesting that the domain cannot fold properly when expressed alone. Consistent with a strong association between CD-SLC4A11 and MD-SLC4A11, these domains specifically associate when coexpressed in HEK-293 cells. We conclude that SLC4A11 is a rare integral membrane protein in which the CD has strong associations with the integral MD, which contributes to membrane transport function.
Role of the kidney in the pathogenesis of hypertension: time for a neo-Guytonian paradigm or a paradigm shift?
Authors: Evans Roger G. , Bie Peter
Published: November 2015

The “Guytonian paradigm” places the direct effect of arterial pressure, on renal excretion of salt and water, at the center of long-term control of blood pressure, and thus the pathogenesis of hypertension. It originated in the sixties and remains influential within the field of hypertension research. However, the concept of one central long-term feedback loop, through which arterial pressure is maintained by its influence on renal function, has been questioned. Furthermore, some concepts in the paradigm are undermined by experimental observations. For example, volume retention and increased cardiac output induced by high salt intake do not necessarily lead to increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral control mechanisms rather than through direct or indirect effects of changes in arterial pressure, compatible with the concept that renal sodium excretion is controlled by parallel actions of different feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do not fully understand the sequence of events underlying the phenomenon of “whole body autoregulation.” Thus the events by which volume retention may develop to hypertension characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal models of hypertension are not “essential hypertension;” progress in our understanding of essential hypertension depends on new results on system functions in patients.
Acclimation and acute temperature effects on population differences in oxidative phosphorylation
Authors: Baris Tara Z. , Crawford Douglas L. , Oleksiak Marjorie F.
Published: November 2015

Temperature changes affect metabolism on acute, acclamatory, and evolutionary time scales. To better understand temperature's affect on metabolism at these different time scales, we quantified cardiac oxidative phosphorylation (OxPhos) in three Fundulus taxa acclimated to 12 and 28°C and measured at three acute temperatures (12, 20, and 28°C). The Fundulus taxa (northern Maine and southern Georgia F. heteroclitus, and a sister taxa, F. grandis) were used to identify evolved changes in OxPhos. Cardiac OxPhos metabolism was quantified by measuring six traits: state 3 (ADP and substrate-dependent mitochondrial respiration); E state (uncoupled mitochondrial activity); complex I, II, and IV activities; and LEAK ratio. Acute temperature affected all OxPhos traits. Acclimation only significantly affected state 3 and LEAK ratio. Populations were significantly different for state 3. In addition to direct effects, there were significant interactions between acclimation and population for complex I and between population and acute temperature for state 3. Further analyses suggest that acclimation alters the acute temperature response for state 3, E state, and complexes I and II: at the low acclimation temperature, the acute response was dampened at low assay temperatures, and at the high acclimation temperature, the acute response was dampened at high assay temperatures. Closer examination of the data also suggests that differences in state 3 respiration and complex I activity between populations were greatest between fish acclimated to low temperatures when assayed at high temperatures, suggesting that differences between the populations become more apparent at the edges of their thermal range.
A three-leg model producing tetrapod and tripod coordination patterns of ipsilateral legs in the stick insect
Authors: Tóth T. I. , Daun-Gruhn S.
Published: November 2015

Insect locomotion requires the precise coordination of the movement of all six legs. Detailed investigations have revealed that the movement of the legs is controlled by local dedicated neuronal networks, which interact to produce walking of the animal. The stick insect is well suited to experimental investigations aimed at understanding the mechanisms of insect locomotion. Beside the experimental approach, models have also been constructed to elucidate those mechanisms. Here, we describe a model that replicates both the tetrapod and tripod coordination pattern of three ipsilateral legs. The model is based on an earlier insect leg model, which includes the three main leg joints, three antagonistic muscle pairs, and their local neuronal control networks. These networks are coupled via angular signals to establish intraleg coordination of the three neuromuscular systems during locomotion. In the present three-leg model, we coupled three such leg models, representing front, middle, and hind leg, in this way. The coupling was between the levator-depressor local control networks of the three legs. The model could successfully simulate tetrapod and tripod coordination patterns, as well as the transition between them. The simulations showed that for the interleg coordination during tripod, the position signals of the levator-depressor neuromuscular systems sent between the legs were sufficient, while in tetrapod, additional information on the angular velocities in the same system was necessary, and together with the position information also sufficient. We therefore suggest that, during stepping, the connections between the levator-depressor neuromuscular systems of the different legs are of primary importance.
Stability of Runge-Kutta Methods for Neutral Delay Differential Equations
Authors: Wen Liping , Liu Xiong , Yu Yuexin
Published: November 2015

