bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombinant Adeno-Associated Virus Utilizes Cell-Specific Infectious Entry Mechanisms
Authors: Weinberg Marc S. , Nicolson Sarah , Bhatt Aadra P. , McLendon Michael , Li Chengwen , Samulski R. Jude
Published: August 2014

Understanding the entry and trafficking mechanism(s) of recombinant adeno-associated virus (rAAV) into host cells can lead to evolution in capsid and vector design and delivery methods, resulting in enhanced transduction and therapeutic gene expression. Variability of findings regarding the early entry pathway of rAAV supports the possibility that rAAV, like other viruses, can utilize more than one infectious entry pathway. We tested whether inhibition of macropinocytosis impacted rAAV transduction of HeLa cells compared to hepatocellular carcinoma cell lines. We found that macropinocytosis inhibitor cytochalasin D blocked rAAV transduction of HeLa cells (>2-fold) but enhanced (10-fold) transduction in HepG2 and Huh7 lines. Similar results were obtained with another macropinocytosis inhibitor, 5-(
N
-ethyl-
N
-isopropyl) amiloride (EIPA). The augmented transduction was due to neither viral binding nor promoter activity, affected multiple rAAV serotypes (rAAV2, rAAV2-R585E, and rAAV8), and influenced single-stranded and self-complementary virions to comparable extents. Follow-up studies using CDC42 inhibitor ML141 and p21-activated kinase 1 (PAK1) siRNA knockdown also resulted in enhanced HepG2 transduction. Microscopy revealed that macropinocytosis inhibition correlated with expedited nuclear entry of the rAAV virions into HepG2 cells. Enhancement of hepatocellular rAAV transduction extended to the mouse liver
in vivo
(4-fold enhancement) but inversely blocked heart tissue transduction (13-fold). This evidence of host cell-specific rAAV entry pathways confers a potent means for controlling and enhancing vector delivery and could help unify the divergent accounts of rAAV cellular entry mechanisms.

IMPORTANCE
There is a recognized need for improved rAAV vector targeting strategies that result in delivery of fewer total particles, averting untoward toxicity and/or an immune response against the vector. A critical step in rAAV transduction is entry and early trafficking through the host cellular machinery, the mechanisms of which are under continued study. However, should the early entry and trafficking mechanisms of rAAV differ across virus serotype or be dependent on host cell environment, this could expand our ability to target particular cells and tissue for selective transduction. Thus, the observation that inhibiting macropinocytosis leads to cell-specific enhancement or inhibition of rAAV transduction that extends to the organismic level exposes a new means of modulating vector targeting.
Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2
Authors: Prescott Emma L. , Brimacombe Claire L. , Hartley Margaret , Bell Ian , Graham Sheila , Roberts Sally
Published: August 2014

The serine-arginine-specific protein kinase SRPK1 is a common binding partner of the E1^E4 protein of diverse human papillomavirus types. We show here for the first time that the interaction between HPV1 E1^E4 and SRPK1 leads to potent inhibition of SRPK1 phosphorylation of host serine-arginine (SR) proteins that have critical roles in mRNA metabolism, including pre-mRNA processing, mRNA export, and translation. Furthermore, we show that SRPK1 phosphorylates serine residues of SR/RS dipeptides in the hinge region of the HPV1 E2 protein in
in vitro
kinase assays and that HPV1 E1^E4 inhibits this phosphorylation. After mutation of the putative phosphoacceptor serine residues, the localization of the E2 protein was altered in primary human keratinocytes; with a significant increase in the cell population showing intense E2 staining of the nucleolus. A similar effect was observed following coexpression of E2 and E1^E4 that is competent for inhibition of SRPK1 activity, suggesting that the nuclear localization of E2 is sensitive to E1^E4-mediated SRPK1 inhibition. Collectively, these data suggest that E1^E4-mediated inhibition of SRPK1 could affect the functions of host SR proteins and those of the virus transcription/replication regulator E2. We speculate that the novel E4 function identified here is involved in the regulation of E2 and SR protein function in posttranscriptional processing of viral transcripts.

IMPORTANCE
The HPV life cycle is tightly linked to the epithelial terminal differentiation program, with the virion-producing phase restricted to differentiating cells. While the most abundant HPV protein expressed in this phase is the E4 protein, we do not fully understand the role of this protein. Few E4 interaction partners have been identified, but we had previously shown that E4 proteins from diverse papillomaviruses interact with the serine-arginine-specific protein kinase SRPK1, a kinase important in the replication cycles of a diverse range of DNA and RNA viruses. We show that HPV1 E4 is a potent inhibitor of this host cell kinase. We show that E4 inhibits SRPK1 phosphorylation, not only of cellular SR proteins involved in regulating alternative splicing of RNA but also the viral transcription/replication regulator E2. Our findings reveal a potential E4 function in regulation of viral late gene expression through the inhibition of a host cell kinase.
Chlorovirus PBCV-1 Encodes an Active Copper-Zinc Superoxide Dismutase
Authors: Kang Ming , Duncan Garry A. , Kuszynski Charles , Oyler George , Zheng Jiayin , Becker Donald F. , Van Etten James L.
Published: August 2014

