bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV Infection Abrogates the Functional Advantage of Natural Killer Cells Educated through KIR3DL1/HLA-Bw4 Interactions To Mediate Anti-HIV Antibody-Dependent Cellular Cytotoxicity
Authors: Parsons Matthew S. , Wren Leia , Isitman Gamze , Navis Marjon , Stratov Ivan , Bernard Nicole F. , Kent Stephen J.
Published: February 2012

Combinations of KIR3DL1 and HLA-Bw4 alleles protect against HIV infection and/or disease progression. These combinations enhance NK cell responsiveness through the ontological process of education. However, educated KIR3DL1+NK cells do not have enhanced degranulation upon direct recognition of autologous HIV-infected cells. Since antibody-dependent cellular cytotoxicity (ADCC) is associated with improved HIV infection outcomes and NK cells overcome inhibition through killer cell immunoglobulin-like receptors (KIR) to mediate ADCC, we hypothesized that KIR3DL1-educated NK cells mediate anti-HIV ADCC against autologous cells. A whole-blood flow cytometry assay was used to evaluate ADCC-induced activation of NK cells. This assay assessed activation (gamma interferon [IFN-γ] production and/or CD107a expression) of KIR3DL1+and KIR3DL1−NK cells, from HLA-Bw4+and HLA-Bw4−HIV-positive and HIV-negative individuals, in response to autologous HIV-specific ADCC targets. KIR3DL1+NK cells were more functional than KIR3DL1−NK cells from HLA-Bw4+, but not HLA-Bw4−, healthy controls. In HIV-infected individuals, no differences in NK cell functionality were observed between KIR3DL1+and KIR3DL1−NK cells in HLA-Bw4+individuals, consistent with dysfunction of NK cells in the setting of HIV infection. Reflecting the partial normalization of NK cell responsiveness following initiation of antiretroviral therapy, a significant correlation was observed between the peripheral CD4+T-lymphocyte counts in antiretroviral therapy-treated subjects and the functionality of NK cells. However, peripheral CD4+T-lymphocyte counts were not correlated with an anti-HIV ADCC functional advantage in educated KIR3DL1+NK cells. The abrogation of the functional advantage of educated NK cells may enhance HIV disease progression. Strategies to enhance the potency of NK cell-mediated ADCC may improve HIV therapies and vaccines.
Identification and Characterization of Three Novel Nuclear Export Signals in the Influenza A Virus Nucleoprotein
Authors: Yu Maorong , Liu Xiaoling , Cao Shuai , Zhao Zhendong , Zhang Ke , Xie Qing , Chen Caiwei , Gao Shengyan , Bi Yuhai , Sun Lei , Ye Xin , Gao George F. , Liu Wenjun
Published: February 2012

The nuclear export of the influenza A virus ribonucleoprotein (vRNP) is crucial for virus replication. As a major component of the vRNP, nucleoprotein (NP) alone can also be shuttled out of the nucleus by interacting with chromosome region maintenance 1 (CRM1) and is therefore hypothesized to promote the nuclear export of the vRNP. In the present study, three novel nuclear export signals (NESs) of the NP—NES1, NES2, and NES3—were identified as being responsible for mediating its nuclear export. The nuclear export of NES3 was CRM1 dependent, whereas that of NES1 or NES2 was CRM1 independent. Inactivation of these NESs led to an overall nuclear accumulation of NP. Mutation of all three NP-NESs significantly impaired viral replication. Based on structures of influenza virus NP oligomers, these three hydrophobic NESs are found present on the surface of oligomeric NPs. Functional studies indicated that oligomerization is also required for nuclear export of NP. Together, these results suggest that the nuclear export of NP is important for virus replication and relies on its NESs and oligomerization.
Measles Virus Glycoprotein-Pseudotyped Lentiviral Vectors Are Highly Superior to Vesicular Stomatitis Virus G Pseudotypes for Genetic Modification of Monocyte-Derived Dendritic Cells
Authors: Humbert J.-M. , Frecha C. , Bouafia F. Amirache , N′Guyen T. H. , Boni S. , Cosset F.-L. , Verhoeyen E. , Halary F.
Published: February 2012

Dendritic cells (DCs) are potent antigen-presenting cells capable of promoting or regulating innate and adaptive immune responses against non-self antigens. To better understand the DC biology or to use them for immune intervention, a tremendous effort has been made to improve gene transfer in these cells. Lentiviral vectors (LVs) have conferred a huge advantage in that they can transduce nondividing cells such as human monocyte-derived DCs (MDDCs) but required high amounts of viral particles and/or accessory proteins such as Vpx or Vpr to achieve sufficient transduction rates. As a consequence, these LVs have been shown to cause dramatic functional modifications, such as the activation or maturation of transduced MDDCs. Taking advantage of new pseudotyped LVs, i.e., with envelope glycoproteins from the measles virus (MV), we demonstrate that MDDCs are transduced very efficiently with these new LVs compared to the classically used vesicular stomatitis virus G-pseudotyped LVs and thus allowed to achieve high transduction rates at relatively low multiplicities of infection. Moreover, in this experimental setting, no activation or maturation markers were upregulated, while MV-LV-transduced cells remained able to mature after an appropriate Toll-like receptor stimulation. We then demonstrate that our MV-pseudotyped LVs use DC-SIGN, CD46, and CD150/SLAM as receptors to transduce MDDCs. Altogether, our results show that MV-pseudotyped LVs provide the most accurate and simple viral method for efficiently transferring genes into MDDCs without affecting their activation and/or maturation status.
Single-Domain Antibody-SH3 Fusions for Efficient Neutralization of HIV-1 Nef Functions
Authors: Bouchet Jérôme , Hérate Cécile , Guenzel Carolin A. , Vérollet Christel , Järviluoma Annika , Mazzolini Julie , Rafie Salomeh , Chames Patrick , Baty Daniel , Saksela Kalle , Niedergang Florence , Maridonneau-Parini Isabelle , Benichou Serge
Published: February 2012

