bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of the Human RAD51 Nucleofilament Restricts HIV-1 Integration
In Vitro
and in Infected Cells
Authors: Cosnefroy O. , Tocco A. , Lesbats P. , Thierry S. , Calmels C. , Wiktorowicz T. , Reigadas S. , Kwon Y. , De Cian A. , Desfarges S. , Bonot P. , San Filippo J. , Litvak S. , Le Cam E. , Rethwilm A. , Fleury H. , Connell P. P. , Sung P. , Delelis O. , Andréola M. L. , Parissi V.
Published: October 2011

Stable HIV-1 replication requires the DNA repair of the integration locus catalyzed by cellular factors. The human RAD51 (hRAD51) protein plays a major role in homologous recombination (HR) DNA repair and was previously shown to interact with HIV-1 integrase (IN) and inhibit its activity. Here we determined the molecular mechanism of inhibition of IN. Our standard
in vitro
integration assays performed under various conditions promoting or inhibiting hRAD51 activity demonstrated that the formation of an active hRAD51 nucleofilament is required for optimal inhibition involving an IN-DNA complex dissociation mechanism. Furthermore we show that this inhibition mechanism can be promoted in HIV-1-infected cells by chemical stimulation of the endogenous hRAD51 protein. This hRAD51 stimulation induced both an enhancement of the endogenous DNA repair process and the inhibition of the integration step. Elucidation of this molecular mechanism leading to the restriction of viral proliferation paves the way to a new concept of antiretroviral therapy based on the enhancement of endogenous hRAD51 recombination activity and highlights the functional interaction between HIV-1 IN and hRAD51.
Conditional CD8+T Cell Escape during Acute Simian Immunodeficiency Virus Infection
Authors: O'Connor Shelby L. , Becker Ericka A. , Weinfurter Jason T. , Chin Emily N. , Budde Melisa L. , Gostick Emma , Correll Michael , Gleicher Michael , Hughes Austin L. , Price David A. , Friedrich Thomas C. , O'Connor David H.
Published: October 2011

CD8+T cell responses rapidly select viral variants during acute human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection. We used pyrosequencing to examine variation within three SIV-derived epitopes (Gag386-394GW9, Nef103-111RM9, and Rev59-68SP10) targeted by immunodominant CD8+T cell responses in acutely infected Mauritian cynomolgus macaques. In animals recognizing all three epitopes, variation within Rev59-68SP10 was associated with delayed accumulation of variants in Gag386-394GW9 but had no effect on variation within Nef103-111RM9. This demonstrates that the entire T cell repertoire, rather than a single T cell population, influences the timing of immune escape, thereby providing the first example of conditional CD8+T cell escape in HIV/SIV infection.
Fatal Pancreatitis in Simian Immunodeficiency Virus SIV
mac251
-Infected Macaques Treated with 2′,3′-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade
Authors: Vaccari Monica , Boasso Adriano , Fenizia Claudio , Fuchs Dietmar , Hryniewicz Anna , Morgan Tia , Weiss Deborah , Doster Melvin N. , Heraud Jean Michel , Shearer Gene M. , Franchini Genoveffa
Published: October 2011

Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4
+
-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV
mac251
and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-
d
-tryptophan (
d
-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.
Adeno-Associated Virus Type 2 Modulates the Host DNA Damage Response Induced by Herpes Simplex Virus 1 during Coinfection
Authors: Vogel Rebecca , Seyffert Michael , Strasser Regina , de Oliveira Anna P. , Dresch Christiane , Glauser Daniel L. , Jolinon Nelly , Salvetti Anna , Weitzman Matthew D. , Ackermann Mathias , Fraefel Cornel
Published: October 2011

Adeno-associated virus type 2 (AAV2) is a human parvovirus that relies on a helper virus for efficient replication. Herpes simplex virus 1 (HSV-1) supplies helper functions and changes the environment of the cell to promote AAV2 replication. In this study, we examined the accumulation of cellular replication and repair proteins at viral replication compartments (RCs) and the influence of replicating AAV2 on HSV-1-induced DNA damage responses (DDR). We observed that the ATM kinase was activated in cells coinfected with AAV2 and HSV-1. We also found that phosphorylated ATR kinase and its cofactor ATR-interacting protein were recruited into AAV2 RCs, but ATR signaling was not activated. DNA-PKcs, another main kinase in the DDR, was degraded during HSV-1 infection in an ICP0-dependent manner, and this degradation was markedly delayed during AAV2 coinfection. Furthermore, we detected phosphorylation of DNA-PKcs during AAV2 but not HSV-1 replication. The AAV2-mediated delay in DNA-PKcs degradation affected signaling through downstream substrates. Overall, our results demonstrate that coinfection with HSV-1 and AAV2 provokes a cellular DDR which is distinct from that induced by HSV-1 alone.
Secretion Modification Region-Derived Peptide Disrupts HIV-1 Nef's Interaction with Mortalin and Blocks Virus and Nef Exosome Release
Authors: Shelton Martin N. , Huang Ming-Bo , Ali Syed A. , Powell Michael D. , Bond Vincent C.
Published: October 2011