Superoxide dismutases (SODs) are metalloproteins that protect organisms from toxic reactive oxygen species by catalyzing the conversion of superoxide anion to hydrogen peroxide and molecular oxygen. Chlorovirus PBCV-1 encodes a 187-amino-acid protein that resembles a Cu-Zn SOD with all of the conserved amino acid residues for binding copper and zinc (named cvSOD). cvSOD has an internal Met that results in a 165-amino-acid protein (named tcvSOD). Both cvSOD and tcvSOD recombinant proteins inhibited nitroblue tetrazolium reduction of superoxide anion generated in a xanthine-xanthine oxidase system in solution. tcvSOD was chosen for further characterization because it was easier to produce. Recombinant tcvSOD also inhibited a riboflavin photochemical reduction system in a polyacrylamide gel assay, which was blocked by the Cu-Zn SOD inhibitor cyanide but not by azide, which inhibits Fe and Mn SODs. A
k
cat
/

K
m

value for cvSOD was determined by stop-flow spectrophotometry as 1.28 × 10
8
M
−1
s
−1
, suggesting that cvSOD-catalyzed O
2
−
dismutation was not a diffusion controlled encounter. The
cvsod
gene was expressed as a late gene, and cvSOD activity was detected in purified virions. Superoxide accumulated rapidly during virus infection, and circumstantial evidence indicates that cvSOD aids its decomposition to benefit virus replication. Cu-Zn SOD homologs have been described to occur in 3 other families of large DNA viruses, poxviruses, baculoviruses, and mimiviruses, which group as a clade. Interestingly, cvSOD does not group in the same clade as the other virus SODs but instead groups in an expanded clade that includes Cu-Zn SODs from many cellular organisms.

IMPORTANCE
Virus infection often leads to an increase in toxic reactive oxygen species in the host, which can be detrimental to virus replication. Viruses have developed various ways to overcome this barrier. As reported in this article, the chloroviruses often encode and package a functional Cu-Zn superoxide dismutase in the virion that presumably lowers the concentration of reactive oxygen induced early during virus infection.
Lysine 63-Linked TANK-Binding Kinase 1 Ubiquitination by Mindbomb E3 Ubiquitin Protein Ligase 2 Is Mediated by the Mitochondrial Antiviral Signaling Protein
Authors: Ye Jung Sook , Kim Nari , Lee Kyoung Jin , Nam Young Ran , Lee Uk , Joo Chul Hyun
Published: August 2014

Beta interferon (IFN-β) is involved in a wide range of cellular functions, and its secretion must be tightly controlled to inhibit viral spreading while minimizing cellular damage. Intracellular viral replication triggers cellular signaling cascades leading to the activation of the transcription factors NF-κB and interferon regulatory factor 3 (IRF3) and IRF7 (IRF3/7), which synergistically bind to the IFN-β gene promoter to induce its expression. The mitochondrial antiviral signaling protein (MAVS) is a governing adaptor protein that mediates signaling communications between virus-sensing proteins and transcription factors. The activity of MAVS in the regulation of IFN-β secretion is affected by many cellular factors. However, the mechanism of MAVS-mediated IRF3/7 activation is not completely understood. Here, we identified a highly conserved DLAIS motif at amino acid positions 438 to 442 of MAVS that is indispensable for IRF3/7 activation. Specifically, the L439S and A440R mutations suppress IRF3/7 activation. Pulldown experiments using wild-type and mutant MAVS showed that mindbomb E3 ubiquitin protein ligase 2 (MIB2) binds to the DLAIS motif. Furthermore, the DLAIS motif was found to be critical for MIB2 binding, the ligation of K63-linked ubiquitin to TANK-binding kinase 1, and phosphorylation-mediated IRF3/7 activation. Our results suggest that MIB2 plays a putative role in MAVS-mediated interferon signaling.

IMPORTANCE
Mitochondrial antiviral signaling protein (MAVS) mediates signaling from virus-sensing proteins to transcription factors for the induction of beta interferon. However, the mechanism underlying activation of MAVS-mediated interferon regulatory factors 3 and 7 (IRF3/7) is not completely understood. We found a highly conserved DLAIS motif in MAVS that is indispensable for IRF3/7 activation through TANK-binding kinase 1 (TBK1) and identified it as the binding site for mindbomb E3 ubiquitin protein ligase 2 (MIB2). The mutations that targeted the DLAIS motif abolished MIB2 binding, attenuated the K63-linked ubiquitination of TBK1, and decreased the phosphorylation-mediated activation of IRF3/7.
Cellular Requirements for Bovine Immunodeficiency Virus Vif-Mediated Inactivation of Bovine APOBEC3 Proteins
Authors: Zhang Wenyan , Wang Hong , Li Zhaolong , Liu Xin , Liu Guanchen , Harris Reuben S. , Yu Xiao-Fang
Published: August 2014