This paper is concerned with the numerical stability of a class of nonlinear neutral delay differential equations. The numerical stability results are obtained for(k,l)-algebraically stable Runge-Kutta methods when they are applied to this type of problem. Numerical examples are given to confirm our theoretical results.
Cracking the Code of Human Diseases Using Next-Generation Sequencing: Applications, Challenges, and Perspectives
Authors: Precone Vincenza , Del Monaco Valentina , Esposito Maria Valeria , De Palma Fatima Domenica Elisa , Ruocco Anna , Salvatore Francesco , D’Argenio Valeria
Published: November 2015

Next-generation sequencing (NGS) technologies have greatly impacted on every field of molecular research mainly because they reduce costs and increase throughput of DNA sequencing. These features, together with the technology’s flexibility, have opened the way to a variety of applications including the study of the molecular basis of human diseases. Several analytical approaches have been developed to selectively enrich regions of interest from the whole genome in order to identify germinal and/or somatic sequence variants and to study DNA methylation. These approaches are now widely used in research, and they are already being used in routine molecular diagnostics. However, some issues are still controversial, namely, standardization of methods, data analysis and storage, and ethical aspects. Besides providing an overview of the NGS-based approaches most frequently used to study the molecular basis of human diseases at DNA level, we discuss the principal challenges and applications of NGS in the field of human genomics.
Slot Parameter Optimization for Multiband Antenna Performance Improvement Using Intelligent Systems
Authors: Demircioglu Erdem , Yagli Ahmet Fazil , Gulgonul Senol , Ankishan Haydar , Tartan Emre Oner , Sazli Murat H. , Imeci Taha
Published: November 2015

This paper discusses bandwidth enhancement for multiband microstrip patch antennas (MMPAs) using symmetrical rectangular/square slots etched on the patch and the substrate properties. The slot parameters on MMPA are modeled using soft computing technique of artificial neural networks (ANN). To achieve the best ANN performance, Particle Swarm Optimization (PSO) and Differential Evolution (DE) are applied with ANN’s conventional training algorithm in optimization of the modeling performance. In this study, the slot parameters are assumed as slot distance to the radiating patch edge, slot width, and length. Bandwidth enhancement is applied to a formerly designed MMPA fed by a microstrip transmission line attached to the center pin of 50 ohm SMA connecter. The simulated antennas are fabricated and measured. Measurement results are utilized for training the artificial intelligence models. The ANN provides 98% model accuracy for rectangular slots and 97% for square slots; however, ANFIS offer 90% accuracy with lack of resonance frequency tracking.
A Hybrid Scheme Based on Pipelining and Multitasking in Mobile Application Processors for Advanced Video Coding
Authors: Asif Muhammad , Taj Imtiaz A. , Ziauddin S. M. , Ahmad Maaz Bin , Tahir M.
Published: November 2015

One of the key requirements for mobile devices is to provide high-performance computing at lower power consumption. The processors used in these devices provide specific hardware resources to handle computationally intensive video processing and interactive graphical applications. Moreover, processors designed for low-power applications may introduce limitations on the availability and usage of resources, which present additional challenges to the system designers. Owing to the specific design of the JZ47x series of mobile application processors, a hybrid software-hardware implementation scheme for H.264/AVC encoder is proposed in this work. The proposed scheme distributes the encoding tasks among hardware and software modules. A series of optimization techniques are developed to speed up the memory access and data transferring among memories. Moreover, an efficient data reusage design is proposed for the deblock filter video processing unit to reduce the memory accesses. Furthermore, fine grained macroblock (MB) level parallelism is effectively exploited and a pipelined approach is proposed for efficient utilization of hardware processing cores. Finally, based on parallelism in the proposed design, encoding tasks are distributed between two processing cores. Experiments show that the hybrid encoder is 12 times faster than a highly optimized sequential encoder due to proposed techniques.
Glycyrrhizic Acid Promotes M1 Macrophage Polarization in Murine Bone Marrow‐Derived Macrophages Associated with the Activation of JNK and NF‐κB
Authors: Mao Yulong , Wang Baikui , Xu Xin , Du Wei , Li Weifen , Wang Youming
Published: November 2015

