bluuebunny/crossref_metadata_2025 huggingface dataset:
Anticrack Nucleation as Triggering Mechanism for Snow Slab Avalanches
Authors: Heierli J. , Gumbsch P. , Zaiser M.
Published: July 2008

Snow slab avalanches are believed to begin by the gravity-driven shear failure of weak layers in stratified snow. The critical crack length for shear crack propagation along such layers should increase without bound as the slope decreases. However, recent experiments show that the critical length of artificially introduced cracks remains constant or, if anything, slightly decreases with decreasing slope. This surprising observation can be understood in terms of volumetric collapse of the weak layer during failure, resulting in the formation and propagation of mixed-mode anticracks, which are driven simultaneously by slope-parallel and slope-normal components of gravity. Such fractures may propagate even if crack-face friction impedes downhill sliding of the snowpack, indicating a scenario in which two separate conditions have to be met for slab avalanche release.
X Inactivation Is a Good Thing
Authors: Marshall Graves Jennifer A.
Published: July 2008

Females Are Mosaics
. X Inactivation and Sex Differences in Disease.
By Barbara R. Migeon
. Oxford University Press, Oxford, 2007. 291 pp. $59.95, £35.99. ISBN 9780195188127.

Discussing the medical consequences of X inactivation and effects on individuals with chromosome abnormalities the author molecular mechanisms for chromosome inactivation and addresses the evolutionary origins of human sex chromosomes.
Comment on "Genetically Determined Differences in Learning from Errors"
Authors: Lucht Michael , Rosskopf Dieter
Published: July 2008

Klein
et al
. (Reports, 7 December 2007, p. 1642) used individuals with a polymorphism adjacent to the dopamine receptor 2 gene as naturally occurring models for reduced brain dopamine receptor density in a probabilistic learning task. We raise the concern that this polymorphism resides in the gene for the kinase ANKK1, where it causes a nonconservative amino acid exchange.
Source Analysis of the Crandall Canyon, Utah, Mine Collapse
Authors: Dreger Douglas S. , Ford Sean R. , Walter William R.
Published: July 2008

Analysis of seismograms from a magnitude 3.9 seismic event on 6 August 2007 in central Utah reveals an anomalous radiation pattern that is contrary to that expected for a tectonic earthquake and which is dominated by an implosive component. The results show that the seismic event is best modeled as a shallow underground collapse. Interestingly, large transverse surface waves require a smaller additional noncollapse source component that might represent either faulting in the rocks above the mine workings or deformation of the medium surrounding the mine. Seismic moment tensor results for nuclear explosions, explosion and other mining cavity collapses, and tectonic earthquakes are compared, and the separation of the different populations indicates that the seismic moment tensor may be used for source-type discrimination.
Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry
Authors: Morrow Eric M. , Yoo Seung-Yun , Flavell Steven W. , Kim Tae-Kyung , Lin Yingxi , Hill Robert Sean , Mukaddes Nahit M. , Balkhy Soher , Gascon Generoso , Hashmi Asif , Al-Saad Samira , Ware Janice , Joseph Robert M. , Greenblatt Rachel , Gleason Danielle , Ertelt Julia A. , Apse Kira A. , Bodell Adria , Partlow Jennifer N. , Barry Brenda , Yao Hui , Markianos Kyriacos , Ferland Russell J. , Greenberg Michael E. , Walsh Christopher A.
Published: July 2008

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, includingPCDH10(protocadherin 10) andDIA1(deleted in autism1, orc3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, includingNHE9(Na+/H+exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of âhomozygosity mappingâ in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.
Drug Target Identification Using Side-Effect Similarity
Authors: Campillos Monica , Kuhn Michael , Gavin Anne-Claude , Jensen Lars Juhl , Bork Peer
Published: July 2008

Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side-effect similarities to infer whether two drugs share a target. Applied to 746 marketed drugs, a network of 1018 side effect–driven drug-drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug-drug relations and validated 13 implied drug-target relations by in vitro binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs.
High-Efficiency Organic Solar Concentrators for Photovoltaics
Authors: Currie Michael J. , Mapel Jonathan K. , Heidel Timothy D. , Goffri Shalom , Baldo Marc A.
Published: July 2008

The cost of photovoltaic power can be reduced with organic solar concentrators. These are planar waveguides with a thin-film organic coating on the face and inorganic solar cells attached to the edges. Light is absorbed by the coating and reemitted into waveguide modes for collection by the solar cells. We report single- and tandem-waveguide organic solar concentrators with quantum efficiencies exceeding 50% and projected power conversion efficiencies as high as 6.8%. The exploitation of near-field energy transfer, solid-state solvation, and phosphorescence enables 10-fold increases in the power obtained from photovoltaic cells, without the need for solar tracking.
A Positive Test of East Antarctica–Laurentia Juxtaposition Within the Rodinia Supercontinent
Authors: Goodge J. W. , Vervoort J. D. , Fanning C. M. , Brecke D. M. , Farmer G. L. , Williams I. S. , Myrow P. M. , DePaolo D. J.
Published: July 2008

