bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latency-Associated Transcript (LAT) Exon 1 Controls Herpes Simplex Virus Species-Specific Phenotypes: Reactivation in the Guinea Pig Genital Model and Neuron Subtype-Specific Latent Expression of LAT
Authors: Bertke Andrea S. , Patel Amita , Imai Yumi , Apakupakul Kathleen , Margolis Todd P. , Krause Philip R. 
Published: July 2009

ABSTRACT
Herpes simplex virus 1 (HSV-1) and HSV-2 cause similar acute infections but differ in their abilities to reactivate from trigeminal and lumbosacral dorsal root ganglia. During latency, HSV-1 and HSV-2 also preferentially express their latency-associated transcripts (LATs) in different sensory neuronal subtypes that are positive for A5 and KH10 markers, respectively. Chimeric virus studies showed that LAT region sequences influence both of these viral species-specific phenotypes. To further map the LAT region sequences responsible for these phenotypes, we constructed the chimeric virus HSV2-LAT-E1, in which exon 1 (from the LAT TATA to the intron splice site) was replaced by the corresponding sequence from HSV-1 LAT. In intravaginally infected guinea pigs, HSV2-LAT-E1 reactivated inefficiently relative to the efficiency of its rescuant and wild-type HSV-2, but it yielded similar levels of viral DNA, LAT, and ICP0 during acute and latent infection. HSV2-LAT-E1 preferentially expressed the LAT in A5+ neurons (as does HSV-1), while the chimeric viruses HSV2-LAT-P1 (LAT promoter swap) and HSV2-LAT-S1 (LAT sequence swap downstream of the promoter) exhibited neuron subtype-specific latent LAT expression phenotypes more similar to that of HSV-2 than that of HSV-1. Rescuant viruses displayed the wild-type HSV-2 phenotypes of efficient reactivation in the guinea pig genital model and a tendency to express LAT in KH10+ neurons. The region that is critical for HSV species-specific differences in latency and reactivation thus lies between the LAT TATA and the intron splice site, and minor differences in the 5′ ends of chimeric sequences in HSV2-LAT-E1 and HSV2-LAT-S1 point to sequences immediately downstream of the LAT TATA.
Stable Docking of Neutralizing Human Immunodeficiency Virus Type 1 gp41 Membrane-Proximal External Region Monoclonal Antibodies 2F5 and 4E10 Is Dependent on the Membrane Immersion Depth of Their Epitope Regions
Authors: Dennison S. Moses , Stewart Shelley M. , Stempel Kathryn C. , Liao Hua-Xin , Haynes Barton F. , Alam S. Munir 
Published: July 2009

ABSTRACT
The binding of neutralizing antibodies 2F5 and 4E10 to human immunodeficiency virus type 1 (HIV-1) gp41 involves both the viral membrane and gp41 membrane proximal external region (MPER) epitopes. In this study, we have used several biophysical tools to examine the secondary structure, orientation, and depth of immersion of gp41 MPER peptides in liposomes and to determine how the orientation of the MPER with lipids affects the binding kinetics of monoclonal antibodies (MAbs) 2F5 and 4E10. The binding of 2F5 and 4E10 both to their respective nominal epitopes and to a biepitope (includes 2F5 and 4E10 epitopes) MPER peptide-liposome conjugate was best described by a two-step encounter-docking model. Analysis of the binding kinetics and the effect of temperature on the binding stability of 2F5 and 4E10 to MPER peptide-liposome conjugates revealed that the docking of 4E10 was relatively slower and thermodynamically less favorable. The results of fluorescence-quenching and fluorescence resonance energy transfer experiments showed that the 2F5 epitope was more solvent exposed, whereas the 4E10 epitope was immersed in the polar-apolar interfacial region of the lipid bilayer. A circular dichroism spectroscopic study demonstrated that the nominal epitope and biepitope MPER peptides adopted ordered structures with differing helical contents when anchored to liposomes. Furthermore, anchoring of MPER peptides to the membrane via a hydrophobic anchor sequence was required for efficient MAb docking. These results support the model that the ability of 2F5 and 4E10 to bind to membrane lipid is required for stable docking to membrane-embedded MPER residues. These data have important implications for the design and use of peptide-liposome conjugates as immunogens for the induction of MPER-neutralizing antibodies.
Overlapping Genes Produce Proteins with Unusual Sequence Properties and Offer Insight into De Novo Protein Creation
Authors: Rancurel Corinne , Khosravi Mahvash , Dunker A. Keith , Romero Pedro R. , Karlin David 
Published: July 2009

