bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Strongly Transdominant Mutation in the Human Immunodeficiency Virus Type 1
gag
Gene Defines an Achilles Heel in the Virus Life Cycle
Authors: Lee Sook-Kyung , Harris Janera , Swanstrom Ronald 
Published: June 2009

ABSTRACT
The human immunodeficiency virus type 1 (HIV-1) protease (PR) makes five obligatory cleavages in the viral Gag polyprotein precursor. The cleavage events release the virion structural proteins from the precursor and allow the virion to undergo maturation to become infectious. The protease cleavage between the matrix protein (MA) domain and the adjacent capsid protein (CA) domain releases CA from the membrane-anchored MA and allows the N terminus of CA to refold into a structure that facilitates the formation of hexamer arrays that represent the structural unit of the capsid shell. In this study, we analyzed the extent to which each of the HIV-1 Gag processing sites must be cleaved by substituting the P1-position amino acid at each processing site with Ile. A mutation that blocks cleavage at the MA/CA processing site (Y132I) displayed a strong transdominant effect when tested in a phenotypic mixing strategy, inhibiting virion infectivity with a 50% inhibitory concentration of only 4% of the mutant relative to the wild type. This mutation is 10- to 20-fold more potent in phenotypic mixing than an inactivating mutation in the viral protease, the target of many successful inhibitors, and more potent than an inactivating mutation at any of the other Gag cleavage sites. The transdominant effect is manifested as the assembly of an aberrant virion core. Virus containing 20% of the Y132I mutant and 80% of the wild type (to assess the transdominant effect on infectivity) was blocked either before reverse transcription (RT) or at an early RT step. The ability of a small amount of the MA/CA fusion protein to poison the oligomeric assembly of infectious virus identifies an essential step in the complex process of virion formation and maturation. The effect of a small-molecule inhibitor that is able to block MA/CA cleavage even partially would be amplified by this transdominant negative effect on the highly orchestrated process of virion assembly.
A Charged Second-Site Mutation in the Fusion Peptide Rescues Replication of a Mutant Avian Sarcoma and Leukosis Virus Lacking Critical Cysteine Residues Flanking the Internal Fusion Domain
Authors: Melder Deborah C. , Yin Xueqian , Delos Sue E. , Federspiel Mark J. 
Published: June 2009

ABSTRACT
The entry process of the avian sarcoma and leukosis virus (ASLV) family of retroviruses requires first a specific interaction between the viral surface (SU) glycoproteins and a receptor on the cell surface at a neutral pH, triggering conformational changes in the viral SU and transmembrane (TM) glycoproteins, followed by exposure to low pH to complete fusion. The ASLV TM glycoprotein has been proposed to adopt a structure similar to that of the Ebola virus GP2 protein: each contains an internal fusion peptide flanked by cysteine residues predicted to be in a disulfide bond. In a previous study, we concluded that the cysteines flanking the internal fusion peptide in ASLV TM are critical for efficient function of the ASLV viral glycoproteins in mediating entry. In this study, replication-competent ASLV mutant subgroup A [ASLV(A)] variants with these cysteine residues mutated were constructed and genetically selected for improved replication capacity in chicken fibroblasts. Viruses with single cysteine-to-serine mutations reverted to the wild-type sequence. However, viruses with both C9S and C45S (C9,45S) mutations retained both mutations and acquired a second-site mutation that significantly improved the infectivity of the genetically selected virus population. A charged-amino-acid second-site substitution in the TM internal fusion peptide at position 30 is preferred to rescue the C9,45S mutant ASLV(A). ASLV(A) envelope glycoproteins that contain the C9,45S and G30R mutations bind the Tva receptor at wild-type levels and have improved abilities to trigger conformational changes and to form stable TM oligomers compared to those of the C9,45S mutant glycoprotein.
Structural and Functional Elements of the Promoter Encoded by the 5′ Untranslated Region of the Venezuelan Equine Encephalitis Virus Genome
Authors: Kulasegaran-Shylini Raghavendran , Atasheva Svetlana , Gorenstein David G. , Frolov Ilya 
Published: June 2009