The positions of Laurentia and other landmasses in the Precambrian supercontinent of Rodinia are controversial. Although geological and isotopic data support an East Antarctic fit with western Laurentia, alternative reconstructions favor the juxtaposition of Australia, Siberia, or South China. New geologic, age, and isotopic data provide a positive test of the juxtaposition with East Antarctica: Neodymium isotopes of Neoproterozoic rift-margin strata are similar; hafnium isotopes of ∼1.4-billion-year-old Antarctic-margin detrital zircons match those in Laurentian granites of similar age; and a glacial clast of A-type granite has a uraniun-lead zircon age of ∼1440 million years, an epsilon-hafnium initial value of +7, and an epsilon-neodymium initial value of +4. These tracers indicate the presence of granites in East Antarctica having the same age, geochemical properties, and isotopic signatures as the distinctive granites in Laurentia.
Tilt the Table Toward Good Choices
Authors: Johnson Eric J.
Published: July 2008

Nudge
. Improving Decisions About Health, Wealth, and Happiness.
By Richard H. Thaler and Cass R. Sunstein
. Yale University Press, New Haven, CT, 2008. 303 pp. $26, £18. ISBN 9780300122237.

The authors marshal results from behavioral economics research to argue for using asymmetric choice architecture to exert a "libertarian paternalism" on social and economic choices.
Neisseria meningitidisPorB, a Toll-Like Receptor 2 Ligand, Improves the Capacity ofFrancisella tularensisLipopolysaccharide To Protect Mice against Experimental Tularemia
Authors: Chiavolini Damiana , Weir Susan , Murphy John R. , Wetzler Lee M.
Published: July 2008

Francisella tularensiscauses severe pneumonia that can be fatal if it is left untreated. Due to its potential use as a biological weapon, research is being conducted to develop an effective vaccine and to select and study adjuvant molecules able to generate a better and long-lasting protective effect. PorB, a porin fromNeisseria meningitidis, is a well-established Toll-like receptor 2 ligand and has been shown to be a promising vaccine adjuvant candidate due to its ability to enhance the T-cell costimulatory activity of antigen-presenting cells both in vitro and in vivo. BALB/c mice were immunized with lipopolysaccharide (LPS) isolated from theF. tularensissubsp.holarcticalive vaccine strain (LVS), with or without PorB fromN. meningitidis, and the antibody levels induced during the vaccination regimen and the level of protection against intranasal challenge with LVS were determined. Antigen administered alone induced a specificF. tularensisLPS immunoglobulin M (IgM) response that was not maintained over the weeks and that conferred protection to only 25% of the mice. In contrast,F. tularensisLPS given in combination with neisserial PorB induced consistent levels of specific IgM throughout the immunization and increased the proportion of surviving mice to 70%. Postchallenge cytokine analysis showed that interleukin-6 (IL-6), monocyte chemoattractant protein 1, and gamma interferon were markers of mortality and that IL-1β was a correlate of survival, independent of the presence of PorB as an adjuvant. These data indicate that neisserial PorB might be an optimal candidate adjuvant for improving the protective effect ofF. tularensisLPS and other subunit vaccines against tularemia, but there is still a need to test its efficacy against virulent type A and type BF. tularensisstrains.
Prevalence of Human Parechovirus in The Netherlands in 2000 to 2007
Authors: van der Sanden Sabine , de Bruin Erwin , Vennema Harry , Swanink Caroline , Koopmans Marion , van der Avoort Harrie
Published: July 2008

Infection with human parechovirus 3 (HPeV3) was described for the first time in Japan in 2004 and reportedly is more often associated with severe disease than infection with HPeV1 or HPeV2. In 2004, infections with HPeV3 were observed for the first time in The Netherlands. Genetic analysis showed several different lineages, suggesting endemic circulation. We analyzed 163 cell culture isolates from the same number of patients tested in routine virological laboratories as part of the national enterovirus surveillance program. Isolates were collected between 2000 and 2007 and could not be characterized by routine methods. In total, 155 isolates (95%) were found positive for HPeV by a reverse transcription-PCR assay targeting the 5′ untranslated region, explaining the majority of the diagnostic deficit in enterovirus surveillance for these years. Typing of the isolates by use of partial genome sequencing of the VP1/2A region revealed the presence of 55 HPeV1, 2 HPeV2, 89 HPeV3, 1 HPeV4, and 8 HPeV5 isolates. We compared isolation dates, age groups affected, and clinical pictures, which were reported as part of the routine surveillance. Clear differences in epidemiology were observed, with HPeV3 occurring at intervals of 2 years and in the spring-summer season, whereas HPeV1 was observed in small numbers throughout each year, with a low in the summer months. HPeV3 infection affected younger children than HPeV1 infection and was significantly more often associated with fever, meningitis, and viremia.
Pharmacoeconomic Analysis of Microbiologic Techniques for Differentiating Staphylococci Directly from Blood Culture Bottles
Authors: Hermsen Elizabeth D. , Shull Sara S. , Klepser Donald G. , Iwen Peter C. , Armbrust Amy , Garrett Jodi , Freifeld Alison G. , Rupp Mark E.
Published: July 2008