Human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) viral infectivity factor (Vif) form a CRL5 E3 ubiquitin ligase complex to suppress virus restriction by host APOBEC3 (A3) proteins. The primate lentiviral Vif complex is composed of the unique cofactor core binding factor β (CBF-β) and canonical ligase components Cullin 5 (CUL5), Elongin B/C (ELOB/C), and RBX2. However, the mechanism by which the Vif protein of the related lentivirus bovine immunodeficiency virus (BIV) overcomes its host A3 proteins is less clear. In this study, we show that BIV Vif interacts with Cullin 2 (CUL2), ELOB/C, and RBX1, but not with CBF-β or CUL5, to form a CRL2 E3 ubiquitin ligase and degrade the restrictive bovine A3 proteins (A3Z2Z3 and A3Z3). RNA interference-mediated knockdown of ELOB or CUL2 inhibited BIV Vif-mediated degradation of these A3 proteins, whereas knockdown of CUL5 or CBF-β did not. BIV Vif with mutations in the BC box (Vif SLQ-AAA) or putative VHL box (Vif YI-AA), which cannot interact with ELOB/C or CUL2, respectively, lost the ability to counteract bovine A3 proteins. Moreover, CUL2 and UBE2M dominant negative mutants competitively inhibited the BIV Vif-mediated degradation mechanism. Thus, although the general strategy for inhibiting A3 proteins is conserved between HIV-1/SIV and BIV, the precise mechanisms can differ substantially, with only the HIV-1/SIV Vif proteins requiring CBF-β as a cofactor, HIV-1/SIV Vif using CUL5-RBX2, and BIV Vif using CUL2-RBX1.

IMPORTANCE
Primate lentivirus HIV-1 and SIV Vif proteins form a ubiquitin ligase complex to target host antiviral APOBEC3 proteins for degradation. However, the mechanism by which the nonprimate lentivirus BIV Vif inhibits bovine APOBEC3 proteins is unclear. In the present study, we determined the mechanism for BIV Vif-mediated degradation of bovine APOBEC3 proteins and found that it differs from the mechanism of HIV-1/SIV Vif by being CBF-β independent and requiring different ubiquitin ligase scaffolding proteins (CUL2-RBX1 instead of CUL5-RBX2). BIV Vif is the only known retroviral protein that can interact with CUL2. This information broadens our understanding of the distinct mechanisms by which the Vif proteins of different lentiviruses facilitate viral infection. This novel mechanism for assembly of the BIV Vif-APOBEC3 ubiquitin ligase complex advances our understanding of viral hijacking of host E3 ubiquitin ligases and illustrates the evolutionary flexibility of lentiviruses.
The Endoplasmic Reticulum Stress Sensor IRE1α Protects Cells from Apoptosis Induced by the Coronavirus Infectious Bronchitis Virus
Authors: Fung To Sing , Liao Ying , Liu Ding Xiang
Published: August 2014

The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1α-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1α protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1α appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1α antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC–alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1α is activated in IBV-infected cells and serves as a survival factor during coronavirus infection.

IMPORTANCE
Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1α), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1α is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis.
Recurrent lip swelling: a diagnostic challenge
Authors: Lakhani Sonam , Barnett Sheena , Tappuni Anwar R , Rajakulasingam Raj K
Published: August 2014

A Caucasian woman in her late 20s was referred to the allergy/chest clinic by her general practitioner with an 8-month history of recurrent facial angio-oedema. She had no history of urticaria or airways symptoms and denied any similar problems previously. She had no family history of similar illness and was not on any regular medications. There was no history of atopy. Initially, a clinical diagnosis of idiopathic angio-oedema was made. Despite being treated with several antihistamines with doses equivalent to 40 mg of cetirizine/day, her problem had failed to respond satisfactorily. Later on, she also revealed history of intermittent gastrointestinal symptoms such as abdominal pain and diarrhoea. Routine investigations were unremarkable. The patient was referred to a dermatology clinic and a diagnosis of orofacial granulomatosis was suggested: a rare granulomatous disease presenting with lip enlargement, which may or may not be associated with Crohn's disease. A biopsy of the oral mucosa was consistent with this diagnosis.
Use of imiquimod for residual acral melanoma
Authors: Sue Gloria R , Hanlon Allison , Lazova Rossitza , Narayan Deepak
Published: August 2014

Recent reports suggest that topical imiquimod cream is an effective treatment option for certain types of melanomas. No reports exist on the efficacy of using imiquimod cream to treat melanoma located on the plantar surface of the foot. We present two patients with a melanoma of the foot who had residual melanoma following surgical excision with acceptable margins. The patients were then treated with topical imiquimod for 8 weeks after which a repeat biopsy of the affected region showed no evidence of residual melanoma in situ. The use of topical imiquimod cream should be considered in the management of residual melanoma in situ of the plantar surface of the foot.
Therapeutic challenges of pancreatic ascites and the role of endoscopic pancreatic stenting
Authors: Karlapudi Sudhakar , Hinohara Tomoya , Clements James , Bakis Gene
Published: August 2014