ABSTRACT
It is widely assumed that new proteins are created by duplication, fusion, or fission of existing coding sequences. Another mechanism of protein birth is provided by overlapping genes. They are created de novo by mutations within a coding sequence that lead to the expression of a novel protein in another reading frame, a process called “overprinting.” To investigate this mechanism, we have analyzed the sequences of the protein products of manually curated overlapping genes from 43 genera of unspliced RNA viruses infecting eukaryotes. Overlapping proteins have a sequence composition globally biased toward disorder-promoting amino acids and are predicted to contain significantly more structural disorder than nonoverlapping proteins. By analyzing the phylogenetic distribution of overlapping proteins, we were able to confirm that 17 of these had been created de novo and to study them individually. Most proteins created de novo are orphans (i.e., restricted to one species or genus). Almost all are accessory proteins that play a role in viral pathogenicity or spread, rather than proteins central to viral replication or structure. Most proteins created de novo are predicted to be fully disordered and have a highly unusual sequence composition. This suggests that some viral overlapping reading frames encoding hypothetical proteins with highly biased composition, often discarded as noncoding, might in fact encode proteins. Some proteins created de novo are predicted to be ordered, however, and whenever a three-dimensional structure of such a protein has been solved, it corresponds to a fold previously unobserved, suggesting that the study of these proteins could enhance our knowledge of protein space.
Impact of Rac1 and Cdc42 Signaling during Early Herpes Simplex Virus Type 1 Infection of Keratinocytes
Authors: Petermann Philipp , Haase Ingo , Knebel-Mörsdorf Dagmar 
Published: July 2009

ABSTRACT
Keratinocytes of the skin or mucosa are the primary entry portals for herpes simplex virus type 1 (HSV-1) in vivo. We hypothesized that dynamics of cell motility and adhesion contribute to the initial steps of HSV-1 infection of epithelial cells, and thus, we investigated the impact of Rac1 and Cdc42, which serve as key regulators of actin dynamics. Measurement of endogenous Rac1 and Cdc42 in the human keratinocyte cell line HaCaT indicated temporary changes in activity levels of Rac1/Cdc42 upon HSV-1 infection. Overexpression of Rac1/Cdc42 mutants in HaCaT cells demonstrated a decrease of infection efficiency with constitutively active Rac1 or Cdc42, while dominant-negative Rac1 had no effect. Accordingly, we addressed whether the absence of Rac1 and/or Cdc42 influenced infection, and we performed RNA interference studies. Both in HaCaT cells and in primary human keratinocytes, reduction of Rac1 and/or Cdc42 did not suppress infection. When mouse epidermis was infected ex vivo, we observed early HSV-1 infection in basal keratinocytes. Similar results were obtained upon infection of mouse epidermis with a keratinocyte-restricted deletion of the rac1 gene, indicating no inhibitory effect on HSV-1 infection in the absence of Rac1. Our results suggest that HSV-1 infection of keratinocytes does not depend on pathways involving Rac1 and Cdc42 and that constitutively active Rac1 and Cdc42 have the potential to interfere with HSV-1 infectivity.
Association of
Rice Gall Dwarf Virus
with Microtubules Is Necessary for Viral Release from Cultured Insect Vector Cells
Authors: Wei Taiyun , Uehara-Ichiki Tamaki , Miyazaki Naoyuki , Hibino Hiroyuki , Iwasaki Kenji , Omura Toshihiro 
Published: July 2009

ABSTRACT

Vector insect cells infected with
Rice gall dwarf virus
, a member of the family
Reoviridae
, contained the virus-associated microtubules adjacent to the viroplasms, as revealed by transmission electron, electron tomographic, and confocal microscopy. The viroplasms, putative sites of viral replication, contained the nonstructural viral proteins Pns7 and Pns12, as well as core protein P5, of the virus. Microtubule-depolymerizing drugs suppressed the association of viral particles with microtubules and prevented the release of viruses from cells without significantly affecting viral multiplication. Thus, microtubules appear to mediate viral transport within and release of viruses from infected vector cells.
Human Cytomegalovirus Exploits ESCRT Machinery in the Process of Virion Maturation
Authors: Tandon Ritesh , AuCoin David P. , Mocarski Edward S. 
Published: July 2009