Differentiating staphylococci in blood cultures is a critical issue, particularly when only one of two cultures is positive by Gram staining for staphylococci. New tests for the identification of
Staphylococcus aureus
allow faster results and definitive treatment compared to the tube coagulase test interpreted at 24 h (TCT24). These newer tests, peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) and real-time PCR (RT-PCR), offer improved sensitivity at higher cost. Data suggest that the tube coagulase test may be interpreted at 4 h (TCT4) with little loss of sensitivity. The impact of variability in turnaround time, sensitivity, specificity, and cost on comparative cost-effectiveness is unknown. Our aim was to establish the cost-effectiveness of TCT24, PNA-FISH, RT-PCR, and TCT4 for direct identification of staphylococci in blood cultures. Decision analysis comparing these strategies was done from the institutional perspective. Besides test variables, other variables included patient risk factors, empirical treatment, and follow-up cultures. Probability and cost estimates came from the literature and institutional data. Base case estimates were derived from institutional rates of 73% contamination when coagulase-negative staphylococci were identified, 67.6% prevalence of risk factors, and 12.4% prevalence of
S. aureus
when one of two cultures yielded staphylococci. Sensitivity analysis was done across a range of probabilities and costs. In the base case, TCT4 and TCT24 were more cost-effective than RT-PCR and PNA-FISH ($78 versus $120 versus $165 per patient, respectively). The advantage of TCT4 and TCT24 remained robust upon sensitivity analysis. TCT4 should be further evaluated as a rapid, cost-effective means for identification of
S. aureus
in blood cultures.
Viability of
Trichomonas vaginalis
in Copan Universal Transport Medium and eSwab Transport Medium
Authors: Rivers C. A. , Schwebke J. R.
Published: July 2008

We compared the use of universal transport medium and eSwab transport medium held at room temperature or 37°C to bedside inoculation and immediate incubation of culture media for the detection of
Trichomonas vaginalis
. There were no significant culturable differences in the sensitivity of either of the transport media to that of bedside inoculation.
Internally Controlled Triplex Quantitative PCR Assay for Human Polyomaviruses JC and BK
Authors: Dumonceaux Timothy J. , Mesa Christine , Severini Alberto
Published: July 2008

We have developed a triplex TaqMan-based quantitative PCR assay for the human polyomaviruses JC (JCPyV) and BK (BKPyV). The assay simultaneously detects and quantifies both JCPyV and BKPyV in human clinical samples, and it includes an internal amplification control consisting of murine polyomavirus (MuPyV) plasmid DNA. We developed the assay for the Roche LightCycler 480 platform with the reporter dyes VIC, 6-FAM, and Cy5 for MuPyV, BKPyV, and JCPyV, respectively. The assay had a high specificity for BKPyV and JCPyV when either viral genome was present alone or in mixed samples over a range of 10
1
to 10
7
copy numbers per reaction. The analytical sensitivity was 50 copies for BKPyV and 10 copies for JCPyV. The use of the MuPyV internal control ensured monitoring of the quality of the extraction and of PCR inhibition, even in samples such as cerebrospinal fluid and plasma in which controls based on host genes cannot be effectively used. In addition, we developed a similar assay using a different dye configuration (6-FAM, VIC, and NED) that could be used on an ABI 7500 Fast platform. This assay had sensitivities similar to those of the LightCycler 480 configuration for BKPyV and JCPyV when either viral genome was present alone, but the sensitivity of detection of BKPyV was greatly decreased when an excess of JCPyV (>100-fold) was present in the sample. This internally controlled combined assay offers greater convenience and cost-effectiveness compared to separate assays for each virus and can also detect unexpected PyV activations by testing for both viruses in all samples.
Novel Genospecies of
Borrelia burgdorferi
Sensu Lato from Rodents and Ticks in Southwestern China
Authors: Chu Chen-Yi , Liu Wei , Jiang Bao-Gui , Wang Ding-Ming , Jiang Wei-Jia , Zhao Qiu-Min , Zhang Pan-He , Wang Zhao-Xiao , Tang Guang-Peng , Yang Hong , Cao Wu-Chun
Published: July 2008

By using multilocus sequence analysis, five
Borrelia valaisiana
-related strains isolated from rodents and ticks in southwestern China were eventually classified as a new genospecies of
B. burgdorferi
sensu lato rather than
B. valaisiana
. The finding explained the differences in transmission cycle and phenotype between
B. valaisiana
strains from Europe and
B. valaisiana
-related strains from eastern Asia.
MVPlex Assay for Direct Detection of Methicillin-Resistant
Staphylococcus aureus
in Naris and Other Swab Specimens
Authors: Podzorski Raymond P. , Li Haijing , Han Jian , Tang Yi-Wei
Published: July 2008

We evaluated the MVPlex assay (Geneco Biomedical Products), which uses target-enriched multiplex PCR amplification followed by liquid array identification, for the detection of methicillin-resistant
Staphylococcus aureus
(MRSA) from 307 dual-swab specimens. By using a combination of culture (Trypticase soy agar-5% sheep blood agar and Columbia CNA agar-5% sheep blood) and an FDA-approved MRSA PCR assay as the “gold standard,” the MVPlex MRSA assay and culture were found to have sensitivities of 97.8% and 84.4% (
P
= 0.002) and specificities of 95.8% and 98.6% (
P
< 0.05), respectively.
Importance of NKT Cells in Resistance to Herpes Simplex Virus, Fate of Virus-Infected Neurons, and Level of Latency in Mice
Authors: Grubor-Bauk Branka , Arthur Jane Louise , Mayrhofer Graham
Published: July 2008