Management of pancreatic ascites poses significant therapeutic challenges. Treatment usually consists of either conservative management or interventional therapy with little consensus between the two options. Conservative therapy is the most common initial treatment option but has high failure rates hence arguing for interventional therapy as a preferred primary treatment option. Endoscopic treatment is particularly appealing due to lower failure rates and mortality than conservative therapy or surgery. We describe a patient with recurrent pancreatic ascites who was successfully managed with endoscopic transpapillary stenting. This report contributes to the limited but growing literature on the management of pancreatic ascites.
Overlooked radiographic finding results in delayed diagnosis of a retained oesophageal foreign body
Authors: Iwama Itaru
Published: August 2014

Ingestion of foreign bodies in children is a commonly occurring event worldwide. Swallowed foreign bodies usually pass successfully through the alimentary canal, from the mouth to the anus, but occasionally they may become lodged in the lumen of the oesophagus and cause complications. Accurate diagnosis of a retained foreign body is crucial in anticipating and preventing complications, but diagnostic delay can occur. We present a case of delayed diagnosis of a foreign body ingestion in an infant. Based on our experience, we emphasise the importance of accurate interpretation of X-rays with particular attention paid to the region of highest suspicion by the first touch physician.
Isolated oedema of the uvula induced by intense snoring and ACE inhibitor
Authors: Rasmussen Eva Rye , Mey Kristianna , Bygum Anette
Published: August 2014

A case of snoring-induced angioedema of uvula is described in a patient who was treated with ACE inhibitor. The patient partially responded to complement C1-inhibitor concentrate and did not suffer any recurrences after the medication was withdrawn. When encountering a patient suffering from swellings of the orofacial area it should be considered whether the mechanism is mast-cell associated or not, as classical antiallergic treatment is ineffective in non-mast-cell-associated disease (ie, bradykinin-mediated angioedema). Other causes of uvular oedema are also discussed.
Diagnostic accuracy of lateral neck radiography in ruling out supraglottitis: a prospective observational study
Authors: Fujiwara Takashi , Okamoto Hiroshi , Ohnishi Yasuhiro , Fukuoka Toshio , Ichimaru Kazuyuki
Published: August 2014

Objective

To assess the diagnostic accuracy of lateral neck radiographs (LNR) for acute supraglottitis in adults.

Design

A single centre prospective observational study.

Setting

Emergency department at Kurashiki Central Hospital, Japan.

Participants

Adult patients who underwent LNR to detect supraglottitis.

Main outcome measures

Presence of supraglottitis, based on nasopharyngeal laryngoscopy or a follow-up telephone call, 7–30 days after the visit.

Results

140 patients had LNR during the study period. 35 patients were excluded from further analysis because of lack of consent. Of the 105 eligible patients, 21 patients (20%) were given the diagnosis of supraglottitis: 17 of 29 with a radiographic abnormality, and 4 of 76 patients without a radiographic abnormality. Three of the four cases where LNR was negative was grade 1, and all cases of grade 3 or higher had abnormal LNR. Sensitivity and specificity (95% CI) of LNR for supraglottitis were 81.0% (64.2 to 97.7) and 85.7% (78.2 to 93.2), respectively. The positive predictive value of LNR was 58.6% (40.7 to 76.5) and the negative predictive value was 94.7% (89.7 to 99.8). The positive likelihood ratio of LNR was 5.67 (3.27 to 9.82) and the negative likelihood ratio was 0.22 (0.10 to 0.51).

Conclusions

LNR showed only moderate sensitivity and specificity for supraglottitis and would miss some cases of supraglottitis if the pre-test probability is high. LNR was very sensitive for grade 3 or higher supraglottitis, but would miss milder cases.

Trial registration

UMIN000011928.
A prospective, observational, multicentre study comparing tenecteplase facilitated PCI versus primary PCI in Indian patients with STEMI (STEPP—AMI)
Authors: Victor Suma M , Subban Vijayakumar , Alexander Thomas , G Bahuleyan C , Srinivas Arun , S Selvamani , Mullasari Ajit S
Published: August 2014

Objective

To compare the efficacy of pharmacoinvasive strategy versus primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). Primary PCI is the preferred treatment for STEMI, but it is not a feasible option for many. A pharmacoinvasive strategy might be a practical solution in the Indian context, although few empirical data exist to guide this approach.

Methods

This is a prospective, observational, multicentre pilot study. Two hundred consecutive patients with STEMI aged 18–75 years, presenting within 12 h of onset of symptoms and requiring a reperfusion strategy, were studied from five primary PCI capable centres in South India. Patients who opted for pharmacoinvasive strategy (n=45) formed group A. Group B consisted of patients treated with primary PCI (n=155). One patient was lost to follow-up at 1 year. The primary end point was a composite of death, cardiogenic shock, reinfarction, repeat revascularisation of a culprit artery and congestive heart failure at 30 days.

Results

The primary end point occurred in 11.1% in group A and in 3.9% in group B, p=0.07 (RR=2.87; 95% CI 0.92 to 8.97). The infarct-related artery patency at angiogram was 82.2% in group A and 22.6% in group B (p<0.001). PCI was performed in 73.3% in group A versus 100% in group B (p<0.001), and a thrombus was present in 26.7% in group A versus 63.2% in group B (p<0.001). Failed fibrinolysis occurred in 12.1% in group A. There was no difference in bleeding risk, 2.2% in group A versus 0.6% in group B, (p=0.4).