ABSTRACT

Venezuelan equine encephalitis virus (VEEV) is one of the most pathogenic members of the
Alphavirus
genus in the
Togaviridae
family. The pathogenesis of this virus depends strongly on the sequences of the structural proteins and on the mutations in the RNA promoter encoded by the 5′ untranslated region (5′UTR) of the viral genome. In this study, we performed a detailed investigation of the structural and functional elements of the 5′-terminal promoter and analyzed the effect of multiple mutations introduced into the VEEV 5′UTR on virus and RNA replication. The results of this study demonstrate that RNA replication is determined by two synergistically functioning RNA elements. One of them is a very 5′-terminal AU dinucleotide, which is not involved in the stable RNA secondary structure, and the second is a short, G-C-rich RNA stem. An increase or decrease in the stem's stability has deleterious effects on virus and RNA replication. In response to mutations in these RNA elements, VEEV replicative machinery was capable of developing new, compensatory sequences in the 5′UTR either containing 5′-terminal AUG or AU repeats or leading to the formation of new, heterologous stem-loops. Analysis of the numerous compensatory mutations suggested that at least two different mechanisms are involved in their generation. Some of the modifications introduced into the 5′ terminus of the viral genome led to an accumulation of the mutations in the VEEV nsPs, which suggested to us that there is a direct involvement of these proteins in promoter recognition. Furthermore, our data provide new evidence that the 3′ terminus of the negative-strand viral genome in the double-stranded RNA replicative intermediate is represented by a single-stranded RNA. Both the overall folding and the sequence determine its efficient function as a promoter for VEEV positive-strand RNA genome synthesis.
Balancing Reversion of Cytotoxic T-Lymphocyte and Neutralizing Antibody Escape Mutations within Human Immunodeficiency Virus Type 1 Env upon Transmission
Authors: Peut Viv , Campbell Shahan , Gaeguta Adriana , Center Rob J. , Wilson Kim , Alcantara Sheilajen , Fernandez Caroline S. , Purcell Damian F. J. , Kent Stephen J. 
Published: June 2009

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) is subject to both neutralizing antibody (NAb) and CD8 T-cell (cytotoxic T-lymphocyte [CTL]) immune pressure. We studied the reversion of the Env CTL escape mutant virus to the wild type and the relationship between the reversion of CTL mutations with N-linked glycosylation site (NLGS)-driven NAb escape in pigtailed macaques. Env CTL mutations either did not revert to the wild type or only transiently reverted 5 to 7 weeks after infection. The CTL escape mutant reversion was coincident, for the same viral clones, with the loss of NLGS mutations. At one site studied, both CTL and NLGS mutations were needed to confer NAb escape. We conclude that CTL and NAb escape within Env can be tightly linked, suggesting opportunities to induce effective multicomponent anti-Env immunity.
Phage Display Selection of Cyclic Peptides That Inhibit Andes Virus Infection
Authors: Hall Pamela R. , Hjelle Brian , Njus Hadya , Ye Chunyan , Bondu-Hawkins Virginie , Brown David C. , Kilpatrick Kathleen A. , Larson Richard S. 
Published: June 2009

ABSTRACT
Specific therapy is not available for hantavirus cardiopulmonary syndrome caused by Andes virus (ANDV). Peptides capable of blocking ANDV infection in vitro were identified using antibodies against ANDV surface glycoproteins Gn and Gc to competitively elute a cyclic nonapeptide-bearing phage display library from purified ANDV particles. Phage was examined for ANDV infection inhibition in vitro, and nonapeptides were synthesized based on the most-potent phage sequences. Three peptides showed levels of viral inhibition which were significantly increased by combination treatment with anti-Gn- and anti-Gc-targeting peptides. These peptides will be valuable tools for further development of both peptide and nonpeptide therapeutic agents.
The Polycomb Group Protein Bmi1 Binds to the Herpes Simplex Virus 1 Latent Genome and Maintains Repressive Histone Marks during Latency
Authors: Kwiatkowski Dacia L. , Thompson Hilary W. , Bloom David C. 
Published: June 2009