Herpes simplex virus type 1 (HSV-1) produces acute mucocutaneous infections, spread to sensory ganglia, and establishment of latency. In addition, neurovirulent strains have potential to invade the central nervous system (CNS), with potentially a lethal outcome. Early activation of defenses at all stages is essential to limit virus load and reduce the risk of neuronal damage, extensive zosteriform skin lesions, and catastrophic spread to the CNS. NKT cells respond rapidly, and we have shown previously that CD1d-deficient mice are compromised in controlling a neuroinvasive isolate of HSV-1. We now compare infection in Jα18 GKO and CD1d GKO mice, allowing direct assessment of the importance of invariant Vα14+NKT cells and deduction of the role of the CD1d-restricted NKT cells with diverse T-cell receptors. The results indicate that both subsets of NKT cells contribute to virus control both in the afferent phase of infection and in determining the mortality, neuroinvasion, loss of sensory neurons, size of zosteriform, lesions and levels of latency. In particular, both are crucial determinants of clinical outcome, providing protection equivalent to a 1-log dose of virus. These NKT cells can be expected to provide protection at doses of virus that might be encountered naturally.
A Single Amino Acid Residue Change in the P Protein of Parainfluenza Virus 5 Elevates Viral Gene Expression
Authors: Timani Khalid A. , Sun Dengyun , Sun Minghao , Keim Celia , Lin Yuan , Schmitt Phuong Tieu , Schmitt Anthony P. , He Biao
Published: July 2008

Parainfluenza virus 5 (PIV5) is a prototypical paramyxovirus. The V/P gene of PIV5 encodes two mRNA species through a process of pseudotemplated insertion of two G residues at a specific site during transcription, resulting in two viral proteins, V and P, whose N termini of 164 amino acid residues are identical. Previously it was reported that mutating six amino acid residues within this identical region results in a recombinant PIV5 (rPIV5-CPI−) that exhibits elevated viral protein expression and induces production of cytokines, such as beta interferon and interleukin 6. Because the six mutations correspond to the shared region of the V protein and the P protein, it is not clear whether the phenotypes associated with rPIV5-CPI− are due to mutations in the P protein and/or mutations in the V protein. To address this question, we used a minigenome system and recombinant viruses to study the effects of mutations on the functions of the P and V proteins. We found that the P protein with six amino acid residue changes (Pcpi−) was more efficient than wild-type P in facilitating replication of viral RNA, while the V protein with six amino acid residue changes (Vcpi−) still inhibits minigenome replication as does the wild-type V protein. These results indicate that elevated viral gene expression in rPIV5-CPI− virus-infected cells can be attributed to a P protein with an increased ability to facilitate viral RNA synthesis. Furthermore, we found that a single amino acid residue change at position 157 of the P protein from Ser (the residue in the wild-type P protein) to Phe (the residue in Pcpi−) is sufficient for elevated viral gene expression. Using mass spectrometry and
33
P labeling, we found that residue S157 of the P protein is phosphorylated. Based on these results, we propose that phosphorylation of the P protein at residue 157 plays an important role in regulating viral RNA replication.
Common Marmosets (Callithrix jacchus) as a Nonhuman Primate Model To Assess the Virulence of Eastern Equine Encephalitis Virus Strains
Authors: Adams A. Paige , Aronson Judith F. , Tardif Suzette D. , Patterson Jean L. , Brasky Kathleen M. , Geiger Robert , de la Garza Melissa , Carrion Ricardo , Weaver Scott C.
Published: July 2008

Eastern equine encephalitis virus (EEEV) produces the most severe human arboviral disease in North America (NA) and is a potential biological weapon. However, genetically and antigenically distinct strains from South America (SA) have seldom been associated with human disease or mortality despite serological evidence of infection. Because mice and other small rodents do not respond differently to the NA versus SA viruses like humans, we tested common marmosets (Callithrix jacchus) by using intranasal infection and monitoring for weight loss, fever, anorexia, depression, and neurologic signs. The NA EEEV-infected animals either died or were euthanized on day 4 or 5 after infection due to anorexia and neurologic signs, but the SA EEEV-infected animals remained healthy and survived. The SA EEEV-infected animals developed peak viremia titers of 2.8 to 3.1 log10PFU/ml on day 2 or 4 after infection, but there was no detectable viremia in the NA EEEV-infected animals. In contrast, virus was detected in the brain, liver, and muscle of the NA EEEV-infected animals at the time of euthanasia or death. Similar to the brain lesions described for human EEE, the NA EEEV-infected animals developed meningoencephalitis in the cerebral cortex with some perivascular hemorrhages. The findings of this study identify the common marmoset as a useful model of human EEE for testing antiviral drugs and vaccine candidates and highlight their potential for corroborating epidemiological evidence that some, if not all, SA EEEV strains are attenuated for humans.
Immune Response in the Absence of Neurovirulence in Mice Infected with M Protein Mutant Vesicular Stomatitis Virus
Authors: Ahmed Maryam , Marino Tracie R. , Puckett Shelby , Kock Nancy D. , Lyles Douglas S.
Published: July 2008