Nef is secreted from infected cells in exosomes and is found in abundance in the sera of HIV-infected individuals. Secreted exosomal Nef (exNef) induces apoptosis in uninfected CD4+T cells and may be a key component of HIV pathogenesis. The exosomal pathway has been implicated in HIV-1 virus release, suggesting a possible link between these two viral processes. However, the underlying mechanisms and cellular components of exNef secretion have not been elucidated. We have previously described a Nef motif, the secretion modification region (SMR; amino acids 66 to 70), that is required for exNef secretion.In silicomodeling data suggest that this motif can form a putative binding pocket. We hypothesized that the Nef SMR binds a cellular protein involved in protein trafficking and that inhibition of this interaction would abrogate exNef secretion. By using tandem mass spectrometry and coimmunoprecipitation with a novel SMR-based peptide (SMRwt) that blocks exNef secretion and HIV-1 virus release, we identified mortalin as an SMR-specific cellular protein. A second set of coimmunoprecipitation experiments with full-length Nef confirmed that mortalin interacts with Nef via Nef's SMR motif and that this interaction is disrupted by the SMRwtpeptide. Overexpression and microRNA knockdown of mortalin revealed a positive correlation between exNef secretion levels and mortalin protein expression. Using antibody inhibition we demonstrated that the Nef/mortalin interaction is necessary for exNef secretion. Taken together, this work constitutes a significant step in understanding the underlying mechanism of exNef secretion, identifies a novel host-pathogen interaction, and introduces an HIV-derived peptide with antiviral properties.
Single-Chain Fv-Based Anti-HIV Proteins: Potential and Limitations
Authors: West Anthony P. , Galimidi Rachel P. , Gnanapragasam Priyanthi N. P. , Bjorkman Pamela J.
Published: October 2011

The existence of very potent, broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) offers the potential for prophylaxis against HIV-1 infection by passive immunization or gene therapy. Both routes permit the delivery of modified forms of IgGs. Smaller reagents are favored when considering ease of tissue penetration and the limited capacities of gene therapy vectors. Immunoadhesin (single-chain fragment variable [scFv]-Fc) forms of IgGs are one class of relatively small reagent that has been explored for delivery by adeno-associated virus. Here we investigated the neutralization potencies of immunoadhesins compared to those of their parent IgGs. For the antibodies VRC01, PG9, and PG16, the immunoadhesins showed modestly reduced potencies, likely reflecting reduced affinities compared to those of the parent IgG, and the VRC01 immunoadhesin formed dimers and multimers with reduced neutralization potencies. Although scFv forms of neutralizing antibodies may exhibit affinity reductions, they provide a means of building reagents with multiple activities. Attachment of the VRC01 scFv to PG16 IgG yielded a bispecific reagent whose neutralization activity combined activities from both parent antibodies. Although the neutralization activity due to each component was partially reduced, the combined reagent is attractive since fewer strains escaped neutralization.
Transcriptional Repression and RNA Silencing Act Synergistically To Demonstrate the Function of the Eleventh Component of the Vaccinia Virus Entry-Fusion Complex
Authors: Wolfe Cindy L. , Ojeda Suany , Moss Bernard
Published: October 2011

Poxviruses have an elaborate system for infecting cells comprising several proteins for attachment and a larger number dedicated to membrane fusion and entry. Thus far, 11 proteins have been identified as components of the vaccinia virus (VACV) entry-fusion complex (EFC), and 10 of these proteins have been shown to be required for entry. J5, the remaining functionally uncharacterized component of the complex, is conserved in all poxviruses, has a predicted C-terminal transmembrane domain, and is an N-terminally truncated paralog of two other EFC proteins. To determine the role of J5, we constructed a mutant that inducibly regulates J5 transcription. Although the virus yield was reduced only about 80% without inducer, the inability to isolate a J5 deletion mutant suggested an essential function. To enhance stringency, we employed RNA silencing alone and together with transcriptional repression of the inducible mutant. The yield of infectious virus was reduced 4- to 5-fold by repression, 2-fold by silencing, and 60-fold by the combination of the two. Virus particles made under the latter conditions appeared to contain a full complement of proteins excluding J5 but had very low infectivity. Further studies indicated that after binding to cells, J5-deficient virions had a defect in core entry and an inability to induce syncytium formation. In addition, we confirmed that J5 is associated with the EFC by affinity purification. These data indicate that J5 is a functional component of the EFC and highlights the advantage of combining transcriptional repression and RNA silencing for stringent reduction of gene expression.
Apparent Expression of Varicella-Zoster Virus Proteins in Latency Resulting from Reactivity of Murine and Rabbit Antibodies with Human Blood Group A Determinants in Sensory Neurons
Authors: Zerboni Leigh , Sobel Raymond A. , Lai Michelle , Triglia Richard , Steain Megan , Abendroth Allison , Arvin Ann
Published: October 2011