HIV-1 Nef is essential for AIDS pathogenesis, but this viral protein is not targeted by antiviral strategies. The functions of Nef are largely related to perturbations of intracellular trafficking and signaling pathways through leucine-based and polyproline motifs that are required for interactions with clathrin-associated adaptor protein complexes and SH3 domain-containing proteins, such as the phagocyte-specific kinase Hck. We previously described a single-domain antibody (sdAb) targeting Nef and inhibiting many, but not all, of its biological activities. We now report a further development of this anti-Nef strategy through the demonstration of the remarkable inhibitory activity of artificial Nef ligands, called Neffins, comprised of the anti-Nef sdAb fused to modified SH3 domains. The Neffins inhibited all key activities of Nef, including Nef-mediated CD4 and major histocompatibility complex class I (MHC-I) cell surface downregulation and enhancement of virus infectivity. When expressed in T lymphocytes, Neffins specifically inhibited the Nef-induced mislocalization of the Lck kinase, which contributes to the alteration of the formation of the immunological synapse. In macrophages, Neffins inhibited the Nef-induced formation of multinucleated giant cells and podosome rosettes, and it counteracted the inhibitory activity of Nef on phagocytosis. Since we show here that these effects of Nef on macrophage and T cell functions were both dependent on the leucine-based and polyproline motifs, we confirmed that Neffins disrupted interactions of Nef with both AP complexes and Hck. These results demonstrate that it is possible to inhibit all functions of Nef, both in T lymphocytes and macrophages, with a single ligand that represents an efficient tool to develop new antiviral strategies targeting Nef.
A Nuclear Export Signal in the Matrix Protein of Influenza A Virus Is Required for Efficient Virus Replication
Authors: Cao Shuai , Liu Xiaoling , Yu Maorong , Li Jing , Jia Xiaojuan , Bi Yuhai , Sun Lei , Gao George F. , Liu Wenjun
Published: February 2012

The influenza A virus matrix 1 protein (M1) shuttles between the cytoplasm and the nucleus during the viral life cycle and plays an important role in the replication, assembly, and budding of viruses. Here, a leucine-rich nuclear export signal (NES) was identified specifically for the nuclear export of the M1 protein. The predicted NES, designated the Flu-A-M1 NES, is highly conserved among all sequences from the influenza A virus subtype, but no similar NES motifs are found in the M1 sequences of influenza B or C viruses. The biological function of the Flu-A-M1 NES was demonstrated by its ability to translocate an enhanced green fluorescent protein (EGFP)-NES fusion protein from the nucleus to the cytoplasm in transfected cells, compared to the even nuclear and cytoplasmic distribution of EGFP. The translocation of EGFP-NES from the nucleus to the cytoplasm was not inhibited by leptomycin B. NES mutations in M1 caused a nuclear retention of the protein and an increased nuclear accumulation of NEP during transfection. Indeed, as shown by rescued recombinant viruses, the mutation of the NES impaired the nuclear export of M1 and significantly reduced the virus titer compared to titers of wild-type viruses. The NES-defective M1 protein was retained in the nucleus during infection, accompanied by a lowered efficiency of the nuclear export of viral RNPs (vRNPs). In conclusion, M1 nuclear export was specifically dependent on the Flu-A-M1 NES and critical for influenza A virus replication.
Replicating Adenovirus-Simian Immunodeficiency Virus (SIV) Recombinant Priming and Envelope Protein Boosting Elicits Localized, Mucosal IgA Immunity in Rhesus Macaques Correlated with Delayed Acquisition following a Repeated Low-Dose Rectal SIV
mac251
Challenge
Authors: Xiao Peng , Patterson L. Jean , Kuate Seraphin , Brocca-Cofano Egidio , Thomas Michael A. , Venzon David , Zhao Jun , DiPasquale Janet , Fenizia Claudio , Lee Eun Mi , Kalisz Irene , Kalyanaraman Vaniambadi S. , Pal Ranajit , Montefiori David , Keele Brandon F. , Robert-Guroff Marjorie
Published: February 2012