Matrix (M) protein mutants of vesicular stomatitis virus (VSV), such as rM51R-M virus, are less virulent than wild-type (wt) VSV strains due to their inability to suppress innate immunity. Studies presented here show that when inoculated intranasally into mice, rM51R-M virus was cleared from nasal mucosa by day 2 postinfection and was attenuated for spread to the central nervous system, in contrast to wt VSV, thus accounting for its reduced virulence. However, it stimulated an antibody response similar to that in mice infected with the wt virus, indicating that it has the ability to induce adaptive immunity in vivo without causing disease. These results support the use of M protein mutants of VSV as vaccine vectors.
Distinct Requirements of Adenovirus E1b55K Protein for Degradation of Cellular Substrates
Authors: Schwartz Rachel A. , Lakdawala Seema S. , Eshleman Heather D. , Russell Matthew R. , Carson Christian T. , Weitzman Matthew D.
Published: July 2008

The E1b55K and E4orf6 proteins of adenovirus type 5 (Ad5) assemble into a complex together with cellular proteins including cullin 5, elongins B and C, and Rbx1. This complex possesses E3 ubiquitin ligase activity and targets cellular proteins for proteasome-mediated degradation. The ligase activity has been suggested to be responsible for all functions of E1b55K/E4orf6, including promoting efficient viral DNA replication, preventing a cellular DNA damage response, and stimulating late viral mRNA nuclear export and late protein synthesis. The known cellular substrates for degradation by E1b55K/E4orf6 are the Mre11/Rad50/Nbs1 DNA repair complex, the tumor suppressor p53, and DNA ligase IV. Here we show that the degradation of individual targets can occur independently of other substrates. Furthermore, we identify separation-of-function mutant forms of E1b55K that can distinguish substrates for binding and degradation. Our results identify distinct regions of E1b55K that are involved in substrate recognition but also imply that there are additional requirements beyond protein association. These mutant proteins will facilitate the determination of the relevance of specific substrates to the functions of E1b55K in promoting infection and inactivating host defenses.
Presence of the Adenovirus IVa2 Protein at a Single Vertex of the Mature Virion
Authors: Christensen Joan B. , Byrd Serena A. , Walker Angela K. , Strahler John R. , Andrews Philip C. , Imperiale Michael J.
Published: July 2008

Assembly of adenovirus particles is thought to be similar to that of bacteriophages, in which the double-stranded DNA genome is inserted into a preformed empty capsid. Previous studies from our and other laboratories have implicated the viral IVa2 protein as a key component of the encapsidation process. IVa2 binds to the packaging sequence on the viral chromosome in a sequence-specific manner, alone and in conjunction with the viral L4 22K protein. In addition, it interacts with the viral L1 52/55-kDa protein, which is required for DNA packaging. Finally, a mutant virus that does not produce IVa2 is unable to produce any capsids. Therefore, it has been proposed that IVa2 nucleates capsid assembly. A prediction of such a model is that the IVa2 protein would be found at a unique vertex of the mature virion. In this study, the location of IVa2 in the virion has been analyzed using immunogold staining and electron microscopy, and the copy number of IVa2 in virions was determined using three independent methods, quantitative mass spectrometry, metabolic labeling, and Western blotting. The results indicate that it resides at a unique vertex and that there are approximately six to eight IVa2 molecules in each particle. These findings support the hypothesis that the IVa2 protein plays multiple roles in the viral assembly process.
Marked Epitope- and Allele-Specific Differences in Rates of Mutation in Human Immunodeficiency Type 1 (HIV-1) Gag, Pol, and Nef Cytotoxic T-Lymphocyte Epitopes in Acute/Early HIV-1 Infection
Authors: Brumme Zabrina L. , Brumme Chanson J. , Carlson Jonathan , Streeck Hendrik , John Mina , Eichbaum Quentin , Block Brian L. , Baker Brett , Kadie Carl , Markowitz Martin , Jessen Heiko , Kelleher Anthony D. , Rosenberg Eric , Kaldor John , Yuki Yuko , Carrington Mary , Allen Todd M. , Mallal Simon , Altfeld Marcus , Heckerman David , Walker Bruce D.
Published: July 2008

During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in ∼80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801;
P
= 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.
Nontemplated Terminal Nucleotidyltransferase Activity of Double-Stranded RNA Bacteriophage φ6 RNA-Dependent RNA Polymerase
Authors: Poranen Minna M. , Koivunen Minni R. L. , Bamford Dennis H.
Published: July 2008

The replication and transcription of double-stranded RNA (dsRNA) viruses occur within a polymerase complex particle in which the viral genome is enclosed throughout the entire life cycle of the virus. A single protein subunit in the polymerase complex is responsible for the template-dependent RNA polymerization activity. The isolated polymerase subunit of the dsRNA bacteriophage φ6 was previously shown to replicate and transcribe given RNA molecules. In this study, we show that this enzyme also catalyzes nontemplated nucleotide additions to single-stranded and double-stranded nucleic acid molecules. This terminal nucleotidyltransferase activity not only is a property of the isolated enzyme but also is detected to take place within the viral nucleocapsid. This is the first time terminal nucleotidyltransferase activity has been reported for a dsRNA virus as well as for a viral particle. The results obtained together with previous high-resolution structural data on the φ6 RNA-dependent RNA polymerase suggest a mechanism for terminal nucleotidyl addition. We propose that the activity is involved in the termination of the template-dependent RNA polymerization reaction on the linear φ6 genome.
An Insect Virus-Encoded MicroRNA Regulates Viral Replication
Authors: Hussain Mazhar , Taft Ryan J. , Asgari Sassan
Published: July 2008