Analyses of varicella-zoster virus (VZV) protein expression during latency have been discordant, with rare to many positive neurons detected. We show that ascites-derived murine and rabbit antibodies specific for VZV proteins
in vitro
contain endogenous antibodies that react with human blood type A antigens in neurons. Apparent VZV neuronal staining and blood type A were strongly associated (by a χ
2
test, α = 0.0003). Adsorption of ascites-derived monoclonal antibodies or antiserum with type A erythrocytes or the use of
in vitro
-derived VZV monoclonal antibodies eliminated apparent VZV staining. Animal-derived antibodies must be screened for anti-blood type A reactivity to avoid misidentification of viral proteins in the neurons of the 30 to 40% of individuals who are blood type A.
Human Coronavirus-Induced Neuronal Programmed Cell Death Is Cyclophilin D Dependent and Potentially Caspase Dispensable
Authors: Favreau Dominique J. , Meessen-Pinard Mathieu , Desforges Marc , Talbot Pierre J.
Published: October 2011

Human coronaviruses (HCoV) are recognized respiratory pathogens. Some HCoV strains, including HCoV-OC43, can invade the central nervous system, where they infect neurons, with unclear consequences. We have previously reported that HCoV-OC43 infection of human neurons activates the unfolded-protein response and caspase-3 and induces cell death and that the viral spike (S) glycoprotein is involved in the process. We now report on underlying mechanisms associated with the induction of programmed cell death (PCD) after infection by the reference HCoV-OC43 virus (rOC/ATCC) and a more neurovirulent and cytotoxic HCoV-OC43 variant harboring two point mutations in the S glycoprotein (rOC/U
S183-241
). Even though caspase-3 and caspase-9 were both activated after infection, the use of caspase inhibitors neither reduced nor delayed virus-induced PCD, suggesting that these proteases are not essential in the process. On the other hand, the proapoptotic proteins BAX, cytochrome
c
(CytC), and apoptosis-inducing factor (AIF) were relocalized toward the mitochondria, cytosol, and nucleus, respectively, after infection by both virus variants. Moreover, LA-N-5 neuronal cells treated with cyclosporine (CsA), an inhibitor of the mitochondrial permeabilization transition pore (mPTP), or knocked down for cyclophilin D (CypD) were completely protected from rOC/ATCC-induced neuronal PCD, underlining the involvement of CypD in the process. On the other hand, CsA and CypD knockdown had moderate effects on rOC/U
S183-241
-induced PCD. In conclusion, our results are consistent with mitochondrial AIF and cyclophilin D being central in HCoV-OC43-induced PCD, while caspases appear not to be essential.
Kaposi's Sarcoma-Associated Herpesvirus-Encoded MicroRNA miR-K12-11 Attenuates Transforming Growth Factor Beta Signaling through Suppression of SMAD5
Authors: Liu Yunhua , Sun Rui , Lin Xianzhi , Liang Deguang , Deng Qiang , Lan Ke
Published: October 2011

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs (pre-miRNAs). Current studies have shown that these miRNAs are involved in regulation of viral and host gene expression, implicating a role in the maintenance of viral latency and suppression of antiviral innate immunity. However, the functions of these miRNAs remain largely unknown. On the basis of the sequence homology between oncogenic miR-155 and KSHV-encoded miR-K12-11, we hypothesized that miR-K12-11 could attenuate transforming growth factor β (TGF-β) signaling, facilitating viral infection and tumorigenesis. In the present study, we demonstrated that ectopic expression of miR-K12-11 in Ramos, a TGF-β-sensitive cell line, downregulated TGF-β signaling and facilitated cell proliferation upon TGF-β treatment by directly targeting SMAD5, an important mediator in TGF-β signaling. In addition, the downregulation of SMAD5 by miR-K12-11 was further confirmed in a
de novo
KSHV infection system or latently infected KSHV-positive B-lymphoma cell lines. More importantly, repression of miR-K12-11 by a specific sponge inhibitor restored the expression of SMAD5 in both
de novo
-infected and latently infected cells. Finally, we found that restoration of SMAD5, in addition to the TGF-β type II receptor, which was epigenetically silenced by the latent viral protein latency-associated nuclear antigen, sensitized BC3 cells to the cytostatic effect of TGF-β signaling. Taken together, our findings highlight a novel mechanism in which miR-K12-11 downregulates TGF-β signaling and suggest that viral miRNAs and proteins may exert a dichotomy regulation in virus-induced oncogenesis by targeting the same signaling pathway.
Risk factors of recurrent hamstring injuries: a systematic review
Authors: de Visser HM , Reijman M , Heijboer MP , Bos PK
Published: October 2011

Background

Although recurrent hamstring injury is a frequent problem with a significant impact on athletes, data on factors determining the risk for a recurrent hamstring injury are scarce.

Objective

To systematically review the literature and provide an overview of risk factors for re-injury of acute hamstring muscle injuries.

Study design

Prospective studies on risk factors for re-injury following acute hamstring injuries were systematically reviewed. Medical databases and reference lists of the included articles were searched. Two reviewers independently selected potential studies and assessed methodological quality; one reviewer extracted the data. A best-evidence synthesis of all studied risk factors was performed.