Conclusions

This pilot study shows that a pharmacoinvasive strategy can be implemented in patients not selected for primary PCI in India and hints at the possibility of similar outcomes. Larger studies are required to confirm these findings.

Trial registration number

Trial is registered with Clinical trial registry of India, CTRI number: REF/2011/07/002556.
Suspect West Nile encephalitis in a horse imported into the UK from Europe
Authors: Fooks A. R. , Horton D. L. , Phipps L. P. , Mansfield K. L. , McCracken F. , Jeffries C. L. , Johnson N. , Wrigley S. , Deuchande R. , Toth B. , Alzola R.
Published: August 2014

The authors have detected West Nile virus‐specific antibodies in a horse in the UK with signs of neurological disease. The horse had recently been imported from Europe and does not represent a threat for onward transmission itself, but highlights the need for vigilance for this zoonotic vector‐borne disease in the UK.
Foliations of Minkowski 2 + 1 spacetime by crooked planes
Authors: Charette Virginie , Kim Youngju
Published: August 2014

Given a regular curve in Minkowski spacetime, we describe necessary and sufficient conditions for this curve to support a family of pairwise-disjoint crooked planes. Using this criterion, we describe crooked foliations along orbit curves of one-parameter groups of Lorentzian isometries.
Search for direct and indirect unitarity violation in neutrino oscillation experiments
Authors: Luo Shu
Published: August 2014

If three standard neutrinos mix with other degree of freedoms like sterile neutrinos, no matter how heavy the sterile neutrino masses are, it could result in the unitarity violation in the MNSP matrix. Nevertheless, the unitarity violation induced by the existence of light or heavy sterile neutrinos can have very different effects on neutrino oscillations, we call the former case direct unitarity violation and the later case the indirect unitarity violation. We will explain in this paper the difference of these two kinds of unitarity violations, then focus on the possibilities of searching the unitarity violation in neutrino oscillation experiments, of which the precision reactor experiments with multiple baselines are discussed in detail.
Interplay of flavor and collider physics
Authors: Mahmoudi Farvah
Published: August 2014

We present an overview on the interplay between direct searches for new physics at the LHC and indirect constraints from flavor physics, with an emphasis on the implications of the recent LHCb results. The complementarity with the Higgs search results will also be addressed. We show the correlations and complementarity between the different sectors in the context of a few specific scenarios in supersymmetry.
Light-front holographic QCD and color confinement
Authors: Brodsky Stanley J. , de Teramond Guy F. , Dosch Hans Günter
Published: August 2014

One of the most fundamental problems in Quantum Chromodynamics is to understand the origin of the mass scale which controls the range of color confinement and the hadronic spectrum. For example, if one sets the Higgs couplings of quarks to zero, then no mass parameters appear in the QCD Lagrangian, and the theory is conformal at the classical level. Nevertheless, hadrons have a finite mass. We show that a mass gap and a fundamental color confinement scale arise when one extends the formalism of de Alfaro, Fubini and Furlan (dAFF) to frame-independent light-front Hamiltonian theory. Remarkably, the resulting light-front potential has a unique form of a harmonic oscillator in the light-front invariant impact variable if one requires that the action remains conformally invariant. The result is a single-variable relativistic equation of motion for [Formula: see text] bound states, a "Light-Front Schrödinger Equation," analogous to the nonrelativistic radial Schrödinger equation, which incorporates color confinement and other essential spectroscopic and dynamical features of hadron physics, including a massless pion for zero quark mass and linear Regge trajectories with the same slope in the radial quantum number and orbital angular momentum. The same light-front equations with the correct hadron spin dependence arise from the holographic mapping of "soft-wall model" modification of AdS5 space with a specific dilaton profile. The corresponding light-front Dirac equation provides a dynamical and spectroscopic model of nucleons. A fundamental mass parameter κ appears, determining the hadron masses and the length scale which underlies hadron structure. Quark masses can be introduced to account for the spectrum of strange hadrons. This Light-Front Holographic approach predicts not only hadron spectroscopy successfully, but also hadron dynamics — hadronic form factors, the QCD running coupling at small virtuality, the light-front wavefunctions of hadrons, ρ electroproduction, distribution amplitudes, valence structure functions, etc. Thus the combination of light-front dynamics, its holographic mapping to gravity in a higher-dimensional space and the dAFF procedure provides new insight into the physics underlying color confinement, chiral invariance, and the QCD mass scale, among the most profound questions in physics.
Dark matter, dark energy and the time evolution of masses in the universe
Authors: Solà Joan
Published: August 2014