MicroRNAs (miRNAs) are small (∼22 nucleotides) noncoding RNAs which play an essential role in gene regulation and affect a wide range of processes, including development, differentiation, and oncogenesis. Here we report the identification of the first miRNA from an insect virus, derived from the major capsid protein (MCP) gene in
Heliothis virescens
ascovirus (HvAV) (HvAV-miR-1). Although MCP was abundantly expressed at all time points 24 h after infection, HvAV-miR-1 expression was strictly regulated and specifically detected from 96 h postinfection. HvAV-miR-1 expression coincided with a marked reduction of the expression of HvAV DNA polymerase I, which is a predicted target. Ectopic expression of full-length and truncated versions of MCP retaining the miRNA sequence significantly reduced DNA polymerase I transcript levels and inhibited viral replication. Our results indicate that HvAV-miR-1 directs transcriptional degradation of DNA polymerase I and regulates HvAV replication. These findings are congruent with recent reports that miR-BART-2 regulates Epstein-Barr virus DNA polymerase expression and suggest that virus-encoded miRNA regulation of virus replication may be a general phenomenon.
Comparing the risk of work-related injuries between immigrants to Canada and Canadian-born labour market participants
Authors: Smith P M , Mustard C A
Published: July 2008

Objectives:

To examine the burden of work-related injuries among immigrants to Canada compared to Canadian-born labour force participants.

Methods:

Using data from the 2003 and 2005 Canadian Community Health Surveys (n = 99 115), two nationally representative population samples, we examined the risk of self-reported, activity limiting work-related injuries among immigrants with varying time periods since arrival in Canada. Models were adjusted for hours of work in the last 12 months as well as various demographic and work-related variables.

Results:

Immigrant men in their first 5 years in Canada reported lower rates of activity limiting injuries compared to Canadian-born respondents. Surprisingly, the percentage of injuries that required medical attention was much higher among recent immigrants compared to Canadian-born respondents, resulting in an increased risk of activity limiting injuries requiring medical attention among immigrant men compared to Canadian-born labour force participants. No excess risk was found among female immigrants compared to Canadian-born female labour market participants.

Conclusions:

Immigrant men in their first 5 years in Canada are at increased risk of work-related injuries that require medical attention. A similar risk is not present among immigrant women. Further, given differences in the number of activity limiting injuries requiring medical attention across immigrant groups, we believe this excess risk among immigrant men may be underestimated in the current data source. Future research should attempt to fully capture the barriers faced by immigrants in obtaining safe employment, the number of injuries that are sustained by immigrants while working, and the consequences of these injuries.
The western termination of the SEMP Fault (eastern Alps) and its bearing on the exhumation of the Tauern Window
Authors: Rosenberg Claudio L. , Schneider Susanne
Published: July 2008

The SEMP (Salzach–Ennstal–Mariazell–Puchberg) Fault strikes along more than 300 km from the southern margin of the Vienna Basin to the northern Tauern Window accommodating a sinistral displacement of 60 km during Tertiary time. We present new structural data, showing that the SEMP Fault continues into the Tauern Window within a 50 km long mylonitic belt of approximately 2 km width, which we term the Ahorn shear zone. This sinistral shear zone, which marks the northern boundary of the Zentral Gneiss, strikes E to ENE, dips subvertically, and is characterized by gently W-dipping to subhorizontal stretching lineations. S-side-up kinematic indicators in the Y–Z fabric plane and a pronounced southward increase in the inferred temperature of sinistral shearing are observed within the shear zone. Microstructural observations indicate that deformation of quartz at the northernmost boundary of the Zentral Gneiss occurred by dislocation glide with only incipient dynamic recrystallization, suggesting a temperature of approximately 300 °C. Further south, temperatures greater than 300 °C are inferred because all samples are affected by dynamic recrystallization of quartz, and dynamic recrystallization of feldspars also occurred in the southernmost part of the shear zone. These findings point to transpressive deformation accommodating a significant component of south-side-up displacement in addition to sinistral shearing. The sinistral mylonitic foliation forms the axial-plane foliation of the large-scale, ENE-striking upright folds of the western Tauern Window. From east to west, deformation becomes increasingly distributed, passing from an area of interconnected shear zones in the east to a homogeneously deformed mylonitic belt in the west, which terminates into a belt of WNW-striking, upright folds. From the above, we suggest the following: (1) the SEMP Fault extended beyond the brittle-ductile transition to a depth where temperatures exceeded 500 °C (>20 km depth?). These mylonites should be included in the seismic interpretation profiles as a major crustal discontinuity; (2) the large-amplitude, upright folds of the Tauern Window formed at the same time as the sinistral mylonites, and hence during south-side-up differential displacement; and (3) part of the 60 km lateral displacement of the SEMP fault is transferred into a vertical displacement at the western end of the Ahorn shear zone and into a fold belt accommodating NNE-oriented shortening, west of the Ahorn shear zone.
On the role and importance of orogen-parallel and -perpendicular extension, transcurrent shearing, and backthrusting in the Monte Rosa nappe and the Southern Steep Belt of the Alps (Penninic zone, Switzerland and Italy)
Authors: Pleuger Jan , Nagel Thorsten J. , Walter Jens M. , Jansen Ekkehard , Froitzheim Nikolaus
Published: July 2008