We have shown that sequential replicating adenovirus type 5 host range mutant human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) recombinant priming delivered first intranasally (i.n.) plus orally and then intratracheally (i.t.), followed by envelope protein boosting, elicits broad cellular immunity and functional, envelope-specific serum and mucosal antibodies that correlate with protection from high-dose SIV and simian/human immunodeficiency virus (SHIV) challenges in rhesus macaques. Here we extended these studies to compare the standard i.n./i.t. regimen with additional mucosal administration routes, including sublingual, rectal, and vaginal routes. Similar systemic cellular and humoral immunity was elicited by all immunization routes. Central and effector memory T cell responses were also elicited by the four immunization routes in bronchoalveolar lavage fluid and jejunal, rectal, and vaginal tissue samples. Cellular responses in vaginal tissue were more compartmentalized, being induced primarily by intravaginal administration. In contrast, all immunization routes elicited secretory IgA (sIgA) responses at multiple mucosal sites. Following a repeated low-dose intrarectal (i.r.) challenge with SIV
mac251
at a dose transmitting one or two variants, protection against acquisition was not achieved except in one macaque in the i.r. immunized group. All immunized macaques exhibited reduced peak viremia compared to that of controls, correlated inversely with prechallenge serum antienvelope avidity, antibody-dependent cellular cytotoxicity (ADCC) titers, and percent antibody-dependent cell-mediated viral inhibition. Both antibody avidity and ADCC titers were correlated with the number of exposures required for infection. Notably, we show for the first time a significant correlation of vaccine-induced sIgA titers in rectal secretions with delayed acquisition. Further investigation of the characteristics and properties of the sIgA should elucidate the mechanism leading to this protective effect.
Draft Genome Sequence of Four Coccolithoviruses: Emiliania huxleyi Virus EhV-88, EhV-201, EhV-207, and EhV-208
Authors: Nissimov Jozef I. , Worthy Charlotte A. , Rooks Paul , Napier Johnathan A. , Kimmance Susan A. , Henn Matthew R. , Ogata Hiroyuki , Allen Michael J.
Published: February 2012

The
Coccolithoviridae
are a group of viruses which infect the marine coccolithophorid microalga
Emiliania huxleyi
. The
Emiliania huxleyi
viruses (known as EhVs) described herein have 160- to 180-nm diameter icosahedral structures, have genomes of approximately 400 kbp, and consist of more than 450 predicted coding sequences (CDSs). Here, we describe the genomic features of four newly sequenced coccolithoviruses (EhV-88, EhV-201, EhV-207, and EhV-208) together with their draft genome sequences and their annotations, highlighting the homology and heterogeneity of these genomes to the EhV-86 model reference genome.
Complete Genome Sequence of Bacteriophage phiAS7, a T7-Like Virus That Infects Aeromonas salmonicida subsp. salmonicida
Authors: Kim Ji Hyung , Son Jee Soo , Choresca Casiano H. , Shin Sang Phil , Han Jee Eun , Jun Jin Woo , Kang Do-Hyung , Oh Chulhong , Heo Soo-Jin , Park Se Chang
Published: February 2012

To date, a number of
Myoviridae
bacteriophages that infect
Aeromonadaceae
have been identified and characterized. However, the genome sequences of
Aeromonas
phages that not belong to the
Myoviridae
have not been investigated yet. Herein, we report the complete genome sequence of
Aeromonas
phage phiAS7, which belongs to the
Podoviridae
and infects
Aeromonas salmonicida
subsp.
salmonicida
.
Early Events in Alphavirus Replication Determine the Outcome of Infection
Authors: Frolov Ilya , Akhrymuk Maryna , Akhrymuk Ivan , Atasheva Svetlana , Frolova Elena I.
Published: February 2012

Alphaviruses are a group of important human and animal pathogens. They efficiently replicate to high titers
in vivo
and in many commonly used cell lines of vertebrate origin. They have also evolved effective means of interfering with development of the innate immune response. Nevertheless, most of the alphaviruses are known to induce a type I interferon (IFN) response
in vivo
. The results of this study demonstrate that the first hours postinfection play a critical role in infection spread and development of the antiviral response. During this window, a balance is struck between virus replication and spread in vertebrate cells and IFN response development. The most important findings are as follows: (i) within the first 2 to 4 h postinfection, alphavirus-infected cells become unable to respond to IFN-β, and this occurs before the virus-induced decrease in STAT1 phosphorylation in response to IFN treatment. (ii) Most importantly, very low, subprotective doses of IFN-β, which do not induce the antiviral response in uninfected cells, have a very strong stimulatory effect on the cells' ability to express type I IFN and activate interferon-stimulated genes during subsequent infection with Sindbis virus (SINV). (iii) Small changes in SINV nsP2 protein affect its ability to inhibit cellular transcription and IFN release. Thus, the balance between type I IFN induction and the ability of the virus to develop further rounds of infection is determined in the first few hours of virus replication, when only low numbers of cells and infectious virus are involved.
Republished article: The impact of diabetic retinopathy: understanding the patient's perspective
Authors: Fenwick E K , Pesudovs K , Rees G , Dirani M , Kawasaki R , Wong T Y , Lamoureux E L
Published: February 2012

Understanding the impact of a condition from the patient's perspective is important, and different types of patient-reported outcomes or instruments are available to help with this. This review article summarises the current evidence on the impact of diabetic retinopathy (DR) and its associated vision impairment on patient-reported outcomes. We have included research that has used a range of outcome measures to assess the impact of DR on generic health-related quality of life, utility, vision-functioning and vision-specific quality of life. This review also offers clarification on frequently misused psychometric terminologies to help clinicians and researchers better understand the literature associated with patient-reported outcome research. Overall, the evidence suggests that DR, particularly in its vision-threatening stages, has a substantial, negative impact on the patient. However, our understanding of the impact of DR is currently restricted due to limitations inherent in currently available patient-reported outcome measures. We conclude by discussing potential directions for future research in this area, such as item banking and computer adaptive testing.
Supervised blood-based self-sample collection and rapid test performance: a valuable alternative to the use of saliva by HIV testing programmes with no medical or nursing staff: Table 1
Authors: Belza María J , Rosales-Statkus M Elena , Hoyos Juan , Segura Pilar , Ferreras Eva , Sánchez Rebeca , Molist Gemma , de la Fuente Luis ,   the Madrid Rapid HIV testing Group
Published: February 2012

