bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection
Authors: Thomas Rasmi , Thio Chloe L. , Apps Richard , Qi Ying , Gao Xiaojiang , Marti Darlene , Stein Judy L. , Soderberg Kelly A. , Moody M. Anthony , Goedert James J. , Kirk Gregory D. , Hoots W. Keith , Wolinsky Steven , Carrington Mary 
Published: April 2012

ABSTRACTVariants near theHLA-DPgene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphicHLA-DPB1andDPA1coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535;550A/G) in the 3′UTR of theHLA-DPB1gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39,P= 0.01, combined ethnic groups). However, we identified a novel variant in theHLA-DPB13′UTR region,496A/G(rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37,P= 0.0001, combined ethnic groups). The496A/Gvariant distinguishes the most protectiveHLA-DPB1allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas550A/Gdoes not.496A/Ghas a stronger effect than any individualHLA-DPB1orDPA1allele and any otherHLAalleles that showed an association with HBV recovery in our European-American cohort. The496GGgenotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
Distinct Effects of Two HIV-1 Capsid Assembly Inhibitor Families That Bind the Same Site within the N-Terminal Domain of the Viral CA Protein
Authors: Lemke Christopher T. , Titolo Steve , von Schwedler Uta , Goudreau Nathalie , Mercier Jean-François , Wardrop Elizabeth , Faucher Anne-Marie , Coulombe René , Banik Soma S. R. , Fader Lee , Gagnon Alexandre , Kawai Stephen H. , Rancourt Jean , Tremblay Martin , Yoakim Christiane , Simoneau Bruno , Archambault Jacques , Sundquist Wesley I. , Mason Stephen W. 
Published: April 2012

ABSTRACT

The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral capsid (CA) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids
in vitro
, and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology, and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an
in vitro
capsid assembly assay based on the association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM), resulted in compounds with potent antiviral activity against wild-type and drug-resistant HIV-1. Nuclear magnetic resonance (NMR) spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors but is expanded significantly by these new, more potent CA inhibitors. Virus release and electron microscopic (EM) studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited the formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action.
CD4+CD25+Regulatory T Cells Impair HIV-1-Specific CD4 T Cell Responses by Upregulating Interleukin-10 Production in Monocytes
Authors: Kwon Douglas S. , Angin Mathieu , Hongo Tomoyuki , Law Kenneth M. , Johnson Jessica , Porichis Filippos , Hart Meghan G. , Pavlik David F. , Tighe Daniel P. , Kavanagh Daniel G. , Streeck Hendrik , Addo Marylyn M. , Kaufmann Daniel E. 
Published: April 2012

ABSTRACTT cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-γ) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-γ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14+monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.
A Triclade DNA Vaccine Designed on the Basis of a Comprehensive Serologic Study Elicits Neutralizing Antibody Responses against All Clades and Subclades of Highly Pathogenic Avian Influenza H5N1 Viruses
Authors: Zhou Fan , Wang Guiqin , Buchy Philippe , Cai Zhipeng , Chen Honglin , Chen Zhiwei , Cheng Genhong , Wan Xiu-Feng , Deubel Vincent , Zhou Paul 
Published: April 2012