During Europe–Adria collision in Tertiary times, the Monte Rosa nappe was penetratively deformed in several stages after an eclogite-facies pressure peak: (1) top-to-the-NW thrust shearing (Mattmark phase, after 40 Ma); (2) orogen-parallel, top-to-the-SW extensional shearing and folding (Malfatta phase); (3) orogen-perpendicular, top-to-the-SE extensional shearing and folding (Mischabel phase, before 30 Ma); and (4) large-scale, upright, SE-vergent folding (Vanzone phase,
c
. 29–28 Ma). Structural analysis and neutron texture goniometry of quartz mylonites show that the Stellihorn shear zone in the Monte Rosa nappe accommodated a complex and multidirectional sequence of shearing movements during the Mattmark, Malfatta and Mischabel phases, and was folded in the Vanzone phase. In the tail-shaped eastward prolongation of the Monte Rosa nappe in the Southern Steep Belt of the Alps, both dextral and sinistral mylonites (Olino phase) were formed during and after the formation of the Vanzone fold, reflecting renewed orogen-parallel (SW–NE) extension contemporaneous with NW–SE shortening from
c
. 29 Ma onward. A similar sequence of deformation stages was identified in the Adula nappe at the eastern border of the Lepontine metamorphic dome. Important consequences arise for the Insubric fault at the southern border of the Lepontine dome: (1) the NW- to N-dipping orientation of the Insubric fault is not a primary feature but resulted from rotation of an originally SE-dipping shear zone after
c
. 30 Ma; and (2), the strong contrast in metamorphic grade across this fault (upper amphibolite facies to the north versus anchizone to the south) results from north-side-up faulting coupled with orogen-parallel extension of the northern block (Lepontine dome), while no such extension occurred in the southern block (Southern Alps). Extension in the northern block started in the Malfatta phase and continued in the Mischabel phase when the foliation in the area which later became the Southern Steep Belt still dipped towards south. During Vanzone/Olino deformation, further unroofing and uplift of the Lepontine dome relative to the South Alpine block took place while the Southern Steep Belt was progressively rotated into its present, overturned position, changing its character from a normal fault into a backthrust. Complex deformation paths in the Southern Steep Belt resulted from the combination of extension of the northern block with strike-slip motion along the Insubric fault.
Metamorphic evolution of a very low- to low-grade metamorphic core complex (Danubian window) in the South Carpathians
Authors: Ciulavu Magda , Mählmann Rafael Ferreiro , Schmid Stefan M. , Hofmann Heiko , Seghedi Antoneta , Frey Martin
Published: July 2008

The Danubian window, characterized by diagenetic to low greenschist facies conditions at a high thermal gradient, is evidently of great interest for methodological studies, because high metamorphic thermal gradient conditions during low grade metamorphism have received little attention so far. The general increase in metamorphic grade from SW to NE in the Danubian window is indicated by mineral Parageneses studies, as well as by illite Kübler index (KI) measurements and organic matter reflectance (OMR). For the first time, this study distinguishes between metamorphic conditions related to Jurassic ocean floor, Cretaceous nappe stacking, post-collisional accommodation and syn-kinematic Getic detachment metamorphism and cooling after Oligocene exhumation.

The occurrence of the prehnite–pumpellyite facies in the Severin–Cosustea units in the southeastern area is the result of Cretaceous metamorphism. Remnants of ocean floor metamorphism prevailed. The highest pressure is constrained by the upper stability limit of prehnite to be at around 4.0 kbar. The Danubian units situated within the diagenetic zone were not below 200 °C, due to epidote formation. The KI, OMR and mineral data, indicate diagenetic conditions. Assuming temperatures between >200 and <250 °C, pressures between 1.8 and 2.6 kbar were calculated using kinetic and numerical maturity models.

Orogenic collisional Cretaceous peak pressure conditions of 4.0±1.0 kbar are found in the Danubian nappes not altered by a subsequent syn-detachment metamorphic overprint. Highest temperatures in chloritoid schists and epidote–hornblende-bearing mylonites have been inferred for samples from the northern border of the Danubian window (between >300 and <400 °C). Along a syn- to post-detachment retrograde pressure path, post-dating the chloritoid formation, the occurrence of clinozoisite+chlorite+quartz suggests temperatures >300 °C in the northwest, while the association andalusite+quartz and biotite+muscovite indicates temperatures between 370 and 400 °C at <3.5 kbar in the northeast.

It is demonstrated that the slope of the regression lines between KI and OMR data gives valuable qualitative information about the relative magnitudes of P and T: the slope of the regression line for the Danubian window samples indicates normal heat flow conditions during nappe stacking and hyperthermal conditions during the formation of the Getic detachment.