Results

Of the 131 articles identified, five prospective follow-up studies fulfilled our inclusion criteria. These studies reported a recurrence incidence of 13.9–63.3% in the same playing season up to 2 years after initial injury. Limited evidence for three risk factors and one protective factor for recurrent hamstring injury was found; patients with a recurrent hamstring injury had an initial injury with a larger volume size as measured on MRI (47.03 vs 12.42 cm3), more often had a Grade 1 initial trauma (Grade 0: 0–30.4%; Grade 1: 60.9–100%; Grade 2: 8.7%) and more often had a previous ipsilateral anterior cruciate ligament (ACL) reconstruction (66.6% vs 17.1%) independent of graft selection. Athletes in a rehabilitation programme with agility/stabilisation exercises rather than strength/stretching exercises had a lower risk for re-injury (7.7% vs 70%). No significant relationship with re-injury was found for 11 related determinants. There was conflicting evidence that a larger cross-sectional area is a risk factor for recurrent hamstring injury.

Conclusions

There is limited evidence that athletes with a larger volume size of initial trauma, a Grade 1 hamstring injury and a previous ipsilateral ACL reconstruction are at increased risk for recurrent hamstring injury. Athletes seem to be at lower risk for re-injury when following agility/stabilisation exercises.
Asymptomatic coronary heart disease in patients with type 2 diabetes with vascular complications: a cross-sectional study
Authors: Tsujimoto Tetsuro , Kajio Hiroshi , Takahashi Yoshihiko , Kishimoto Miyako , Noto Hiroshi , Yamamoto-Honda Ritsuko , Kamimura Munehiro , Morooka Miyako , Kubota Kazuo , Shimbo Takuro , Hiroe Michiaki , Noda Mitsuhiko
Published: October 2011

Background

Recent studies have suggested that microvascular and macrovascular diseases are associated with coronary events.

Objective

To test the hypothesis that asymptomatic coronary heart disease (CHD) may be present in many patients with diabetes with vascular complications.

Design

From April 2009 to August 2010, the authors conducted a cross-sectional study to assess the prevalence of asymptomatic CHD among patients with type 2 diabetes with vascular complications at a national diabetes centre in Japan. Eligibility criteria included patients with type 2 diabetes with no known CHD and one or more of the following four criteria: (1) proliferative diabetic retinopathy or after photocoagulation; (2) estimated glomerular filtration rate <30 ml/min/1.73 m2or an estimated glomerular filtration rate <45 ml/min/1.73 m2plus albuminuria; (3) peripheral arterial disease; and (4) cerebrovascular disease. Each patient underwent a stress single-photon emission computed tomography; patients with myocardial perfusion abnormalities then underwent coronary angiography.

Results

A total of 1008 patients with type 2 diabetes were screened, and 122 eligible patients consented to participate. Stress single-photon emission computed tomography revealed myocardial perfusion abnormalities in 96 (79%) patients. Of the 112 patients who completed the study protocol, 59 (53%) had asymptomatic CHD with ≥50% diameter stenosis. Additionally, 35 (31%) patients had multivessel disease or left main disease, and 42 (38%) had a coronary artery with ≥75% diameter stenosis. In the multivariate logistic-regression analysis to identify coronary risk factors associated with asymptomatic CHD, the only significant predictor was male sex (OR 6.18; 95% CI 2.30 to 16.64; p<0.001).

Conclusions

Asymptomatic CHD with ≥50% diameter stenosis and myocardial perfusion abnormalities was detected in more than half of the patients with type 2 diabetes with vascular complications.
Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen
Authors: Cassidy Eugene M , O'Sullivan Iomhar , Bradshaw Paula , Islam Tariq , Onovo Chidozie
Published: October 2011

The aim of the study was to compare symptom-triggered and standard benzodiazepine regimens for the treatment of alcohol withdrawal syndrome in an emergency department clinical decision unit. The authors found that the symptom-triggered approach reduced cumulative benzodiazepine dose and length of stay.
Aurora-B protein expression is linked to initial response to taxane-based first-line chemotherapy in stage III ovarian carcinoma
Authors: Beussel S , Hasenburg A , Bogatyreva L , Hauschke D , Werner M , Lassmann S
Published: October 2011

Aims

Aurora kinases are central to cell proliferation and considered to be prognostic/predictive markers and therapeutic targets for epithelial cancers. Here, the prognostic/predictive value of Aurora-B protein expression was evaluated in patients with serous, FIGO stage III ovarian carcinomas treated with taxane- or platinum-based first-line chemotherapy (1st-CTx).

Methods

Immunohistochemistry was performed on tissue microarrays, including 80 ovarian carcinomas and 18 non-neoplastic ovaries, previously characterised for Aurora-A protein expression. None or marginal (score 0+1), moderate (score 2) and strong (score 3) Aurora-B protein expression was correlated with clinico-pathological parameters as well as recurrence-free survival (RFS) and overall survival (OS).

Results

While non-neoplastic ovaries were negative for Aurora-B, almost all (79/80; 99%) ovarian carcinomas exhibited Aurora-B positive tumour cells, with score 1 in 41/80 (51%), score 2 in 23/80 (29%) and score 3 in 15/80 (19%) cases. Aurora-B and Aurora-A protein expression correlated significantly (p=0.002). In optimal debulked patients, Aurora-B protein expression was associated with RFS (p=0.011, n=53) and marginally with OS (p=0.460; n=53). Moreover, Aurora-B protein expression was predictive for RFS of optimal debulked patients with taxane-based (p=0.006; n=32), but not with platinum-based (p=0.720; n=20) 1st-CTx. Aurora-B protein expression was not linked to OS in optimal debulked patients with either of the two 1st-CTx.