Objectives

Some saliva-based HIV testing programmes have resulted in an unacceptable percentage of false positives. Many countries require blood-based testing programmes to have doctors/nurses. The authors evaluate whether, after brief training and under the supervision of a skilled counsellor, blood-based self-sample collection and rapid test performance could be a valuable alternative.

Methods

208 Spanish-speaking attendees at a street-based HIV testing programme in Madrid participated in the study. Participants were tested twice, first in the study and then in the programme, using the same finger-stick whole-blood rapid test (Determine HIV-1/2 Ag/Ab Combo®). Based on previously adapted instructions, the study counsellor explained the procedure to follow throughout the test. Participants then performed the test under the guidance of the counsellor. Demographic and risk behaviour data were collected by a self-administered questionnaire. The test results in the programme and the study were read by the study counsellor.

Results

99.0% (95% CI 96.6% to 99.9%) of participants had a valid result in the study test, the same percentage as in the programme test conducted by the doctor/nurse. Two persons had invalid test results in both the study and the programme, but they were not the same persons.

Conclusion

The study provides clear evidence that this methodology is a valuable alternative to saliva for HIV testing programmes when medical or nursing staff required to take blood samples is not available.
Efficiency considerations of donor fatigue, universal access to ARTs and health systems
Authors: Grépin Karen A
Published: February 2012

Objectives

To investigate trends in official development assistance for health, HIV and non-HIV activities over time and to discuss the efficiency implications of these trends in the context of achieving universal access to treatment and health systems.

Methods

Official development assistance for health, HIV programmes and non-HIV programmes were tracked using data from 2000 to 2009. A review of the literature on efficiency, treatment and health systems was conducted.

Findings

The rate of growth of donor funding to HIV programmes has slowed in recent years at levels below those required to sustain programmes and to move towards universal access to treatment. These trends are likely due to increased pressure on foreign aid budgets and donor fatigue for HIV programmes.

Conclusions

There is great need to consider how the limited resources available can be used most efficiently to increase the number of lives saved and to ensure that these resources also benefit health systems. Improving efficiency is much more than just improving the productive efficiency and also about ensuring that resources are going to where they will be the most beneficial and making investments that are the most efficient over time. These choices may be essential to achieving the goal of universal access to treatment as well as the sustainability of these programmes.
High prevalence of HIV and sexually transmitted infections among male sex workers in Abidjan, Côte d'Ivoire: need for services tailored to their needs
Authors: Vuylsteke Bea , Semde Gisèle , Sika Lazare , Crucitti Tania , Ettiegne Traore Virginie , Buve Anne , Laga Marie
Published: February 2012

Objectives

To assess condom use and prevalence of sexually transmitted infections (STI) and HIV among male sex workers (MSW) in Abidjan, Côte d'Ivoire.

Methods

A cross-sectional survey was conducted between October 2007 and January 2008 among MSW attending a sex worker clinic in Abidjan. A short questionnaire was administered in a face-to-face interview, and the participants were asked to provide a urine sample for STI testing and to self-collect transudate of the gingival mucosa for anonymous HIV testing, using a rapid test. A rectal swab for STI testing was taken by a physician. Molecular amplification assays were performed for the detection ofChlamydia trachomatis,Neisseria gonorrhoeaeandTrichomonas vaginalis.

Results

96 MSW participated in the survey, their median age was 27 years and the median duration of sex work was 5 years. Consistent condom use with clients during the last working day was 86.0%, and consistent condom use with the regular partner during the last week was 81.6%. HIV infection was detected in 50.0% of the participants. The prevalence ofN gonorrhoeaewas 12.8%, chlamydia infection was present in 3.2% andTvaginalisin 2.1% of the study participants.

Conclusions

HIV and STI rates found in this study confirm the high risk and vulnerability status of MSW in Côte d'Ivoire. There is a definite need for studies exploring risk and risk perceptions among MSW in more depth and for services tailored to their needs, including developing and validating simple algorithms for the diagnosis of STI in MSW and men who have sex with men.
The expansion of HIV-1 in colonial Léopoldville, 1950s: driven by STDs or STD control?
Authors: Pépin Jacques
Published: February 2012

Objectives

To understand the factors that drove the exponential spread of HIV-1 in Léopoldville (Kinshasa) in the 1950s.

Methods

A review of colonial and post-colonial health service reports, medical publications, and demographic and social science research in Léopoldville.