ABSTRACTBecause of their rapid evolution, genetic diversity, broad host range, ongoing circulation in birds, and potential human-to-human transmission, H5N1 influenza viruses remain a major global health concern. Their high degree of genetic diversity also poses enormous burdens and uncertainties in developing effective vaccines. To overcome this, we took a new approach, i.e., the development of immunogens based on a comprehensive serologic study. We constructed DNA plasmids encoding codon-optimized hemagglutinin (HA) from 17 representative strains covering all reported clades and subclades of highly pathogenic avian influenza H5N1 viruses. Using DNA plasmids, we generated the corresponding H5N1 pseudotypes and immune sera. We performed an across-the-board pseudotype-based neutralization assay and determined antigenic clusters by cartography. We then designed a triclade DNA vaccine and evaluated its immunogenicity and protection in mice. We report here that (sub)clades 0, 1, 3, 4, 5, 6, 7.1, and 9 were grouped into antigenic cluster 1, (sub)clades 2.1.3.2, 2.3.4, 2.4, 2.5, and 8 were grouped into another antigenic cluster, with subclade 2.2.1 loosely connected to it, and each of subclades 2.3.2.1 and 7.2 was by itself. Importantly, the triclade DNA vaccine encoding HAs of (sub)clades 0, 2.3.2.1, and 7.2 elicited broadly neutralizing antibody responses against all H5 clades and subclades and protected mice against high-lethal-dose heterologous H5N1 challenge. Thus, we conclude that broadly neutralizing antibodies against all H5 clades and subclades can indeed be elicited with immunogens on the basis of a comprehensive serologic study. Further evaluation and optimization of such an approach in ferrets and in humans is warranted.
Uncommon Pathways of Immune Escape Attenuate HIV-1 Integrase Replication Capacity
Authors: Brockman Mark A. , Chopera Denis R. , Olvera Alex , Brumme Chanson J. , Sela Jennifer , Markle Tristan J. , Martin Eric , Carlson Jonathan M. , Le Anh Q. , McGovern Rachel , Cheung Peter K. , Kelleher Anthony D. , Jessen Heiko , Markowitz Martin , Rosenberg Eric , Frahm Nicole , Sanchez Jorge , Mallal Simon , John Mina , Harrigan P. Richard , Heckerman David , Brander Christian , Walker Bruce D. , Brumme Zabrina L. 
Published: April 2012

ABSTRACT

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early (
n
= 88) and chronic (
n
= 304) infections and measured the
in vitro
RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (
R
= −0.2;
P
= 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all
q
< 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF
114–121
) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ∼35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.
A Single Amino Acid at the Hemagglutinin Cleavage Site Contributes to the Pathogenicity and Neurovirulence of H5N1 Influenza Virus in Mice
Authors: Zhang Yi , Sun Yipeng , Sun Honglei , Pu Juan , Bi Yuhai , Shi Yi , Lu Xishan , Li Jing , Zhu Qingyu , Gao George F. , Yang Hanchun , Liu Jinhua 
Published: April 2012

ABSTRACT

H5 influenza viruses containing a motif of multiple basic amino acids at the hemagglutinin (HA) cleavage site (HACS) are highly pathogenic in chicken but display different virulence phenotypes in mammals. Previous studies have shown that multiple basic amino acids of H5N1 influenza virus are a prerequisite for lethality in mice. However, it remains unclear which specific residue at the cleavage site affects the pathogenicity of H5N1 in mammals. A comprehensive genetic analysis of the H5N1 HACS showed that residues at P6 (position 325, by H3 numbering) were the most polymorphic, including serine (S), arginine (R), deletion (*), glycine (G), and isoleucine (I). To determine whether a single residue at P6 could affect virulence, we introduced different mutations at P6 of an avirulent clade 7 H5N1 strain, rg325G, by reverse genetics. Among the recombinant viruses, the rg325S virus showed the highest cleavage efficiency
in vitro
. All these viruses were highly pathogenic in chicken but exhibited different virulences in mice. The rg325S virus exhibited the highest pathogenicity in terms of unrestricted organ tropism and neurovirulence. Remarkably, the HA-325S substitution dramatically increased the pathogenicity of H5N1 viruses of other clades, including clades 2.2, 2.3.2, and 2.3.4, indicating that this residue impacts genetically divergent H5N1 viruses. An analysis of predicted structures containing these mutations showed that the cleavage site loop with 325S was the most exposed, which might be responsible for the efficient cleavage and high virulence. Our results demonstrate that an amino acid substitution at the P6 cleavage site alone could modulate the virulence of H5N1 in mice.
Structural Insight into the Unique Properties of Adeno-Associated Virus Serotype 9
Authors: DiMattia Michael A. , Nam Hyun-Joo , Van Vliet Kim , Mitchell Matthew , Bennett Antonette , Gurda Brittney L. , McKenna Robert , Olson Norman H. , Sinkovits Robert S. , Potter Mark , Byrne Barry J. , Aslanidi George , Zolotukhin Sergei , Muzyczka Nicholas , Baker Timothy S. , Agbandje-McKenna Mavis 
Published: April 2012