The roots and rhizomes of Glycyrrhiza species (licorice) have been widely used as natural sweeteners and herbal medicines. The aim of this study is to investigate the effect of glycyrrhizic acid (GA) from licorice on macrophage polarization. Both phenotypic and functional activities of murine bone marrow‐derived macrophages (BMDMs) treated by GA were assessed. Our results showed that GA obviously increased the cell surface expression of CD80, CD86, and MHCII molecules. Meanwhile, GA upregulated the expression of CCR7 and the production of TNF‐α, IL‐12, IL‐6, and NO (the markers of classically activated (M1) macrophages), whereas it downregulated the expression of MR, Ym1, and Arg1 (the markers of alternatively activated (M2) macrophage). The functional tests showed that GA dramatically enhanced the uptake of FITC‐dextran and E. coli K88 by BMDMs and decreased the intracellular survival of E. coli K88 and S. typhimurium. Moreover, we demonstrated that JNK and NF‐κB activation are required for GA‐induced NO and M1‐related cytokines production, while ERK1/2 pathway exhibits a regulatory effect via induction of IL‐10. Together, these findings indicated that GA promoted polarization of M1 macrophages and enhanced its phagocytosis and bactericidal capacity. The results expanded our knowledge about the role of GA in macrophage polarization.
The Polymorphisms with Cataract Susceptibility Impair the EPHA2 Receptor Stability and Its Cytoprotective Function
Authors: Yang Jin , Li Dan , Fan Qi , Cai Lei , Qiu Xiaodi , Zhou Peng , Lu Yi
Published: November 2015

Despite accumulating evidence revealing susceptibility genes for age-related cataract, its pathophysiology leading to visual impairment at the cellular and molecular level remains poorly understood. Recent bioinformatic studies uncovered the association of two single nucleotide polymorphisms in human EPHA2, rs2291806 and rs1058371, with age-related cataract. Here we investigated the role of EPHA2 in counteracting oxidative stress-induced apoptosis of lens epithelial cells. The cataract-associated missense mutations resulted in the destabilization of EPHA2 receptor without altering the mRNA transcription. The cytoprotective and antiapoptotic function of EPHA2 in lens epithelial cells was abolished by the functional polymorphisms. Furthermore, our results suggest that the downstream signaling of activated EPHA2 promotes the antioxidative capacity of lens epithelial cells to eradicate the overproduction of reactive oxygen species. In contrast, the overexpression of EPHA2 with nonsynonymous mutations in the lens epithelial cells offered limited antioxidative protection against oxidative stress. Thus, our study not only sheds the light on the potential cytoprotective function of EPHA2 signaling in lens but also provides the cellular mechanisms underlying the pathogenesis of age-related cataract.
Visible Light Catalytic Degradation of Aniline Wastewater over Multishaped BiOBr Microcrystals
Authors: Zhang Jun , Li Huabo , Yao Hairui , Zhang Hao
Published: November 2015

The photooxidation process of aniline-containing simulated wastewater under visible light irradiation over BiOBr microcrystal grains with different shapes was studied. The distinctive surface microstructures of the BiOBr microcrystals, like clustered flower petals and quadrate lamellas, were produced by using imidazole ionic liquid and inorganic bromide as Br sources and by solvothermal and hydrothermal route, respectively. The ionic liquid not only can impact the products’ morphology, but also can largely improve the photocatalytic activity of the BiOBr microcrystals due to the soft templating effect. The top degradation ratio of the aniline wastewater photocatalyzed by lamellar BiOBr crystals is 23.71%, but the equivalent value photocatalyzed by flower petal-like BiOBr crystals is almost twice as much; that is, it reaches 46.51%. The photodegradation effect and mechanism over differently shaped BiOBr microcrystals have been compared.
Nerve Blockage Attenuates Postoperative Inflammation in Hippocampus of Young Rat Model with Surgical Trauma
Authors: He Yi , Li Zhi , Zuo Yun-Xia
Published: November 2015