Results

Sex work appeared early in the history of Léopoldville, driven by a strong gender imbalance. Throughout the colonial era, sex work was of a low-risk type, with ‘free women’ having a few regular clients. This sufficed for the persistence of HIV-1, but probably not for the dramatic expansion that occurred in the 1950s. During that decade, genital ulcerative diseases were uncommon and their effect on HIV-1 transmission must have been modest. Circumstantial evidence indicates that this expansion may have been related to parenteral transmission of HIV-1 in the city's sexually transmitted disease clinic, where up to 500 injections were administered daily using syringes and needles that were merely rinsed between patients. Most intravenous injections were given to treat syphilis in patients who never had any clinical evidence of this disease but only had a positive non-treponemal serology, often because of prior yaws infection. An outbreak of ‘inoculation hepatitis’ was reported among these patients in 1951–1952. It is only after the Congo's independence (1960) that, in a context of pauperisation, a pattern of sex work appeared in Léopoldville wherein women had sex with more than 1000 clients each year, allowing the sexual amplification of the virus.

Conclusions

It is plausible that the exponential amplification of HIV-1 in Léopoldville occurred mostly parenterally in the 1950s and sexually in the 1960s.
A NEURO-FUZZY BASED MODEL FOR ACCURATE ESTIMATION OF THE LYAPUNOV EXPONENTS OF AN UNKNOWN DYNAMICAL SYSTEM
Authors: RAZJOUYAN JAVAD , GHARIBZADEH SHAHRIAR , FALLAH ALI , KHAYAT OMID , GHERGHEREHCHI MITRA , AFARIDEH HOSSEIN , MOGHADDASI MEHDI
Published: February 2012

A neuro-fuzzy based model is proposed in this paper for estimating the Lyapunov exponents of an unknown dynamical system according solely to a set of observations. Several approaches have been presented in recent years; most of them using the approximation of both the function of the trajectory of observations and the partial derivatives, to yield the Jacobian matrix of the function. The Jacobian matrix is then employed in the Jacobian-based methods that extract the Lyapunov exponents by QR-decomposition. While the accurate estimation of Lyapunov exponents has been sought, most of the related papers mainly focus on the accuracy of the trajectory approximation. In this paper, an Adaptive Neuro-Fuzzy Inference System is presented and stated to be an efficient tool for such a purpose. Structural parameters of the proposed model as the embedding dimension and the delay time are calculated by the Takens theorem and autocorrelation function, respectively. Model validation is performed by cross approximate entropy. Then, the promising performance of the proposed model as an accurate estimation of the Lyapunov exponents and its robustness to the measurement noise are finally evaluated.
QUANTUM GRAVITY AND DARK MATTER
Authors: HO CHIU MAN , MINIC DJORDJE , NG Y. JACK
Published: February 2012

We propose a connection between global physics and local galactic dynamics via quantum gravity. The salient features of cold dark matter (CDM) and modified Newtonian dynamics (MOND) are combined into a unified scheme by introducing the concept of MONDian dark matter which behaves like CDM at cluster and cosmological scales but emulates MOND at the galactic scale.
EFFECTIVE INFORMATION LOSS OUTSIDE THE HORIZON
Authors: MATHUR SAMIR D.
Published: February 2012

If a system falls through a black hole horizon, then its information is lost to an observer at infinity. But we argue that the accessible information is lost before the horizon is crossed. The temperature of the hole limits information carrying signals from a system that has fallen too close to the horizon. Extremal holes have T = 0, but there is a minimum energy required to emit a quantum in the short proper time left before the horizon is crossed. If we attempt to bring the system back to infinity for observation, then acceleration radiation destroys the information. All three considerations give a critical distance from the horizon [Formula: see text], where rH is the horizon radius and ΔE is the energy scale characterizing the system. For systems in string theory where we pack information as densely as possible, this acceleration constraint is found to have a geometric interpretation. These estimates suggest that in theories of gravity we should measure information not as a quantity contained inside a given system, but in terms of how much of that information can be reliably accessed by another observer.
OBSERVATIONAL CONSTRAINTS ON STRONG GRAVITY
Authors: DONE CHRIS
Published: February 2012

Accretion onto a black hole transforms the darkest objects in the universe to the brightest. The high energy radiation emitted from the accretion flow before it disappears forever below the event horizon lights up the regions of strong spacetime curvature close to the black hole, enabling strong field tests of General Relativity. I review the observational constraints on strong gravity from such accretion flows, and show how the data strongly support the existence of such fundamental General Relativistic features of a last stable orbit and the event horizon. However, these successes also imply that gravity does not differ significantly from Einstein's predictions above the event horizon, so any new theory of quantum gravity will be very difficult to test.
Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice
Authors: Datta Nabanita S. , Samra Tareq A. , Abou-Samra Abdul B.
Published: February 2012

Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.
Membrane complement regulators protect against fibrin exudation increases in a severe peritoneal inflammation model in rats
Authors: Mizuno Masashi , Ito Yasuhiko , Mizuno Tomohiro , Harris Claire L. , Suzuki Yasuhiro , Okada Noriko , Matsuo Seiichi , Morgan B. Paul
Published: February 2012