ABSTRACT
The mechanism by which herpes simplex virus 1 (HSV-1) establishes latency in sensory neurons is largely unknown. Recent studies indicate that epigenetic modifications of the chromatin associated with the latent genome may play a key role in the transcriptional control of lytic genes during latency. In this study, we found both constitutive and facultative types of heterochromatin to be present on the latent HSV-1 genome. Deposition of the facultative marks trimethyl H3K27 and histone variant macroH2A varied at different sites on the genome, whereas the constitutive marker trimethyl H3K9 did not. In addition, we show that in the absence of the latency-associated transcript (LAT), the latent genome shows a dramatic increase in trimethyl H3K27, suggesting that expression of the LAT during latency may act to promote an appropriate heterochromatic state that represses lytic genes but is still poised for reactivation. Due to the presence of the mark trimethyl H3K27, we examined whether Polycomb group proteins, which methylate H3K27, were present on the HSV-1 genome during latency. Our data indicate that Bmi1, a member of the Polycomb repressive complex 1 (PRC1) maintenance complex, associates with specific sites in the genome, with the highest level of enrichment at the LAT enhancer. To our knowledge, these are the first data demonstrating that a virus can repress its gene transcription to enter latency by exploiting the mechanism of Polycomb-mediated repression.
Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production
Authors: Lin Adora A. , Tripathi Pulak K. , Sholl Allyson , Jordan Michael B. , Hildeman David A. 
Published: June 2009

ABSTRACTIntracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-γ). Here, we assessed the role of CD4+T cells and IFN-γ on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-γ, CCL2 (MCP-1), CCL3 (MIP-1α), and CCL5 (RANTES) in the cerebrospinal fluid (CSF). Mice deficient in IFN-γ had decreased CSF levels of CCL3, CCL5, and CXCL10 (IP-10), and decreased activation of both resident CNS and infiltrating antigen-presenting cells (APCs). The effects of IFN-γ signaling on macrophage lineage cells was assessed using transgenic mice, called “macrophages insensitive to interferon gamma” (MIIG) mice, that express a dominant-negative IFN-γ receptor under the control of the CD68 promoter. MIIG mice had decreased levels of CCL2, CCL3, CCL5, and CXCL10 compared to controls despite having normal numbers of LCMV-specific CD4+T cells in the CNS. MIIG mice also had decreased recruitment of infiltrating macrophages and decreased activation of both resident CNS and infiltrating APCs. Finally, MIIG mice were significantly protected from LCMV-induced anorexia and weight loss. Thus, these data suggest that CD4+T-cell production of IFN-γ promotes signaling in macrophage lineage cells, which control (i) the production of proinflammatory cytokines and chemokines, (ii) the recruitment of macrophages to the CNS, (iii) the activation of resident CNS and infiltrating APC populations, and (iv) anorexic weight loss.
Spurious and counterfeit drugs: a growing industry in the developing world
Authors: Gautam C S , Utreja A , Singal G L 
Published: June 2009

Abstract
Spread of spurious/counterfeit/substandard drugs is a modern day menace which has been recognised internationally, especially so in developing countries. The problem assumes added significance in view of rapid globalisation. The market of spurious and counterfeit drugs is a well-organised, white collar crime. Poverty, high cost of medicines, lack of an official supply chain, legislative lacunae, easy accessibility to computerised printing technology, ineffective law enforcement machinery, and light penalties provide the counterfeiters with an enormous economic incentive without much risk. The consequences of the use of such medicines may vary from therapeutic failure to the occurrence of serious adverse events and even death. Proper drug quality monitoring, enforcement of laws and legislation, an effective and efficient regulatory environment, and awareness and vigilance on part of all stakeholders can help tackle this problem.
Prevalence of diagnosed depression in South Asian and white European people with type 1 and type 2 diabetes mellitus in a UK secondary care population
Authors: Ali S , Davies M J , Taub N A , Stone M A , Khunti K 
Published: June 2009

Abstract

Aim
To examine the prevalence and correlates of diagnosed depression among South Asians and white Europeans with type 1 and type 2 diabetes mellitus, attending a specialist diabetes clinic in the UK.