ABSTRACT
Adeno-associated virus serotype 9 (AAV9) has enhanced capsid-associated tropism for cardiac muscle and the ability to cross the blood-brain barrier compared to other AAV serotypes. To help identify the structural features facilitating these properties, we have used cryo-electron microscopy (cryo-EM) and three-dimensional image reconstruction (cryo-reconstruction) and X-ray crystallography to determine the structure of the AAV9 capsid at 9.7- and 2.8-Å resolutions, respectively. The AAV9 capsid exhibits the surface topology conserved in all AAVs: depressions at each icosahedral two-fold symmetry axis and surrounding each five-fold axis, three separate protrusions surrounding each three-fold axis, and a channel at each five-fold axis. The AAV9 viral protein (VP) has a conserved core structure, consisting of an eight-stranded, β-barrel motif and the αA helix, which are present in all parvovirus structures. The AAV9 VP differs in nine variable surface regions (VR-I to -IX) compared to AAV4, but at only three (VR-I, VR-II, and VR-IV) compared to AAV2 and AAV8. VR-I differences modify the raised region of the capsid surface between the two-fold and five-fold depressions. The VR-IV difference produces smaller three-fold protrusions in AAV9 that are less “pointed” than AAV2 and AAV8. Significantly, residues in the AAV9 VRs have been identified as important determinants of cellular tropism and transduction and dictate its antigenic diversity from AAV2. Hence, the AAV9 VRs likely confer the unique infection phenotypes of this serotype.
OBSERVATIONS OF PARTICLE ACCELERATION IN THE BLAST WAVES OF GAMMA-RAY BURSTS
Authors: CURRAN PETER A. 
Published: April 2012

The electron energy distribution index, p, is a fundamental parameter of the process by which electrons at shock fronts are accelerated to relativistic speeds and by which they radiate, via synchrotron emission. This acceleration process is applicable to a myriad of astronomical jet sources such as AGN, X-ray binaries and gamma-ray bursts (GRBs), as well as to particle acceleration in the solar wind and supernovae, and the acceleration of cosmic rays. The accurate measurement of the distribution of p is of fundamental importance to differentiate between the possible theories of electron acceleration at any relativistic shock front; there is division as to whether p has a universal value or whether it has a distribution, and if so, what that distribution is. Here one such source of synchrotron emission is examined: the blast waves of GRB afterglows observed by the Swift satellite. Within the framework of the GRB blast wave model, the constraints placed on the distribution of p by the observed X-ray spectral and temporal indices are examined and the distribution parametrized. The results show that the observed distribution of spectral indices is inconsistent with an underlying distribution of p composed of a single discrete value but consistent with a Gaussian distribution centred at p = 2.4 and having a width of 0.6. This finding disagrees with theoretical work that argues for a single, universal value of p, but also demonstrates that the width of the distribution is not as wide as has been suggested by some authors.
LARGE-SCALE MAGNETIC FIELD IN ACCRETION DISKS AND RELATIVISTIC POYNTING-FLUX JETS
Authors: LOVELACE R. V. E. , BISNOVATYI-KOGAN G. S. 
Published: April 2012