Conclusions

Aurora-B protein expression frequently occurs in serous, FIGO stage III ovarian carcinomas, making it a ‘drugable’ molecular target in the majority of ovarian carcinoma patients. Moreover, Aurora-B protein expression is predictive for initial response to taxane-based 1st-CTx in optimal debulked, late stage ovarian carcinoma patients.
Ten problematical issues identified by pathology review for multidisciplinary gynaecological oncology meetings
Authors: McCluggage W Glenn
Published: October 2011

Pathology review of gynaecological cancer specimens is often carried out as part of the working of gynaecological oncology multidisciplinary team meetings. This review describes the author's experience regarding the most common issues identified during this process. Ten subjects are covered; these range from histopathological interpretational errors to non-interpretational areas, for example, inappropriate use of the term ‘microinvasive cervical carcinoma’ and the use of inappropriate staging systems. This review is intended to be of practical use to the surgical pathologist reporting gynaecological cancer specimens.
Fibroid in pregnancy: characteristics, complications, and management
Authors: Zaima Ahmed , Ash Alok
Published: October 2011

Fibroid in pregnancy is common in clinical obstetric practice. The topic is becoming more relevant in contemporary obstetrics due to the demographic shift towards delayed childbearing, the rising rate of obesity, and many pregnancies occurring after the treatment of fibroids. However, there are conflicting reports in the literature on many so-called fibroid complications in pregnancy, and there are inadequate data on the optimum management strategy. An evidence base is lacking on the pregnancy outcome of many conventional and newer treatment modalities of fibroids. This review addresses the characteristics and behaviour of fibroids during pregnancy, their incidence and demography, diagnosis, the complications that can arise during pregnancy and their antenatal management, the labour pattern, mode of delivery and the postpartum course, with critical appraisal of the literature together with certain special situations such as pregnancy after various types of myomectomy and uterine arterial embolisation.
PARTIAL ISOMETRIES OF A SUB-RIEMANNIAN MANIFOLD
Authors: DATTA MAHUYA
Published: October 2011

In this article, we obtain the following generalization of isometric C1-immersion theorem of Nash and Kuiper. Let M be a smooth manifold of dimension m and H a rank k subbundle of the tangent bundle TM with a Riemannian metric gH. Then the pair (H, gH) defines a sub-Riemannian structure on M. We call a C1-map f : (M, H, gH) → (N, h) into a Riemannian manifold (N, h) a partial isometry if the derivative map df restricted to H is isometric, that is if f*h|H = gH. We prove that if f0 : M → N is a smooth map such that df0|H is a bundle monomorphism and [Formula: see text], then f0 can be homotoped to a C1-map f : M → N which is a partial isometry, provided dim N > k. As a consequence of this result, we obtain that every sub-Riemannian manifold (M, H, gH) admits a partial isometry in ℝn, provided n ≥ m + k.
AN INFRARED ORIGIN OF LEPTONIC MIXING AND ITS TEST AT DEEPCORE
Authors: TERRANOVA F.
Published: October 2011

Fermion mixing is generally believed to be a low-energy manifestation of an underlying theory whose energy scale is much larger than the electroweak scale. In this paper we investigate the possibility that the parameters describing lepton mixing actually arise from the low-energy behavior of the neutrino interacting fields. In particular, we conjecture that the measured value of the mixing angles for a given process depends on the number of unobservable flavor states at the energy of the process. We provide a covariant implementation of such conjecture, draw its consequences in a two-neutrino family approximation and compare these findings with current experimental data. Finally we show that this infrared origin of mixing will be manifest at the Ice Cube DeepCore array, which measures atmospheric oscillations at energies much larger than the tau lepton mass; it will hence be experimentally tested in a short time scale.
SOME COMBINATORIAL PROPERTIES OF THE SYMMETRIC MONOID
Authors: LARADJI A. , UMAR A.
Published: October 2011

Let Tnbe the full transformation semigroup of a finite set, say Xn= {1, 2, …, n}, and for a given full transformation α : Xn→ Xnlet F(α) = {x ∈ Xn: xα = x} be its set of fixed points. In this note we obtain and discuss formulae for F(n, r, k) = |{α ∈ Tn: | Im α| = r ∧ |F(α)| = k}|.
Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells
Authors: Genetet Sandrine , Ripoche Pierre , Picot Julien , Bigot Sylvain , Delaunay Jean , Armari-Alla Corinne , Colin Yves , Mouro-Chanteloup Isabelle
Published: October 2011