Peritonitis and the rare sequela of encapsulating peritoneal sclerosis (EPS) are serious problems in patients on peritoneal dialysis therapy. Chronic and persistent peritoneal injuries may be a risk factor of EPS. We previously reported that a chronic, proliferative peritonitis developed when zymosan was administered intraperitoneally following scraping injury of rat peritoneum (Mizuno M, Ito Y, Hepburn N, Mizuno T, Noda Y, Yuzawa Y, Harris CL, Morgan BP, Matsuo S. J Immunol 183: 1403–1412, 2009). Peritoneal membrane complement regulators (CRegs), especially Crry and CD59, protected from injury by inhibiting local complement activation, suggesting that CRegs play important roles in maintaining homeostasis in rat peritoneum. Here, we investigated roles of complement in the development of EPS by neutralizing CReg function with monoclonal antibodies (MAbs). Proliferative peritonitis was induced by scraping the peritoneum, followed by daily intraperitoneal administration of zymosan. When either Crry or CD59 alone was neutralized by MAb, the tissue injuries were not significantly changed compared with rats without neutralizing MAb. When both Crry and CD59 were neutralized in this model, severe fibrin exudation was observed on the peritoneal surface on day 5, accompanied by inflammatory cell infiltration, resembling the early stages of development of EPS. Dense peritoneal deposition of C3 fragments and membrane attack complex were observed, along with the fibrin exudates. Intravenous administration of cobra venom factor, which profoundly activates complement, further enhanced these pathological changes. Our results show that complement activation in injured peritoneum drives peritoneal inflammation, and that enhancement of complement activation by inhibiting CReg and/or enhancing systemic activation contributes to the initiation of EPS; therefore, anti-complement agents might be of therapeutic value in humans for the treatment of EPS.
RKIP Suppresses Breast Cancer Metastasis to the Bone by Regulating Stroma-Associated Genes
Authors: Bevilacqua Elena , Frankenberger Casey A. , Rosner Marsha Rich
Published: February 2012

In the past decade cancer research has recognized the importance of tumorstroma interactions for the progression of primary tumors to an aggressive and invasive phenotype and for colonization of new organs in the context of metastasis. The dialogue between tumor cells and the surrounding stroma is a complex and dynamic phenomenon, as many cell types and soluble factors are involved. While the function of many of the players involved in this cross talk have been studied, the regulatory mechanisms and signaling pathways that control their expression haven’t been investigated in depth. By using a novel, interdisciplinary approach applied to the mechanism of action of the metastasis suppressor, Raf kinase inhibitory protein (RKIP), we identified a signaling pathway that suppresses invasion and metastasis through regulation of stroma-associated genes. Conceptually, the approach we developed uses a master regulator and expression arrays from breast cancer patients to formulate hypotheses based on clinical data. Experimental validation is followed by further bioinformatic analysis to establish the clinical significance of discoveries. Using RKIP as an example we show here that this multi-step approach can be used to identify gene regulatory mechanisms that affect tumor-stroma interactions that in turn influence metastasis to the bone or other organs.
The Experience in Nicaragua: Childhood Leukemia in Low Income Countries—The Main Cause of Late Diagnosis May Be “Medical Delay”
Authors: De Angelis C. , Pacheco C. , Lucchini G. , Arguello M. , Conter V. , Flores A. , Biondi A. , Masera G. , Baez F.
Published: February 2012

Background. The event-free survival for pediatric leukemia in low-income Countries is much lower than in high-income countries. Late diagnosis, which is regarded as a contributing factor, may be due to “parental” or “medical” delay.Procedures. The present study analyses determinants of lag time from first symptoms to diagnosis of leukemia, comparing pediatric (0–16 years old) patients in two referral centers, one in Nicaragua and one in Italy. An observational retrospective study was conducted to assess factors influencing the time to diagnosis.Results. 81 charts of children diagnosed with acute myeloid leukemia or lymphoblastic leukemia were analyzed from each centre. Median lag time to diagnosis was higher in Nicaragua than in Italy (29 versus 14 days,P<0.001) and it was mainly due to “physician delay” (16.5 versus 7 days,P<0.001), whereas “patient delay” from symptoms to first medical assessment was similar in the two centers (7 versus 5 days,P=0.27). Moreover, median lag time from symptoms to diagnosis was decreased in Nicaraguan districts were a specific training program upon childhood oncological diseases was carried out (20.5 versus 40 days,P=0.0019).Conclusions. Our study shows that delay in diagnosis of childhood leukemia is mainly associated with “physician delay” and it may be overcome by programs of continuous medical education.
Traditional Chinese Herbal Patch for Short-Term Management of Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Wang Xuezong , Cao Yuelong , Pang Jian , Du Jiong , Guo Chaoqing , Liu Ting , Wei Songpu , Zheng Yuxin , Chen Rongming , Zhan Hongsheng
Published: February 2012

Objective. To assess the short-term efficacy and safety of two kinds of Traditional Chinese herbal patches, Fufang Nanxing Zhitong Gao (FNZG) and Shangshi Jietong Gao (SJG), for painful knee osteoarthritis (OA).Methods. Patients were randomly enrolled in a double-blind, placebo-controlled study to receive FNZG (n=60), SJG (n=60), or placebo patch (n=30) for 7 days. Outcome measures included visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Traditional Chinese Medicine Syndrome Questionnaire (TCMSQ) subscale.Results. Although there was no significant difference among, three groups in short-term pain management, patients receiving FNZG got significant improvement in symptom of fear of coldness as compared with placebo patch (P=0.029). The most common local adverse events of rash, itching, erythema, and slightly damaged skin were observed in 7% of participants.Conclusions. FNZG may be a useful treatment for symptom of knee OA and merits long-term study in broader populations.
β-Catenin Signalling in Glioblastoma Multiforme and Glioma-Initiating Cells
Authors: Nager Mireia , Bhardwaj Deepshikha , Cantí Carles , Medina Loreta , Nogués Pere , Herreros Judit
Published: February 2012