ABSTRACT

The endosomal sorting complex required for transport (ESCRT) machinery controls the incorporation of cargo into intraluminal vesicles of multivesicular bodies. This machinery is used during envelopment of many RNA viruses and some DNA viruses, including herpes simplex virus type 1. Other viruses mature independent of ESCRT components, instead relying on the intrinsic behavior of viral matrix and envelope proteins to drive envelopment. Human cytomegalovirus (HCMV) maturation has been reported to proceed independent of ESCRT components (A. Fraile-Ramos et al. Cell. Microbiol. 9:2955-2967, 2007). A virus complementation assay was used to evaluate the role of dominant-negative (DN) form of a key ESCRT ATPase, vacuolar protein sorting-4 (Vps4
DN
) in HCMV replication. Vps4
DN
specifically inhibited viral replication, whereas wild-type-Vps4 had no effect. In addition, a DN form of charged multivesicular body protein 1 (CHMP1
DN
) was found to inhibit HCMV. In contrast, DN tumor susceptibility gene-101 (Tsg101
DN
) did not impact viral replication despite the presence of a PTAP motif within pp150/ppUL32, an essential tegument protein involved in the last steps of viral maturation and release. Either Vps4
DN
or CHMP1
DN
blocked viral replication at a step after the accumulation of late viral proteins, suggesting that both are involved in maturation. Both Vps4A and CHMP1A localized in the vicinity of viral cytoplasmic assembly compartments, sites of viral maturation that develop in CMV-infected cells. Thus, ESCRT machinery is involved in the final steps of HCMV replication.
T-Cell Vaccination Reduces Simian Immunodeficiency Virus Levels in Semen
Authors: Whitney James B. , Luedemann Corinne , Hraber Peter , Rao Srinivas S. , Mascola John R. , Nabel Gary J. , Letvin Norman L. 
Published: July 2009

ABSTRACT
Recent findings suggest that most sexual transmission of human immunodeficiency virus type 1 (HIV-1) occurs during the acute phase of infection when viral replication is most intense. Here, we show that vaccine-elicited cellular immune responses can significantly reduce simian immunodeficiency virus levels in the semen during the period of primary infection in monkeys. A vaccine that decreases the quantity of HIV-1 in the semen of males during primary infection might decrease HIV-1 transmission in human populations and therefore affect the spread of AIDS.
Low concentrations of vancomycin stimulate biofilm formation in some clinical isolates ofStaphylococcus epidermidis
Authors: Cargill J S , Upton M 
Published: July 2009

Aims:To examine the response ofStaphylococcus epidermidisisolates from prosthetic orthopaedic infections to vancomycin concentrations below the minimum inhibitory concentration.Methods:Staphylococcal biofilms were grown in 96-well flat-bottomed cell culture plates under a variety of culture conditions and stained using an ammonium crystal violet solution. Optical density (450 nm wavelength) was recorded to estimate the biofilm density for each strain. Population analysis and time-kill studies were also performed on selected isolates.Results:A range of responses were observed, including increased biofilm density at drug concentrations approaching the minimum inhibitory concentration. This increased density was associated with the presence of a more resistant population identified on population analysis but without an apparent effect on the time-kill curves.Conclusions:The ability of some strains to show increased biofilm density could be a factor in the failure of vancomycin therapy reported in some cases. The demonstration that low concentrations of vancomycin may increase the density of newly formingS epidermidisbiofilms may indicate an area of potential concern in the use of vancomycin in orthopaedic implants and intravascular catheter locks, and may partially account for some cases of treatment failure.
Genetic Polymorphisms in Cytotoxic T-Lymphocyte Antigen 4 and Cancer: The Dialectical Nature of Subtle Human Immune Dysregulation
Authors: Sun Tong , Hu Zhibin , Shen Hongbing , Lin Dongxin 
Published: July 2009

Abstract
Genetic polymorphisms in the human genome are an important component of genotypic variability including one's immune status. Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene have been linked to susceptibility to autoimmune disease. Interestingly, we have recently shown that an SNP in the CTLA-4 coding region (49A &gt; G) is also associated with susceptibility to human cancer, but the risk allele for susceptibility to cancer (allele A) is the opposite of that found for susceptibility to autoimmune disease (allele G), which has been confirmed by a meta-analysis of reported studies. These findings indicate an important role of the dialectical nature of T-cell immune dysregulation in human disorders, such as autoimmune disease and cancer. The requisites of CTLA-4 polymorphisms for susceptibility to cancer and response to targeted therapy are discussed in this review. [Cancer Res 2009;69(15):6011–4]
HIPK2 Regulation by MDM2 Determines Tumor Cell Response to the p53-Reactivating Drugs Nutlin-3 and RITA
Authors: Rinaldo Cinzia , Prodosmo Andrea , Siepi Francesca , Moncada Alice , Sacchi Ada , Selivanova Galina , Soddu Silvia 
Published: July 2009