In red cells, Rh-associated glycoprotein (RhAG) acts as an ammonia channel, as demonstrated by stopped-flow analysis of ghost intracellular pH (pHi) changes. Recently, overhydrated hereditary stomatocytosis (OHSt), a rare dominantly inherited hemolytic anemia, was found to be associated with a mutation (Phe65Ser or Ile61Arg) in RHAG. Ghosts from the erythrocytes of four of the OHSt patients with a Phe65Ser mutation were resealed with a pH-sensitive probe and submitted to ammonium gradients. Alkalinization rate constants, reflecting NH3 transport through the channel and NH3 diffusion unmediated by RhAG, were deduced from time courses of fluorescence changes. After subtraction of the constant value found for Rhnull lacking RhAG, we observed that alkalinization rate constant values decreased ∼50% in OHSt compared with those of controls. Similar RhAG expression levels were found in control and OHSt. Since half of the expressed RhAG in OHSt most probably corresponds to the mutated form of RhAG, as expected from the OHSt heterozygous status, this dramatic decrease can be therefore related to the loss of function of the Phe65Ser-mutated RhAG monomer.
Sleep deprivation induces excess diuresis and natriuresis in healthy children
Authors: Mahler B. , Kamperis K. , Schroeder M. , Frøkiær J. , Djurhuus J. C. , Rittig S.
Published: October 2011

Urine production is reduced at night, allowing undisturbed sleep. This study was undertaken to show the effect of sleep deprivation (SD) on urine production in healthy children. Special focus was on gender and children at an age where enuresis is still prominent. Twenty healthy children (10 girls) underwent two 24-h studies, randomly assigned to either sleep or SD on the first study night. Diet and fluid intake were standardized. Blood samples were drawn every 4 h during daytime and every 2 h at night. Urine was fractionally collected. Blood pressure and heart rate were noninvasively monitored. Blood was analyzed for plasma antidiuretic hormone (AVP), atrial natriuretic peptide (ANP), angiotensin II, aldosterone, and renin. Urine was analyzed for aquaporin-2 and PGE2. Successful SD was achieved in all participants with a minimum of 4 h 50 min, and full-night SD was obtained in 50% of the participants. During SD, both boys and girls produced markedly larger amounts of urine than during normal sleep (477 ± 145 vs. 291 ± 86 ml, P < 0.01). SD increased urinary excretion of sodium (0.17 ± 0.05 vs. 0.10 ± 0.03 mmol·kg−1·h−1) whereas solute-free water reabsorption remained unchanged. SD induced a significant fall in nighttime plasma AVP ( P < 0.01), renin ( P < 0.05), angiotensin II ( P < 0.001), and aldosterone ( P < 0.05) whereas plasma ANP levels remained uninfluenced ( P = 0.807). Nighttime blood pressure and heart rate were significantly higher during SD (mean arterial pressure: 78.5 ± 8.0 vs. 74.7 ± 8.7 mmHg, P < 0.001). SD leads to natriuresis and excess diuresis in healthy children. The underlying mechanism could be a reduced nighttime dip in blood pressure and a decrease in renin-angiotensin-aldosterone system levels during sleep deprivation.
Endothelin-1 mediates attenuated carotid baroreceptor activity by intermittent hypoxia
Authors: Peng Ying-Jie , Nanduri Jayasri , Zhang Xin , Wang Ning , Raghuraman Gayatri , Seagard Jeanne , Kumar Ganesh K. , Prabhakar Nanduri R.
Published: October 2011

The objectives of the present study were to examine the effects of intermittent hypoxia (IH) on arterial baroreflex function and assess the underlying mechanism(s). Experiments were performed on adult male rats treated with 14 days of IH (15 s of hypoxia, 5 min of normoxia; 8 h/day) or normoxia (control). Arterial blood pressures were elevated in IH-treated rats, and this effect was associated with attenuated heart rate and splanchnic sympathetic nerve responses to arterial baroreflex activation. In IH-treated rats, carotid baroreceptor responses to elevated sinus pressures were attenuated. Endothelin-1 (ET-1) levels were elevated in the carotid sinus region of IH-treated rats, and this effect was associated with increased endothelin converting enzyme (ECE) activity, which generates biologically active ET-1. ETA receptor antagonist prevented the effects of IH on carotid baroreceptor activity. In IH-treated rats, reactive oxygen species (ROS) levels were elevated in the carotid sinus region, and antioxidant treatment prevented the effects of IH on ET-1 levels, ECE activity, carotid baroreceptor activity, and baroreflex function. These results demonstrate that 1) IH attenuates arterial baroreflex function, which is in part due to reduced carotid baroreceptor responses to elevated carotid sinus pressure, and 2) IH-induced carotid baroreceptor dysfunction involves reactive oxygen species-dependent upregulation of ET-1 signaling in the carotid sinus region.
Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS
Authors: Schuster J. E. , Fu R. , Siddique T. , Heckman C. J.
Published: October 2011

Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 μM riluzole for 4–9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1G93A motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1G93A motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2–3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 μM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective.
The role of haptic feedback when manipulating nonrigid objects
Authors: Danion Frédéric , Diamond Jonathan S. , Flanagan J. Randall
Published: October 2011