The traditional "explanation" for the observed acceleration of the universe is the existence of a positive cosmological constant. However, this can hardly be a truly convincing explanation, as an expanding universe is not expected to have a static vacuum energy density. So, it must be an approximation. This reminds us of the so-called fundamental "constants" of nature. Recent and past measurements of the fine structure constant and of the proton–electron mass ratio suggest that basic quantities of the standard model, such as the QCD scale parameter, Λ QCD , might not be conserved in the course of the cosmological evolution. The masses of the nucleons and of the atomic nuclei would be time-evolving. This can be consistent with General Relativity provided the vacuum energy itself is a dynamical quantity. Another framework realizing this possibility is QHD (Quantum Haplodynamics), a fundamental theory of bound states. If one assumes that its running couplings unify at the Planck scale and that such scale changes slowly with cosmic time, the masses of the nucleons and of the DM particles, including the cosmological term, will evolve with time. This could explain the dark energy of the universe.
Black hole emission of vector particles in (1+1) dimensions
Authors: Kruglov S. I.
Published: August 2014

We investigate the radiation of spin-1 particles by black holes in (1+1) dimensions within the Proca equation. The process is considered as quantum tunneling of bosons through an event horizon. It is shown that the emission temperature for the Schwarzschild background geometry is the same as the Hawking temperature corresponding to scalar particles emission. We also obtain the radiation temperatures for the de Sitter, Rindler and Schwarzschild–de Sitter space–times. In a particular case when two horizons in Schwarzschild–de Sitter space–time coincides, the Nariai temperature is recovered. The thermodynamical entropy of a black hole is calculated for Schwarzschild–de Sitter space–time having two horizons.
SU(8) family unification with boson–fermion balance
Authors: Adler Stephen L.
Published: August 2014

We formulate an SU(8) family unification model motivated by requiring that the theory should incorporate the graviton, gravitinos, and the fermions and gauge fields of the standard model, with boson–fermion balance. Gauge field SU(8) anomalies cancel between the gravitinos and spin ½ fermions. The 56 of scalars breaks SU(8) to SU(3) family × SU(5) × U(1)/Z5, with the fermion representation content needed for "flipped" SU(5) with three families, and with residual scalars in the 10 and [Formula: see text] representations that break flipped SU(5) to the standard model. Dynamical symmetry breaking can account for the generation of 5 representation scalars needed to break the electroweak group. Yukawa couplings of the 56 scalars to the fermions are forbidden by chiral and gauge symmetries, so in the first stage of SU(8) breaking fermions remain massless. In the limit of vanishing gauge coupling, there are N = 1 and N = 8 supersymmetries relating the scalars to the fermions, which restrict the form of scalar self-couplings and should improve the convergence of perturbation theory, if not making the theory finite and "calculable." In an Appendix we give an analysis of symmetry breaking by a Higgs component, such as the (1, 1)(-15) of the SU(8) 56 under SU(8) ⊃ SU(3) × SU(5) × U(1), which has nonzero U(1) generator.
Detecting the Determinant Attributes of Entrepreneurial Orientation within the Italian University Departments
Authors: Riviezzo Angelo
Published: August 2014

In the context of public universities the use of the entrepreneurial orientation construct is not widespread and still there is no precise definition of what it means. It is, in fact, necessary to consider the peculiarities of universities and then adopt a coherent operationalization of the construct. The main aim of this paper is to identify the determinant attributes of the entrepreneurial orientation within the Italian universities. To this aim, the study moves from a recent and innovative definition of the public universities' entrepreneurial orientation proposed in the literature, and is based on survey data from 103 Italian university departments. A multiple regression analysis and an importance-performance analysis are used to investigate the relationship between the dimensions and the single items used to operationalize the entrepreneurial orientation and the entrepreneurial orientation perceived by the surveyed department heads. The findings show that not all the dimensions and the items considered affect in the same way the Italian university entrepreneurial orientation. Implications and limitations are discussed.
An Estimated Model of New Venture Creation: Theories and Determinants in Tunisia
Authors: Khefacha Islem , Belkacem L. , Mansouri F.
Published: August 2014

The main purpose of this research is to investigate the relationship between the new venture decision and a series of social, demographic, and cultural factors in Tunisia. Even though these factors have been the subject of several entrepreneurship studies, it is still difficult to identify which one impact significantly the decision to create a new enterprise. Data has been provided by the National Tunisian Global Entrepreneurship Monitor 2010 Project, based on the analysis of a sample of 339 cases. Through the utilization of a logistical regression, the main findings of the study show that the interaction between the three factors "perceived opportunities", "network" and "knowing other entrepreneurs" increase significantly the probability to create a new venture, while the main effect of "knowing other entrepreneurs" has a negative impact. We discuss the implications of our results for policy-makers with useful information in designing and implementing policies to promote enterprise development.
Single File Dynamics Advances with a Focus on Biophysical Relevance
Authors: Flomenbom Ophir
Published: August 2014

In this review (appearing in the Special Issue on single file dynamics in biophysics and related extensions), three recently treated variants in file dynamics are presented: files with density that is not fixed, files with heterogeneous particles, and files with slow particles. The results in these files include:

• In files with a density law that is not fixed, but decays as a power law with an exponent a the distance from the origin, the particle in the origin mean square displacement (MSD) scales like MSD ~ t[1+a]/2, with a Gaussian probability density function (PDF). This extends the scaling, MSD ~ t1/2, seen in a constant density file.