It is hypothesized that central nervous system inflammation induced by systematic inflammation due to surgical trauma plays a critical role in postoperative cognitive dysfunction. The potential inhibitory effect of nerve blockage with local anesthetics on peripheral inflammatory response has been reported. We hypothesize that nerve blockage may be effective in reducing postoperative inflammation and cognitive decline. The rats at the age of 4 weeks were subjected to general anesthesia and humeral fracture fixation, in combination with brachial plexus block, saline versus ropivacaine, respectively. The rats from control group underwent general anesthesia only. The expression of proinflammatory cytokines in plasma and in hippocampus was measured. Open field test and new object recognition task were performed before surgery and on postoperative days (POD) 1, 3, and 7. Compared with control group, the level of cytokines in plasma and hippocampus revealed an obvious increase in surgery groups. The effect of brachial plexus block on decreasing cytokines was observed. The rats exposed to surgery without brachial plexus block showed behavior impairment. Our results indicated that nerve blockage could downregulate proinflammatory cytokines in hippocampus after humeral fixation surgery, which may ameliorate the postoperative cognitive dysfunction in young rats.
Anatomical Basis for the Cardiac Interventional Electrophysiologist
Authors: Sánchez-Quintana Damián , Doblado-Calatrava Manuel , Cabrera José Angel , Macías Yolanda , Saremi Farhood
Published: November 2015

The establishment of radiofrequency catheter ablation techniques as the mainstay in the treatment of tachycardia has renewed new interest in cardiac anatomy. The interventional arrhythmologist has drawn attention not only to the gross anatomic details of the heart but also to architectural and histological characteristics of various cardiac regions that are relevant to the development or recurrence of tachyarrhythmias and procedural related complications of catheter ablation. In this review, therefore, we discuss some anatomic landmarks commonly used in catheter ablations including the terminal crest, sinus node region, Koch’s triangle, cavotricuspid isthmus, Eustachian ridge and valve, pulmonary venous orifices, venoatrial junctions, and ventricular outflow tracts. We also discuss the anatomical features of important structures in the vicinity of the atria and pulmonary veins, such as the esophagus and phrenic nerves. This paper provides basic anatomic information to improve understanding of the mapping and ablative procedures for cardiac interventional electrophysiologists.
Strength, Multijoint Coordination, and Sensorimotor Processing Are Independent Contributors to Overall Balance Ability
Authors: Lawrence Emily L. , Cesar Guilherme M. , Bromfield Martha R. , Peterson Richard , Valero-Cuevas Francisco J. , Sigward Susan M.
Published: November 2015

For young adults, balance is essential for participation in physical activities but is often disrupted following lower extremity injury. Clinical outcome measures such as single limb balance (SLB), Y-balance (YBT), and the single limb hop and balance (SLHB) tests are commonly used to quantify balance ability following injury. Given the varying demands across tasks, it is likely that such outcome measures provide useful, although task-specific, information. But the extent to which they are independent and contribute to understanding the multiple contributors to balance is not clear. Therefore, the purpose of this study was to investigate the associations among these measures as they relate to the different contributors to balance. Thirty-seven recreationally active young adults completed measures including Vertical Jump, YBT, SLB, SLHB, and the new Lower Extremity Dexterity test. Principal components analysis revealed that these outcome measures could be thought of as quantifying the strength, multijoint coordination, and sensorimotor processing contributors to balance. Our results challenge the practice of using a single outcome measure to quantify the naturally multidimensional mechanisms for everyday functions such as balance. This multidimensional approach to, and interpretation of, multiple contributors to balance may lead to more effective, specialized training and rehabilitation regimens.
The Potential of Concentrated Solar Power for Remote Mine Sites in the Northern Territory, Australia
Authors: Baig M. H. , Surovtseva D. , Halawa E.
Published: November 2015

The Northern Territory (NT) is among the regions in Australia and the world with the highest solar radiation intensities. The NT has many mine sites which consume significant amount of fossil fuel with consequent greenhouse gas (GHG) emissions. The environmental concern related to the fossil fuel consumption and availability of immense solar energy resource in the NT open the possibilities for considering the provision of power to the mining sites using proven solar technologies. Concentrating solar power (CSP) systems are deemed as the potential alternatives to current fossil fuel based generating systems in mining industry in the NT. The finding is based on consideration of the major factors in determining the feasibility of CSP system installation, with particular reference to the NT mine sites. These are plant design requirements, climatic, environmental, and other requirements, and capital and operating costs. Based on these factors, four mine sites have been identified as having the potential for CSP plants installation. These are McArthur River Mine, Ranger Mine, Northern Territory Gold Mines, and Tanami Operations. Each site could be served by one CSP plant to cater for the needs of mining operation and the local communities.