Humans can learn to manipulate objects with complex dynamics, including nonrigid objects with internal degrees of freedom. The first aim of this study was to assess the contribution of haptic feedback when learning to manipulate a nonrigid object. The second aim was to evaluate how learning without haptic feedback influences subsequent learning with haptic feedback and vice versa. The task involved moving a simulated mass—attached to a grasped handle via a simulated, damped spring—to a target as quickly as possible. In the haptic plus vision (HV) condition, appropriate forces were applied to the handle, which was attached to a robot. In the vision only (V) condition, these forces were turned off. Participants completed 80 trials in each condition, with one-half starting with the HV condition. Both groups exhibited significant learning, as measured by movement time, in both conditions. For the condition performed first, initial performance, learning rate, and final performance were better with haptic feedback. Prior experience in the HV condition led to faster learning and better final performance in the V condition. However, prior experience in the V condition led to slower learning and worse final performance in the HV condition. In the V condition, all participants tended to keep the mass close to the hand. In the HV condition, participants who started with the HV condition allowed the mass to move away from the hand, whereas participants who started with the V condition continued to keep the mass close to the hand. We conclude that haptic feedback as well as prior experience with haptic feedback enhance the ability to control nonrigid objects and that training without haptic feedback can lead to persisting detrimental effects when subsequently dealing with haptic feedback.
Serotonin modulates the population activity profile of olfactory bulb external tufted cells
Authors: Liu Shaolin , Aungst Jason L. , Puche Adam C. , Shipley Michael T.
Published: October 2011

Serotonergic neurons in the raphe nuclei constitute one of the most prominent neuromodulatory systems in the brain. Projections from the dorsal and median raphe nuclei provide dense serotonergic innervation of the glomeruli of olfactory bulb. Odor information is initially processed by glomeruli, thus serotonergic modulation of glomerular circuits impacts all subsequent odor coding in the olfactory system. The present study discloses that serotonin (5-HT) produces excitatory modulation of external tufted (ET) cells, a pivotal neuron in the operation of glomerular circuits. The modulation is due to a transient receptor potential (TRP) channel-mediated inward current induced by activation of 5-HT2Areceptors. This current produces membrane depolarization and increased bursting frequency in ET cells. Interestingly, the magnitude of the inward current and increased bursting inversely correlate with ET cell spontaneous (intrinsic) bursting frequency: slower bursting ET cells are more strongly modulated than faster bursting cells. Serotonin thus differentially impacts ET cells such that the mean bursting frequency of the population is increased. This centrifugal modulation could impact odor processing by: 1) increasing ET cell excitatory drive on inhibitory neurons to increase presynaptic inhibition of olfactory sensory inputs and postsynaptic inhibition of mitral/tufted cells; and/or 2) coordinating ET cell bursting with exploratory sniffing frequencies (5–8 Hz) to facilitate odor coding.
Roles of the subthalamic nucleus and subthalamic HCN channels in absence seizures
Authors: Kase Daisuke , Inoue Tsuyoshi , Imoto Keiji
Published: October 2011

Absence seizures consist of a brief and sudden impairment of consciousness. They are characterized by bilaterally synchronized spike and wave discharges (SWDs), which reflect abnormal oscillations in the thalamocortical loops. Recent studies have suggested that the basal ganglia are involved in generation of the SWDs, but their roles are poorly understood at the molecular and cellular levels. Here we studied the pathophysiological roles of the basal ganglia, using in vivo and in vitro measurements of tottering mice, a well-established model of absence epilepsy. We found that the membrane excitability in subthalamic nucleus (STN) neurons was enhanced in tottering mice, which resulted from reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity. Pharmacological blockade and activation of HCN channel activity in vitro bidirectionally altered the membrane excitability of the STN neurons. Furthermore, these pharmacological modulations of HCN channel activity in the STN in vivo bidirectionally altered the mean SWD duration. In addition, STN deep brain stimulation modulated SWDs in a frequency-dependent manner. These results indicate that STN is involved in the rhythm maintenance system of absence seizures.
A Review of Wireless and PLC Propagation Channel Characteristics for Smart Grid Environments
Authors: Güzelgöz Sabih , Arslan Hüseyin , Islam Arif , Domijan Alexander
Published: October 2011

Wireless, power line communication (PLC), fiber optic, Ethernet, and so forth are among the communication technologies on which smart grid communication infrastructure is envisioned to be built. Among these, wireless and PLC-based solutions are attractive considering the cost of initial deployment. Wireless communication deployment in smart grid covers a variety of environments such as indoor, outdoor, and electric-power-system facilities. Similar diversity is expected in PLC deployment as well covering low voltage (LV), medium voltage (MV), and high voltage (HV) segments of the grid. In spite of being attractive, wireless and PLC channels are very harsh posing great challenges to performance of communication systems. In proposing solutions to smart grid communication needs, two approaches are likely to be followed. One is based on the use of existing wireless and PLC technologies with some modifications, and the other relies upon developing novel communication protocols particularly addressing the smart grid needs. Both of these approaches require an in-depth knowledge of communication channel characteristics. The aim of this study is to reveal the wireless and PLC channel characteristics of smart grid environments in terms of several parameters such as path loss and attenuation, time dispersion, time selectivity, amplitude statistics, and noise characteristics.
Microsurgical Reconstruction of Large, Locally Advanced Cutaneous Malignancy of the Head and Neck
Authors: Hill Joseph L. , Rinker Brian
Published: October 2011