• When, in addition, the particles' diffusion coefficients are distributed like a power law with an exponent γ (around the origin), the MSD follows MSD ~ t[1-γ]/[2/(1+a) - γ], with a Gaussian PDF.

• In anomalous files that are renewal, namely, when all particles attempt a jump together, yet, with jump times taken from a PDF that decays as a power law with an exponent -1 - ε, ψ(t) ~ t-1-ε, the MSD scales like the MSD of the corresponding normal file, in the power ε.

• In anomalous files of independent particles, the MSD is very slow and scales like MSD ~ log2(t). Even more exciting, the particles form clusters, defining a dynamical phase transition: depending on the anomaly power ε, the percentage of particles in clusters ξ follows [Formula: see text], yet when ε > 1, fluidity rather than clusters is seen.

We talk about utilizing these results while focusing on biophysical processes and applications: dynamics in channels, membranes, biosensors, etc.

[Formula: see text] Special Issue Comments: In this article, results about recently suggested variants in single file dynamics appear: heterogeneous files and slow files, yet also, the relevance with biophysical processes. It is related to the Special Issue articles about expansions in files,61files with force,62and the zig zag occurrences in files.63
Minimizing Stack and Communication Memory Usage in Real-Time Embedded Applications
Authors: Zeng Haibo , Natale Marco Di , Zhu Qi
Published: August 2014

In the development of real-time embedded applications, especially those on systems-on-chip, an efficient use of RAM memory is as important as the effective scheduling of the computation resources. The protection of communication and state variables accessed by concurrent tasks must provide real-time schedulability guarantees while using the least amount of memory. Several schemes, including preemption thresholds, have been developed to improve schedulability and save stack space by selectively disabling preemption. However, the design synthesis problem is still open. In this article, we target the assignment of the scheduling parameters to minimize memory usage for systems of practical interest, including designs compliant with automotive standards. We propose algorithms either proven optimal or shown to improve on randomized optimization methods like simulated annealing.
Visualising evolutionary search spaces
Authors: McDermott James
Published: August 2014

Understanding the structure of search spaces can help us to design better search algorithms, and it is natural to try to understand search spaces by visualising them. For typical evolutionary search spaces, like the space of genetic programming trees, visualising them directly is impossible, because of their large dimensionality. However, we can use the idea of
distances
on search spaces to project them into two dimensions, expose their structure, and obtain useful and attractive visualisations.
Unshackling evolution
Authors: Cheney Nick , MacCurdy Robert , Clune Jeff , Lipson Hod
Published: August 2014

In 1994, Karl Sims' evolved virtual creatures showed the potential of evolutionary algorithms to produce natural, complex morphologies and behaviors [30]. One might assume that nearly 20 years of improvements in computational speed and evolutionary algorithms would produce far more impressive organisms, yet the creatures evolved in the field of artificial life today are not obviously more complex, natural, or intelligent. Fig. 2 demonstrates an example of similar complexity in robots evolved 17 years apart.
Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons
Authors: Mohammed Mazher , Ootsuka Youichirou , Yanagisawa Masashi , Blessing William
Published: August 2014

Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24–26°C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is “spontaneous” and when the interaction is provoked by threatening or salient environmental events.
Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice
Authors: Leelahavanichkul Asada , Souza Ana Carolina P. , Street Jonathan M. , Hsu Victor , Tsuji Takayuki , Doi Kent , Li Lingli , Hu Xuzhen , Zhou Hua , Kumar Parag , Schnermann Jürgen , Star Robert A. , Yuen Peter S. T.
Published: August 2014

Acute kidney injury (AKI) dramatically increases sepsis mortality, but AKI diagnosis is delayed when based on serum creatinine (SCr) changes, due in part, to decreased creatinine production. During experimental sepsis, we compared serum cystatin C (sCysC), SCr, and blood urea nitrogen (BUN) to inulin glomerular filtration rate (iGFR) before or 3–18 h after cecal ligation and puncture (CLP)-induced sepsis in CD-1 mice. sCysC had a faster increase and reached peak levels more rapidly than SCr in both sepsis and bilateral nephrectomy (BiNx) models. sCysC was a better surrogate of iGFR than SCr during sepsis. Combining sCysC with SCr values into a composite biomarker improved correlation with iGFR better than any biomarker alone or any other combination. We determined the renal contribution to sCysC handling with BiNx. sCysC and SCr were lower post-BiNx/CLP than post-BiNx alone, despite increased inflammatory and nonrenal organ damage biomarkers. Sepsis decreased CysC production in nephrectomized mice without changing body weight or CysC space. Sepsis decreased sCysC production and increased nonrenal clearance, similar to effects of sepsis on SCr. sCysC, SCr, and BUN were measured 6 h postsepsis to link AKI with mortality. Mice with above-median sCysC, BUN, or SCr values 6 h postsepsis died earlier than mice with below-median values, corresponding to a substantial AKI association with sepsis mortality in this model. sCysC performs similarly to SCr in classifying mice at risk for early mortality. We conclude that sCysC detects AKI early and better reflects iGFR in CLP-induced sepsis. This study shows that renal biomarkers need to be evaluated in specific contexts.
A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation
Authors: McGee Meredith J. , Danziger Zachary C. , Bamford Jeremy A. , Grill Warren M.
Published: August 2014