Abstract
In the past few years, much effort has been devoted to show the single-target specificity of nongenotoxic, p53 reactivating compounds. However, the divergent biological responses induced by the different compounds, even in the same tumor cells, demand additional mechanistic insights, whose knowledge may lead to improved drug design or selection of the most potent drug combinations. To address the molecular mechanism underlying induction of mitotic arrest versus clinically more desirable apoptosis, we took advantage of two MDM2 antagonists, Nutlin-3 and RITA, which respectively produce these two outcomes. We show that, along with p53 reactivation, the proapoptotic p53-activator HIPK2 is degraded by MDM2 in Nutlin-3–treated cells, but activated by transiently reduced MDM2 levels in RITA-treated ones. Gain- and loss-of-function experiments revealed the functional significance of MDM2-mediated HIPK2 regulation in cell decision between mitotic arrest and apoptosis in both types of p53 reactivation. These data indicate that strategies of p53 reactivation by MDM2 inhibition should also take into consideration MDM2 targets other than p53, such as the apoptosis activator HIPK2. [Cancer Res 2009;69(15):6241–8]
Racial Survival Disparity in Head and Neck Cancer Results from Low Prevalence of Human Papillomavirus Infection in Black Oropharyngeal Cancer Patients
Authors: Settle Kathleen , Posner Marshall R. , Schumaker Lisa M. , Tan Ming , Suntharalingam Mohan , Goloubeva Olga , Strome Scott E. , Haddad Robert I. , Patel Shital S. , Cambell Earl V. , Sarlis Nicholas , Lorch Jochen , Cullen Kevin J. 
Published: July 2009

Abstract
The burden of squamous cell carcinoma of the head and neck (SCCHN) is greater for blacks than for whites, especially in oropharyngeal cases. We previously showed retrospectively that disease-free survival was significantly greater in white than in black SCCHN patients treated with chemoradiation, the greatest difference occurring in the oropharyngeal subgroup. Oropharyngeal cancer is increasing in incidence and in its association with human papillomavirus (HPV) infection; HPV-positive oropharyngeal cancer patients have significantly better outcomes (versus HPV-negative). These collective data led to the present analyses of overall survival (OS) in our retrospective cohort and of OS and HPV status (tested prospectively in pretreatment biopsy specimens) in the phase 3, multicenter TAX 324 trial of induction chemotherapy followed by concurrent chemoradiation in SCCHN patients. Median OS in the retrospective cohort of 106 white and 95 black SCCHN patients was 52.1 months (white) versus only 23.7 months (black; P = 0.009), due entirely to OS in the subgroup of patients with oropharyngeal cancer—69.4 months (whites) versus 25.2 months (blacks; P = 0.0006); no significant difference by race occurred in survival of non-oropharyngeal SCCHN (P = 0.58). In TAX 324, 196 white patients and 28 black patients could be assessed for HPV status. Median OS was significantly worse for black patients (20.9 months) than for white patients (70.6 months; P = 0.03) and dramatically improved in HPV-positive (not reached) versus HPV-negative (26.6 months, 5.1 hazard ratio) oropharyngeal patients (P &lt; 0.0001), 49% of whom were HPV-16 positive. Overall, HPV positivity was 34% in white versus 4% in black patients (P = 0.0004). Survival was similar for black and white HPV-negative patients (P = 0.56). This is the first prospective assessment of confirmed HPV status in black versus white SCCHN patients. Worse OS for black SCCHN patients was driven by oropharyngeal cancer outcomes, and that for black oropharyngeal cancer patients by a lower prevalence of HPV infection. These findings have important implications for the etiology, prevention, prognosis, and treatment of SCCHN.
Oropharyngeal Cancer, Race, and the Human Papillomavirus
Authors: Brawley Otis W. 
Published: July 2009