Large, locally advanced cutaneous malignancy of the head and neck region is rare. However, when present, they impart a significant reconstructive challenge. These cancers have a tendency to invade peripheral tissues covering a large surface area as well as expose deeper structures such as skull, dura, orbit, and sinus after resection. Complicating the reconstructive dilemma is the high incidence of individuals who have undergone previous surgery in the region as well as adjuvant radiation therapy, which may preclude the use of local flaps or skin graft. Free tissue transfer provides a reconstructive surgeon the ability to provide well-vascularized tissue with adequate volume not limited by arc of rotation.
Surface Effects on the Vibration and Buckling of Double-Nanobeam-Systems
Authors: Wang Dong-Hui , Wang Gang-Feng
Published: October 2011

Surface effects on the transverse vibration and axial buckling of double-nanobeam-system (DNBS) are examined based on a refined Euler-Bernoulli beam model. For three typical deformation modes of DNBS, we derive the natural frequency and critical axial load accounting for both surface elasticity and residual surface tension, respectively. It is found that surface effects get quite important when the cross-sectional size of beams shrinks to nanometers. No matter for vibration or axial buckling, surface effects are just the same in three deformation modes and usually enhance the natural frequency and critical load. However, the interaction between beams is clearly distinct in different deformation modes. This study might be helpful for the design of nano-optomechanical systems and nanoelectromechanical systems.
An Optimal Error Estimates of H1‐Galerkin Expanded Mixed Finite Element Methods for Nonlinear Viscoelasticity‐Type Equation
Authors: Che Haitao , Wang Yiju , Zhou Zhaojie
Published: October 2011

We investigate a H1‐Galerkin mixed finite element method for nonlinear viscoelasticity equations based on H1‐Galerkin method and expanded mixed element method. The existence and uniqueness of solutions to the numerical scheme are proved. A priori error estimation is derived for the unknown function, the gradient function, and the flux.
Current Status of Immunomodulatory and Cellular Therapies in Preclinical and Clinical Islet Transplantation
Authors: Chhabra Preeti , Brayman Kenneth L.
Published: October 2011

Clinical islet transplantation is a -cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the -cells regenerative capacity of stem cells.
Synthesis, Characterization, and Evaluation of Radical Scavenging Ability of Ellagic Acid-Loaded Nanogels
Authors: Behl Gautam , Sharma Monal , Dahiya Saurabh , Chhikara Aruna , Chopra Madhu
Published: October 2011

Ellagic acid (EA), a potential antioxidant phytochemical has low aqueous solubility and bioavailability. In this paper, encapsulation of ellagic acid has been carried out into the biodegradable disulfide crosslinked poly (ethylene glycol) PEO-based nanogels synthesized via AGET (activator generated electron transfer) ATRP (atom transfer radical polymerization), and their radical scavenging ability was evaluated. The encapsulation of the EA was carried out at two drug loading percentages, that is, 10 and 20 wt.% of the nanogels. 1,1-Diphenyl-2-picryldrazyl (DPPH) assay was utilized in order to assess the radical scavenging ability of the ellagic acid-loaded nanogels. A drug-loading level of about 2.5 wt.% was achieved with encapsulation efficiency of about 25% at 10 wt.% of the EA w.r.t nanogels, which was found to increase to about 4.7 wt.% with decreased encapsulation efficiency of 23.5% as EA content was increased to 20wt.% of the nanogels. Ellagic acid loading was found to be accompanied with increase in the size of the nanogels from144.6±39.52 nm for neat nanogels to217.8±105.5and633±160.1 nm at 2.5 and 4.7 wt.% drug loading level. The nanogels were found to be capable of scavenging radicals and biocompatible on human cervical cancer cell lines (HeLa cells) at appropriate concentrations.
NF-κB Signaling in the Brain of Autistic Subjects
Authors: Malik Mazhar , Tauqeer Zujaja , Sheikh Ashfaq M. , Wen Guang , Nagori Amenah , Yang Kun , Brown W. Ted , Li Xiaohong
Published: October 2011

Autism is a neurodevelopmental disorder characterized by problems in communication, social skills, and repetitive behavior. Recent studies suggest that apoptotic and inflammatory mechanisms may contribute to the pathogenesis of this disorder. Nuclear factor-κB (NF-κB) is an important gene transcriptional factor involved in the mediation of inflammation and apoptosis. This study examined the activities of the NF-κB signaling pathway in the brain of autistic subjects and their age-matched controls. The NF-κB activation is also determined in the brain of BTBR mice, which is a promising animal model for study of pathogenic mechanisms responsible for autism. Our results showed that the level of IKKαkinase, which phosphorylates the inhibitory subunit IκBα, is significantly increased in the cerebellum of autistic subjects. However, the expression and phosphorylation of IκBαare not altered. In addition, our results demonstrated that the expression of NF-κB (p65), and the phosphorylation/activation of NF-κB (p65) at Ser536 are not significantly changed in the cerebellum and cortex of both autistic subjects and BTBR mice. Our findings suggest that the NF-κB signaling pathway is not disregulated in the brain of autistic subjects and thus may not be significantly involved in the processes of abnormal inflammatory responses suggested in autistic brain.