Electrical stimulation of pudendal afferents can inhibit bladder contractions and increase bladder capacity. Recent results suggest that stimulation-evoked bladder inhibition is mediated by a mechanism other than activation of sympathetic bladder efferents in the hypogastric nerve, generating α-adrenergic receptor-mediated inhibition at the vesical ganglia and/or β-adrenergic receptor-mediated direct inhibition of the detrusor muscle. We investigated several inhibitory neurotransmitters that may instead be necessary for stimulation-evoked inhibition and found that intravenous picrotoxin, a noncompetitive GABAAantagonist, significantly and reversibly blocked pudendal afferent stimulation-evoked inhibition of bladder contractions in a dose-dependent manner. Similarly, intravenous picrotoxin also blocked pudendal afferent stimulation-evoked inhibition of nociceptive bladder contractions evoked by acetic acid infusion. Furthermore, intrathecal administration of picrotoxin at the lumbosacral spinal cord also blocked bladder inhibition by pudendal afferent stimulation. On the other hand, glycinergic, adrenergic, or opioidergic mechanisms were not necessary for bladder inhibition evoked by pudendal afferent stimulation. These results identify a lumbosacral spinal GABAergic mechanism of bladder inhibition evoked by pudendal afferent stimulation.
Semicarbazide-sensitive amine oxidase (SSAO) inhibition ameliorates kidney fibrosis in a unilateral ureteral obstruction murine model
Authors: Wong May , Saad Sonia , Zhang Jie , Gross Simon , Jarolimek Wolfgang , Schilter Heidi , Chen Jason A. , Gill Anthony J. , Pollock Carol A. , Wong Muh Geot
Published: August 2014

Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme known for its dual function in mediating inflammation and reactive oxygen species production. However, the role of SSAO inhibitors in limiting kidney fibrosis is unclear. We aimed to determine the effectiveness of a SSAO inhibitor (SSAOi; PXS4728A) as an antifibrotic agent using a 7-day unilateral ureteric obstruction (UUO) model of acute kidney fibrosis in 6- to 8-wk-old mice. The experimental groups were 1) Sham operated; 2) UUO; 3) UUO+SSAOi (2 mg/kg); 4) UUO+telmisartan, an angiotensin receptor blocker (3 mg/kg); and 5) UUO+SSAOi+telmisartan. Kidney tissue was analyzed for histological evidence of tubulointerstitial fibrosis, nitrotyrosine staining, and mRNA expression of markers associated with fibrosis and inflammation. Kidney SSAO activity was determined by radiometric [14C]benzylamine methodology. Our results show that SSAOi effectively suppresses UUO-mediated SSAO activity. Extracellular matrix markers, namely, fibronectin, collagen IV protein, and nitrotyrosine staining, were lower in UUO+SSAOi mice compared with untreated UUO mice. This was consistent with the attenuated mRNA expression of collagen IV and fibronectin. SSAOi effectively inhibited transforming growth factor-β1 (TGF-β1) and monocyte chemoattractant protein-1 (MCP-1) expression to a similar extent to that observed with telmisartan. Individually, SSAOi and telmisartan induced a reduction in interstitial leukocyte and macrophage accumulation. However, the combination of SSAOi and telmisartan was more effective at reducing inflammatory cell infiltration. These results demonstrate that SSAO inhibition significantly suppresses profibrotic and proinflammatory cytokine secretion, reduces oxidative stress, and limits inflammatory cell accumulation and extracellular matrix expression in an acute model of renal fibrosis.
Reversible deactivation of higher-order posterior parietal areas. I. Alterations of receptive field characteristics in early stages of neocortical processing
Authors: Cooke Dylan F. , Goldring Adam B. , Baldwin Mary K. L. , Recanzone Gregg H. , Chen Arnold , Pan Tingrui , Simon Scott I. , Krubitzer Leah
Published: August 2014

Somatosensory processing in the anesthetized macaque monkey was examined by reversibly deactivating posterior parietal areas 5L and 7b and motor/premotor cortex (M1/PM) with microfluidic thermal regulators developed by our laboratories. We examined changes in receptive field size and configuration for neurons in areas 1 and 2 that occurred during and after cooling deactivation. Together the deactivated fields and areas 1 and 2 form part of a network for reaching and grasping in human and nonhuman primates. Cooling area 7b had a dramatic effect on receptive field size for neurons in areas 1 and 2, while cooling area 5 had moderate effects and cooling M1/PM had little effect. Specifically, cooling discrete locations in 7b resulted in expansions of the receptive fields for neurons in areas 1 and 2 that were greater in magnitude and occurred in a higher proportion of sites than similar changes evoked by cooling the other fields. At some sites, the neural receptive field returned to the precooling configuration within 5–22 min of rewarming, but at other sites changes in receptive fields persisted. These results indicate that there are profound top-down influences on sensory processing of early cortical areas in the somatosensory cortex.