Glioblastoma multiforme (GBM) is a commonly occurring brain tumor with a poor prognosis. GBM can develop both “de novo” or evolve from a previous astrocytoma and is characterized by high proliferation and infiltration into the surrounding tissue. Following treatment (surgery, radiotherapy, and chemotherapy), tumors often reappear. Glioma-initiating cells (GICs) have been identified in GBM and are thought to be responsible for tumors initiation, their continued growth, and recurrence.β-catenin, a component of the cell-cell adhesion complex and of the canonical Wnt pathway, regulates proliferation, adhesion, and migration in different cell types.β-catenin and components of the Wnt canonical pathway are commonly overexpressed in GBM. Here, we review previous work on the role of Wnt/β-catenin signalling in glioma initiation, proliferation, and invasion. Understanding the molecular mechanisms regulating GIC biology and glioma progression may help in identifying novel therapeutic targets for GBM treatment.
Stability Analysis and Design of Time‐Varying Nonlinear Systems Based on Impulsive Fuzzy Model
Authors: Wang Yuangan , Yu Honglin , Zhang Xiaohong , Li Dong
Published: February 2012

This paper develops a general analysis and design theory for nonlinear time‐varying systems represented by impulsive T‐S fuzzy control model, which extends conventional T‐S fuzzy model. In the proposed, model impulse is viewed as control input of T‐S model, and impulsive distance is the major controller to be designed. Several criteria on general stability, asymptotic stability, and exponential stability are established, and a simple design algorithm is provided with stability of nonlinear time‐invariant systems. Finally, the numerical simulation for the predator‐prey system with functional response and impulsive effects verify the effectiveness of the proposed methods.
A Risk Prediction Index for Amiodarone-Induced Thyrotoxicosis in Adults with Congenital Heart Disease
Authors: Stan Marius N. , Hess Erik P. , Bahn Rebecca S. , Warnes Carole A. , Ammash Naser M. , Brennan Michael D. , Thapa Prabin , Montori Victor M.
Published: February 2012

Amiodarone therapy in adults with congenital heart disease (CHD) is associated with a significant risk of amiodarone-induced thyrotoxicosis (AIT). We developed a risk index to identify those patients being considered for amiodarone treatment who are at high risk for AIT. We reviewed the health records of adults with CHD and assessed the association between potential clinical predictors and AIT. Significant predictors were included in multivariate analyses. The parameter estimates from multivariate analysis were subsequently used to develop a risk index. 169 adults met eligibility criteria and 23 developed AIT. The final model included age, cyanotic heart disease and BMI. The risk index developed identified 3 categories of risk. Their AIT likelihood ratios were: 0.37 for low risk (95% CI 0.15–0.92); 1.12 for medium risk (95% CI 0.65–1.91); and 3.47 for high risk (95% CI 1.7–7.11). The AIT predicted risk in our population was 5% for the low risk group, 15% for the medium risk group and 47% for the high risk group.Conclusions. We derived the first model to quantify the risk for developing AIT among adults with CHD. Before using it clinically to help selecting among alternative antiarrhythmic options, it needs validation in an independent population.
Case Report: Safety and Efficacy of Tocilizumab in a Patient with Rheumatoid Arthritis and Chronic Hepatitis C
Authors: Iebba Filippo , Di Sora Fiorella , Tarasi Agapito , Leti Wilma , Montella Tatiana , Montella Francesco
Published: February 2012

Tocilizumab is a monoclonal humanized anti-IL-6-receptor antibody used for the treatment of rheumatoid arthritis. The safety of tocilizumab in HCV patients is an open question. We report on safety and efficacy of tocilizumab in a 71-year-old female with rheumatoid arthritis and chronic hepatitis C. Monotherapy with tocilizumab (8 mg/kg every 4 weeks, i.v.) was prescribed after the discontinuation, determined by clinical inefficacy, of anti-TNF-alfa agents (adalimumab and, subsequently, etanercept). We have registered an optimal and rapid clinical response to tocilizumab with early remission (SDAI <3.3 since 4 weeks). The safety was good with no adverse events and maintenance, during a six-month followup, of normal liver enzymes. These data suggest a good safety profile of tocilizumab in patients with rheumatoid arthritis and chronic hepatitis C virus pathology.
Modulation of C1-Inhibitor and Plasma Kallikrein Activities by Type IV Collagen
Authors: Ravindran Sriram , Schapira Marc , Patston Philip A.
Published: February 2012

The contact system of coagulation can be activated when in contact with biomaterials. As collagen is being tested in novel biomaterials in this study, we have investigated how type IV collagen affects plasma kallikrein and C1-inhibitor. Firstly, we showed C1-inhibitor binds to type IV collagen with a Kd of 0.86 μM. The effects of type IV collagen on plasma kallikrein, factor XIIa, and β-factor XIIa activity and on C1-inhibitor function were determined. Factor XIIa rapidly lost activity in the presence of type IV collagen, whereas plasma kallikrein and β-factor XIIa were more stable. The rate of inhibition of plasma kallikrein by C1-inhibitor was decreased by type IV collagen in a dose-dependent manner. These studies could be relevant to the properties of biomaterials, which contain collagen, and should be considered in the testing for biocompatibility.
Static, Vibration, and Transient Dynamic Analyses by Beam Element with Adaptive Displacement Interpolation Functions
Authors: Li Shuang , Hu Jinjun , Zhai Changhai , Xie Lili
Published: February 2012