Abstract
This perspective on Settle et al. (beginning on p. 776 in this issue of the journal) discusses the racial disparity in oropharyngeal cancer survival in relation to the biological factor human papillomavirus and its association with sexual behavior. This discussion is expanded to a more general consideration of biological and nonbiological (e.g., socioeconomic and cultural) factors affecting racial disparities in disease.
Orbito-frontal Cortex is Necessary for Temporal Context Memory
Authors: Duarte Audrey , Henson Richard N. , Knight Robert T. , Emery Tina , Graham Kim S. 
Published: July 2009

Abstract
Lesion and neuroimaging studies suggest that orbito-frontal cortex (OFC) supports temporal aspects of episodic memory. However, it is unclear whether OFC contributes to the encoding and/or retrieval of temporal context and whether it is selective for temporal relative to nontemporal (spatial) context memory. We addressed this issue with two complimentary studies: functional magnetic resonance imaging to measure OFC activity associated with successful temporal and spatial context memory during encoding and retrieval in healthy young participants, and a neuropsychological investigation to measure changes in spatial and temporal context memory in OFC lesion patients. Imaging results revealed that OFC contributed to encoding and retrieval of associations between objects and their temporal but not their spatial contexts. Consistent with this, OFC patients exhibited impairments in temporal but not spatial source memory accuracy. These results suggest that OFC plays a critical role in the formation and subsequent retrieval of temporal context.
Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task
Authors: de Frias Cindy M. , Marklund Petter , Eriksson Elias , Larsson Anne , Öman Lena , Annerbrink Kristina , Bäckman Lars , Nilsson Lars-Göran , Nyberg Lars 
Published: July 2009

Abstract
The catechol O-methyltransferase (COMT) gene—encoding an enzyme that is essential for the degradation of dopamine (DA) in prefrontal cortex (PFC)—contains a single nucleotide polymorphism (val/met) important for cognition. According to the tonic–phasic hypothesis, individuals carrying the low-enzyme-activity allele (met) are characterized by enhanced tonic DA activity in PFC, promoting sustained cognitive representations in working memory. Val carriers have reduced tonic but enhanced phasic dopaminergic activity in subcortical regions, enhancing cognitive flexibility. We tested the tonic–phasic DA hypothesis by dissociating sustained and transient brain activity during performance on a 2-back working memory test using mixed blocked/event-related functional magnetic resonance imaging. Participants were men recruited from a random sample of the population (the Betula study) and consisted of 11 met/met and 11 val/val carriers aged 50 to 65 years, matched on age, education, and cognitive performance. There were no differences in 2-back performance between genotype groups. Met carriers displayed a greater transient medial temporal lobe response in the updating phase of working memory, whereas val carriers showed a greater sustained PFC activation in the maintenance phase. These results support the tonic–phasic theory of DA function in elucidating the specific phenotypic influence of the COMT val158met polymorphism on different components of working memory.
New York City Storm Surges: Climatology and an Analysis of the Wind and Cyclone Evolution
Authors: Colle Brian A. , Rojowsky Katherine , Buonaito Frank 
Published: July 2009

Abstract
A climatological description (“climatology”) of storm surges and actual flooding (storm tide) events from 1959 to 2007 is presented for the New York City (NYC) harbor. The prevailing meteorological conditions associated with these surges are also highlighted. Two surge thresholds of 0.6–1.0 m and &gt;1.0 m were used at the Battery, New York (south side of Manhattan in NYC), to identify minor and moderate events, respectively. The minor-surge threshold combined with a tide at or above mean high water (MHW) favors a coastal flood advisory for NYC, and the moderate surge above MHW leads to a coastal flood warning. The number of minor surges has decreased gradually during the last several decades at NYC while the number of minor (storm tide) flooding events has increased slightly given the gradual rise in sea level. There were no moderate flooding events at the Battery from 1997 to 2007, which is the quietest period during the last 50 yr. However, if sea level rises 12–50 cm during the next century, the number of moderate flooding events is likely to increase exponentially. Using cyclone tracking and compositing of the NCEP global reanalysis (before 1979) and regional reanalysis (after 1978) data, the mean synoptic evolution was obtained for the NYC surge events. There are a variety of storm tracks associated with minor surges, whereas moderate surges favor a cyclone tracking northward along the East Coast. The average surface winds at NYC veer from northwesterly at 48 h before the time of maximum surge to a persistent period of east-northeasterlies beginning about 24 h before the surge. There is a relatively large variance in wind directions and speeds around the time of maximum surge, thus suggesting the importance of other factors (fetch, storm duration and track, etc.).