Study design and methods
A cross-sectional study was conducted using the hospital clinic’s computerised database. Medical and demographic data were extracted for 6230 people with diabetes attending the clinic between 2003 and 2005. Multiple logistic regression was used to model ethnic differences in the probability of diagnosed depression after controlling for demographic and diabetes related factors. Analyses were conducted separately for type 1 and type 2 diabetes.

Results
The unadjusted prevalence of depression in people with type 1 and type 2 diabetes was 8.0% and 9.3%, respectively. Risk factors for depression in type 1 diabetes included female gender, diabetes related complications, and comorbidities. In people with type 2 diabetes the risk factors for depression included younger age, diabetes related complications, comorbidities, insulin use and deprivation. In addition, white Europeans were significantly more likely to be diagnosed with depression compared to South Asians (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.21 to 2.08; p&lt;0.001). Further interaction analyses revealed no evidence that the association between ethnicity and depression differed according to any of the other factors examined in this study.

Conclusions
The findings add to the limited body of knowledge regarding ethnic differences in depression and diabetes. Among those with type 2 diabetes, white Europeans had nearly 60% higher adjusted odds of diagnosed depression compared to South Asians. Disparities may be due to differences in presentation or identification of depression between these two ethnic groups.
Ruptured abdominal aortic aneurysm: a surgical emergency with many clinical presentations
Authors: Assar A N , Zarins C K 
Published: June 2009

Abstract
Ruptured abdominal aortic aneurysm (AAA) is one of the most fatal surgical emergencies, with an overall mortality rate of 90%. Most AAAs rupture into the retroperitoneal cavity, which results in the classical triad of pain, hypotension, and a pulsatile mass. However, this triad is seen in only 25–50% of patients, and many patients with ruptured AAA are misdiagnosed. It is likely that different sites of rupture of AAA determine a variety of common and uncommon clinical presentations, the recognition of which can save many lives. This article reviews the different sites of rupture of infrarenal AAA and explores the evidence behind the various clinical presentations seen in patients with ruptured AAA.
Novel therapeutic agents and strategies for the management of chronic kidney disease mineral and bone disorder
Authors: Connor A 
Published: June 2009

Abstract
Abnormalities in the serum concentrations of calcium, phosphate, parathyroid hormone and vitamin D develop with declining renal function, leading in turn to renal osteodystrophy. Observational data now suggest that these disturbances in bone and mineral metabolism play an important role in the development of vascular calcification and subsequent cardiovascular disease, contributing to the high burden of cardiovascular disease within this population. A new nomenclature—“chronic kidney disease mineral and bone disorder”—has been introduced to describe this broader clinical syndrome and reflect the new emphasis that has been placed upon its management. This article describes the current therapeutic options for this condition, focusing particularly on the novel medications and strategies that have recently been introduced, and highlighting promising therapeutic possibilities for the future.
Deep hypothermia impact on acid–base parameters and liver antioxidant status in an in vivo rat model
Authors: Alva Norma , Carbonell Teresa , Palomeque Jesús 
Published: June 2009