An approach to analyzing structures by using beam elements is developed with adaptive displacement interpolation functions. First, the element stiffness matrix and equivalent nodal loads are derived on the basis of the equilibrium between nodal forces and section forces rather than the compatibility between nodal deformations and section deformations, which avoids discretization errors caused by the limitation of conventional polynomial interpolation functions. Then, six adaptive element displacement interpolation functions are derived and extended to include several cases, such as beams with variable cross‐section, variable material properties, and many different steps in cross‐section and/or material properties. To make the element usable in dynamic analyses, consistent mass matrix (CMM) and diagonally lumped mass matrix (LMM) are constructed using the presented adaptive displacement interpolation functions. All these features have made the element elegant, which is tested with a number of simple static, vibration, and dynamic examples to show its accuracy.
Specific EEG Changes Associated with Atrophy of Hippocampus in Subjects with Mild Cognitive Impairment and Alzheimer's Disease
Authors: Moretti D. V. , Prestia A. , Fracassi C. , Binetti G. , Zanetti O. , Frisoni G. B.
Published: February 2012

We evaluated the association between hippocampal atrophy and increase of the EEG markers alpha3/alpha2 relative power ratio in mild cognitive impairment (MCI) and Alzheimer's disease patients. Seventy-nine subjects with MCI and 11 patients with AD underwent EEG recording and MRI scan. The MCI group was subdivided in three subgroups according to growing hippocampal atrophy. The groups were characterized by alpha3/alpha2 relative power ratio. In AD patients group mapped hippocampal regions were computed and related with alpha3/alpha2 power ratio. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of hippocampus both in MCI and in Alzheimer's disease patients. This finding confirms the possible diagnostic role of EEG markers as diagnostic and prognostic factors in patient with prodromal and declared Alzheimer's disease.
Straightforward Procedure for Laboratory Production of DNA Ladder
Authors: Lan Vo Thi Thuong , Loan Pham Thi Thanh , Duong Pham Anh Thuy , Thanh Le Thi , Ha Ngo Thi , Thuan Ta Bich
Published: February 2012

DNA ladder is commonly used to determine the size of DNA fragments by electrophoresis in routine molecular biology laboratories. In this study, we report a new procedure to prepare a DNA ladder that consists of 10 fragments from 100 to 1000 bp. This protocol is a combination of routinely employed methods: cloning, PCR, and partial digestion with restriction enzymes. DNA fragments of 100 bp with unique restriction site at both ends were self-ligated to create a tandem repeat. Once being cloned, the tandem repeat was rapidly amplified by PCR and partially digested by restriction enzymes to produce a ladder containing multimers of the repeated DNA fragments. Our procedure for production of DNA ladder could be simple, time saving, and inexpensive in comparison with current ones widely used in most laboratories.
Dietary Ganglioside Reduces Proinflammatory Signaling in the Intestine
Authors: Miklavcic John Janez , Schnabl Kareena Leanne , Mazurak Vera Christine , Thomson Alan Bryan Robert , Clandinin Michael Thomas
Published: February 2012

Gangliosides are integral to the structure and function of cell membranes. Ganglioside composition of the intestinal brush border and apical surface of the colon influences numerous cell processes including microbial attachment, cell division, differentiation, and signaling. Accelerated catabolism of ganglioside in intestinal disease results in increased proinflammatory signaling. Restoring proper structure and function to the diseased intestine can resolve inflammation, increase resistance to infection, and improve gut integrity to induce remission of conditions like necrotizing enterocolitis (NEC) and Crohn's disease (CD). Maintaining inactive state of disease may be achieved by reducing the rate that gangliosides are degraded or by increasing intake of dietary ganglioside. Collectively, the studies outlined in this paper indicate that the amount of gangliosides GM3 and GD3 in intestinal mucosa is decreased with inflammation, low level of GM3 is associated with higher production of proinflammatory signals, and ganglioside content of intestinal mucosa can be increased by dietary ganglioside.
Ovarian Volume Correlates Strongly with the Number of Nongrowing Follicles in the Human Ovary
Authors: Kelsey Thomas W. , Wallace W. Hamish B.
Published: February 2012

A reliable indirect measure of ovarian reserve for the individual woman remains a challenge for reproductive specialists. Using descriptive statistics from a large-scale study of ovarian volumes, we have developed a normative model for healthy females for ages 25 through 85. For average values, this model has a strong and positive correlation (r=0.89) with our recent model of nongrowing follicles (NGFs) in the human ovary for ages 25 through 51. When both models are log-adjusted, the correlation increases tor=0.99, over the full range of ovarian volume. Furthermore we can deduce that an ovary of 3 cm3volume (or less) contains approximately 1000 NGF (or fewer). These strong correlations indicate that ovarian volume is a useful factor in the indirect estimation of human ovarian reserve for the individual woman.