High thermal gradient conditions can easily be explained by partly isothermal decompression during the Getic detachment event, the elevation of the geotherm being caused by crustal thinning and rapid exhumation of the Danubian units. Probably, also a higher heat-flux prevailed at the end of the Getic detachment, at a time when the retrograde chloritoid decomposition reactions took place, documenting late-stage HT greenschist facies metamorphism.
Calcareous nannofossil age constraints on Miocene flysch sedimentation in the Outer Dinarides (Slovenia, Croatia, Bosnia-Herzegovina and Montenegro)
Authors: Mikes Tamás , Báldi-Beke Mária , Kázmér Miklós , Dunkl István , von Eynatten Hilmar
Published: July 2008

Flysch deposits are associated with the Outer Dinaride nappe front. They overlie Eocene platform carbonate to bathyal marl successions that subsequently cover Cretaceous platform carbonates of Apulia and the Dinaride nappes. Planktonic foraminifer biostratigraphy indicates Eocene age of flysch sedimentation. New calcareous nannofossil data reveal that several assemblages are present; besides the dominant Mid-Eocene species, Cretaceous, Paleocene, Oligocene and Miocene taxa were also identified throughout the entire flysch belt. Widespread occurrence of nannofossil species of zone NN4-6 indicates that flysch deposition lasted up to at least the Mid-Miocene. Ubiquitous occurrence of various pre-Miocene taxa demonstrates that extensive, possibly submarine, sediment recycling has occurred in the Cenozoic. As flysch remnants are typically sandwiched between thrust sheets, these new stratigraphic ages give a lower bracket on deformation age of the coastal range. The data provide a link between Cretaceous compression in the Bosnian Flysch and recent deformation in the Adriatic offshore area.
Tertiary subduction, collision and exhumation recorded in the Adula nappe, central Alps
Authors: Nagel Thorsten J.
Published: July 2008

The Adula nappe in the Central Alps represents a lithospheric mélange assembled in a south-dipping subduction zone during the Tertiary orogenic cycle. It consists of several heterogeneous lobes which are stacked in a forward-dipping duplex geometry. Eclogites, garnet peridotites and garnet-white-mica schists record southward-increasing peak pressure conditions which culminate at 12–17 kbar/500–600 °C in the north and 30 kbar/800–850 °C in the south. Some studies infer even higher peak pressures for the garnet peridotite body of Alpe Arami. The present-day metamorphic field gradient for peak pressures exceeds the lithostatic pressure gradient. So far, only eclogites and garnet peridotites from the Cima Lunga complex in the south and the adjacent Southern Steep Belt have yielded Tertiary metamorphic ages for the peak-pressure stage. Some recent studies propose that the Adula nappe got assembled after the formation of high-pressure assemblages in eclogites and garnet peridotites and reject regional high-pressure conditions in Tertiary times. This scenario, however, is in conflict with the observed continuity of metamorphic field gradients and post-peak-pressure structures. Amphibolite facies conditions post-date formation of the Central Alpine nappe stack. In this paper, the associated field gradient is explained through southward-increasing temperatures during near-isothermal decompression.

The main mylonitic foliation in the Adula nappe post-dates peak-pressure conditions. It is associated with top-to-the-north shearing and southward-increasing amounts of decompression from eclogite facies to amphibolite facies conditions. Also, the present-day supra-lithostatic field gradient for peak pressures probably results from this deformation phase and is here related to substantial vertical flattening during northward shearing. All subsequent structures affect established nappe boundaries. Pervasive Oligocene deformation events in the Adula nappe are coeval with intense shearing along the so-called Insubric mylonites and occur during ongoing isothermal decompression to around 5 kbar. They are associated with orogen-oblique to orogen-parallel stretching of unspecified amount which may considerably contribute to the exhumation of the Lepontine dome already before the onset of the well-known Miocene extension.
Geodynamic evolution of an Alpine terrane—the Austroalpine basement to the south of the Tauern Window as a part of the Adriatic Plate (eastern Alps)
Authors: Schulz Bernhard , Steenken André , Siegesmund Siegfried
Published: July 2008

The Austroalpine basement underwent a multistage Precambrian to Tertiary evolution. Meta-magmatic rocks occur in pre-Early Ordovician and post-Early Ordovician units. Protolith zircon ages and whole-rock trace element data define two magmatic evolution lines. An older trend with Th/Yb typical of subduction-related metamorphism, started by 590 Ma N-MORB-type and 550–530 Ma volcanic arc basalt-type basic suites which mainly involved depleted mantle sources, and was continued by mainly crustal-source 470–450 Ma acid magmatic suites. A presumably younger evolution by tholeiitic MORB-type and 430 Ma alkaline within-plate basalt-type suites is characterized by an intraplate mantle metasomatism and multicomponent sources. These magmatic trends can be related to a Neoproterozoic to Ordovician active margin and a subsequent Palaeo-Tethys passive margin along the north-Gondwanan periphery. During Variscan collision, the Austroalpine basement underwent multiphase deformation and metamorphism. Early deformation involved non-coaxial shearing with formation of sheath folds and calcsilicategneiss bodies in some regions. Syndeformational clockwise P–T paths in lower basement parts passed high-pressure and high-temperature amphibolite-facies stages and are interpreted by a Devonian to Carboniferous crustal stacking. A post-collisional Permian thermal event is documented by pegmatite intrusions, LP-HT assemblages and monazite ages. Ductile overprinting under greenschist-facies conditions during the Cretaceous is indicated by foliated pegmatites and monazite ages in samples with retrogressed garnet. The emplacement of the Oligocene Rieserferner pluton was controlled by sinistral shear zone deformation along the Defereggen–Antholz–Vals line. Shear zone activity ceased at 15 Ma and was superseded by brittle strike-slip movements along NW and SE trending faults.