Although clinical hypothermia is used for reducing postischemic damage, injurious effects have also been reported. To determine whether hypoxia and oxidative stress are induced by systemic deep hypothermia, we used an in vivo rat model keeping the arterial Pco2constant. Animals were divided into 4 groups: sham, 2 h deep hypothermia (21 °C), 1 h posthypothermia (rewarmed to 37 °C after 2 h deep hypothermia), and 3 h normothermia. Blood gases, portal vein blood flow, arterial pressure, and heart rate were monitored throughout the experiment. Liver enzyme antioxidant activity was also examined. The hemodynamic parameters decreased drastically during hypothermia, but were fully restored after rewarming. No changes in hepatic antioxidant activity (catalase, glutathione peroxidase, and superoxide dismutase) were observed. The redox level in liver (GSH/GSSG ratio) was preserved in hypothermia but decreased when animals were rewarmed. ALT did not increase and no evidence of tissue hypoxia was detected in liver regarding the restricted flow during hypothermia. With the described protocol, deep hypothermia is regarded as an experimental safe model.
Growth and reproduction of female eastern and whitebelly spinner dolphins incidentally killed in the eastern tropical Pacific tuna purse-seine fishery
Authors: Larese Jason P. , Chivers Susan J. 
Published: June 2009

Life-history parameters are estimated for two forms of the spinner dolphin ( Stenella longirostris (Gray, 1828)): the eastern subspecies ( Stenella longirostris orientalis Perrin, 1990) and the whitebelly hybrid. The data analyzed (n = 3138 eastern and 3099 whitebelly spinner dolphins) were collected between 1968 and 1994 from female dolphins incidentally killed in the yellowfin tuna ( Thunnus albacares (Bonnaterre, 1788)) purse-seine fishery that operates in the eastern tropical Pacific Ocean. Eastern spinner dolphins averaged 79.7 cm at birth, 121.5 cm at 1 year, and 171.5 cm at asymptotic length, and had a mean annual pregnancy rate of 0.351 and a calving interval of 2.84 years. Whitebelly spinner dolphins averaged 80.2 cm at birth, 122.5 cm at 1 year, and 177.1 cm at asymptotic length, and had a mean annual pregnancy rate of 0.329 and calving interval of 3.04 years. The mean age at attainment of sexual maturity was estimated to be 8.7 and 8.4 years for eastern and whitebelly spinner dolphins, respectively, which are 3.2 and 1.7 years older than those previously published. This difference indicates that the mean reproductive output during a female’s life is lower than previously expected and likely translates into lower population growth rates.
Summer Severe-Rainfall Frequency Trend and Variability over Ontario, Canada
Authors: Cao Zuohao , Ma Jianmin 
Published: June 2009

Abstract
During the last two decades (1979–2002), there has been an ever-increasing frequency of summer severe-rainfall events over Ontario, Canada. This observed upward trend is robust as demonstrated through the Mann–Kendall test with consideration of removing a lag-1 autoregressive process. It is shown through composite analyses using the NCEP reanalysis data that in the presence of warming conditions the summer severe-rainfall events occur more frequently over Ontario, especially under atmospheric conditions with stronger low-level cyclonic circulations and more precipitable water. Further analyses indicate that over north and central Ontario the summer severe-rainfall frequency is linked with a positive trend of precipitable water whereas over central and south Ontario there is a strong interannual response of summer severe-rainfall frequency to the changes in precipitable water through the variations of air temperature.
The Role of the Sahara Low in Summertime Sahel Rainfall Variability and Change in the CMIP3 Models
Authors: Biasutti M. , Sobel A. H. , Camargo Suzana J. 
Published: June 2009

Abstract
Projections for twenty-first-century changes in summertime Sahel precipitation differ greatly across models in the third Coupled Model Intercomparison Project (CMIP3) dataset and cannot be explained solely in terms of discrepancies in the projected anomalies in global SST.
This study shows that an index describing the low-level circulation in the North Atlantic–African region, namely, the strength of the low-level Saharan low, correlates with Sahel rainfall in all models and at the time scales of both interannual and interdecadal natural variability and of the forced centennial trend.
An analysis of Sahel interannual variability provides evidence that variations in the Sahara low can be a cause, not just a consequence, of variations in Sahel rainfall and suggests that a better understanding of the sources of model discrepancy in Sahel rainfall predictions might be gained from an analysis of the mechanisms influencing changes in the Sahara low.