In earlier works we pointed out that the disk's surface layers are non-turbulent and thus highly conducting (or non-diffusive) because of hydrodynamic and/or magnetorotational (MRI) instabilities are suppressed high in the disk where the magnetic and radiation pressures are larger than the plasma thermal pressure. We have derived equations for the vertical profiles of stationary accretion flows (with radial and azimuthal components), and the profiles of the large-scale, magnetic field taking into account the turbulent viscosity and diffusivity and the fact that the turbulence vanishes at the surface of the disk. Our recent analysis in Ref. 1 shows that the inward or outward advection of the large-scale magnetic field depends on the ratio [Formula: see text] of the accretion power going into magnetic disk winds to the viscous power dissipation and the plasma-β which is the ratio of the midplane plasma pressure to the magnetic pressure. Recent radio emission, polarization, and Faraday rotation maps of the radio jet of the galaxy 3C303 have been obtained in Ref. 2 and show that one component of this jet has a galactic-scale electric current of ~ 3 × 1018 A flowing along the jet axis. We show that this current can be used to calculate the electromagnetic energy flow in this magnetically dominated jet.
MULTIWAVELENGTH OBSERVATIONS OF PKS 0528+134 IN QUIESCENCE
Authors: BÖTTCHER MARKUS , PALMA NORMAN 
Published: April 2012

We present results of multiwavelength observations of the ultraluminous radio-loud quasar PKS 0528+134 in quiescence in the Fall of 2009. Significant flux variability on a time-scale of several hours was found in the optical regime, accompanied by a weak trend of spectral softening with increasing flux. The optical flux is weakly polarized with rapid variations of the degree and direction of polarization. Optical spectropolarimetry suggests a trend of increasing degree of polarization with increasing wavelength. Together with the spectral variability, this provides evidence for an unpolarized, slowly variable emission component, possibly thermal emission from the accretion disk, contributing towards the blue end of the optical spectrum. We find that even in the quiescent state, the bolometric luminosity of PKS 0528+134 is dominated by its γ-ray emission. A leptonic single-zone jet model produced acceptable fits to the SEDs with contributions to the high-energy emission from both synchrotron self-Compton radiation and Comptonization of direct accretion disk emission. The moderate variability on long time scales, compared to the expected radiative cooling time scales, implies the existence of on-going particle acceleration, while the observed optical polarization variability seems to point towards a turbulent acceleration process.
Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
Authors: Rudin Charles M. , Hann Christine L. , Garon Edward B. , Ribeiro de Oliveira Moacyr , Bonomi Philip D. , Camidge D. Ross , Chu Quincy , Giaccone Giuseppe , Khaira Divis , Ramalingam Suresh S. , Ranson Malcolm R. , Dive Caroline , McKeegan Evelyn M. , Chyla Brenda J. , Dowell Barry L. , Chakravartty Arunava , Nolan Cathy E. , Rudersdorf Niki , Busman Todd A. , Mabry Mack H. , Krivoshik Andrew P. , Humerickhouse Rod A. , Shapiro Geoffrey I. , Gandhi Leena 
Published: April 2012

Abstract
Purpose: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy.
Experimental Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates.
Results: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III–IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro–gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit.
Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163–9. ©2012 AACR.
Dibenzophenanthridines as Inhibitors of Glutaminase C and Cancer Cell Proliferation
Authors: Katt William P. , Ramachandran Sekar , Erickson Jon W. , Cerione Richard A. 
Published: April 2012

Abstract
One hallmark of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. Glutaminase, a mitochondrial enzyme, plays a key role in the metabolism of glutamine in cancer cells, and its inhibition could significantly impact malignant transformation. The small molecule 968, a dibenzophenanthridine, was recently shown to inhibit recombinantly expressed glutaminase C, to block the proliferation and anchorage-independent colony formation of human cancer cells in culture, and to inhibit tumor formation in mouse xenograft models. Here, we examine the structure–activity relationship that leads to 968-based inhibition of glutaminase and cancer cell proliferation, focusing upon a “hot-spot” ring previously identified as critical to 968 activity. We find that the hot-spot ring must be substituted with a large, nonplanar functionality (e.g., a t-butyl group) to bestow activity to the series, leading us to a model whereby the molecule binds glutaminase at a previously undescribed allosteric site. We conduct docking studies to locate potential 968-binding sites and proceed to test a specific set of docking solutions via site-directed mutagenesis. We verify the results from our initial assay of 968 and its analogues by cellular studies using MDA-MB-231 breast cancer cells. Mol Cancer Ther; 11(6); 1269–78. ©2012 AACR.