Abstract
Influenza A virus (IAV) circulation patterns differ in North America and South America, with influenza seasons often characterized by different subtypes and strains. However, South America ...is relatively undersampled considering the size of its population. To address this gap, we sequenced the complete genomes of 220 IAVs collected between 2009 and 2016 from hospitalized patients in southern Brazil. New genetic drift variants were introduced into southern Brazil each season from a global gene pool, including four H3N2 clades (3c, 3c2, 3c3, and 3c2a) and five H1N1pdm clades (clades 6, 7, 6b, 6c, and 6b1). In 2016, H1N1pdm viruses belonging to a new 6b1 clade caused a severe influenza epidemic in southern Brazil that arrived early and spread rapidly, peaking mid-autumn. Inhibition assays showed that the A/California/07/2009(H1N1) vaccine strain did not protect well against 6b1 viruses. Phylogenetically, most 6b1 sequences that circulated in southern Brazil belong to a single transmission cluster that rapidly diffused across susceptible populations, leading to the highest levels of influenza hospitalization and mortality seen since the 2009 pandemic. Continuous genomic surveillance is needed to monitor rapidly evolving IAVs for vaccine strain selection and understand their epidemiological impact in understudied regions.
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Hydrogen sulfide (H
2
S) is emerging as an important member of the gasotransmitter family that includes nitric oxide and carbon monoxide. We have recently reported that H
2
S is an ...important immunomodulatory molecule that potentiates the activation of human and murine T cells. As H
2
S signaling in T cells plays a vital functional role, it is critical to identify the relevant signaling target(s) and define the role of H
2
S in T cell differentiation and effector function. We have found that nanomolar levels of H
2
S dose‐dependently enhance HIF1α protein levels in activated T cells by 65% under hypoxic conditions. Under these conditions, H
2
S also enhanced VEGF gene expression. Consistent with recent reports of HIF1α‐dependent T cell differentiation, we observed an increase in Th17 cells and a decrease in Treg cells when splenic T cells were differentiated in the presence of 1000 nM H
2
S. We are currently characterizing the regulation of hypoxic T cell metabolism by H
2
S and the proximal target of H
2
S in this hypoxic response pathway. This work has exciting implications for understanding the progression of inflammatory bowel disease and for development of antitumor immune therapies.
Mosquito-borne chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae, which causes fever, rash and severe persistent polyarthralgia in ...humans. Since there are currently no FDA licensed vaccines or antiviral therapies for CHIKV, the development of vaccine candidates is of critical importance. Historically, live-attenuated vaccines (LAVs) for protection against arthropod-borne viruses have been created by blind cell culture passage leading to attenuation of disease, while maintaining immunogenicity. Attenuation may occur via multiple mechanisms. However, all examined arbovirus LAVs have in common the acquisition of positively charged amino acid substitutions in cell-surface attachment proteins that render virus infection partially dependent upon heparan sulfate (HS), a ubiquitously expressed sulfated polysaccharide, and appear to attenuate by retarding dissemination of virus particles in vivo. We previously reported that, like other wild-type Old World alphaviruses, CHIKV strain, La Réunion, (CHIKV-LR), does not depend upon HS for infectivity. To deliberately identify CHIKV attachment protein mutations that could be combined with other attenuating processes in a LAV candidate, we passaged CHIKV-LR on evolutionarily divergent cell-types. A panel of single amino acid substitutions was identified in the E2 glycoprotein of passaged virus populations that were predicted to increase electrostatic potential. Each of these substitutions was made in the CHIKV-LR cDNA clone and comparisons of the mutant viruses revealed surface exposure of the mutated residue on the spike and sensitivity to competition with the HS analog, heparin, to be primary correlates of attenuation in vivo. Furthermore, we have identified a mutation at E2 position 79 as a promising candidate for inclusion in a CHIKV LAV.
Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. Although the survival rate for GBM has improved with recent advancements in treatment, the prognosis remains generally ...poor.
We conducted a retrospective review of GBM patients seen in National University Hospital, Singapore, and Tan Tock Seng Hospital, Singapore, from January 2002 to December 2011. Data on disease and treatment factors was collected and correlated with survival.
Data on a total of 107 GBM patients was analysed. Their median survival time was 15.1 months and the two-year survival rate was 23.5%, which is comparable with data published in other series. The factors associated with improved median survival time were radiotherapy dose > 50 Gy (16.1 months vs. 8.7 months, p = 0.01) and adjuvant concurrent chemotherapy (16.4 months vs. 9.2 months, p = 0.003).
GBM confers a poor prognosis. Adjuvant radiotherapy and chemotherapy are associated with improved survival. Ethnicity may be a contributing factor to differences in GBM incidence and prognosis.
The increasing number of annotated genome sequences in public databases has made it possible to study the length distributions and domain composition of proteins at unprecedented resolution. To ...identify factors that influence protein length in metazoans, we performed an analysis of all domain-annotated proteins from a total of 49 animal species from Ensembl (v.56) or EnsemblMetazoa (v.3). Our results indicate that protein length constraints are not fixed as a linear function of domain count and can vary based on domain content. The presence of repeating domains was associated with relaxation of the constraints that govern protein length. Conversely, for proteins with unique domains, length constraints were generally maintained with increased domain counts. It is clear that mean (and median) protein length and domain composition vary significantly between metazoans and other kingdoms; however, the connections between function, domain content, and length are unclear. We incorporated Gene Ontology (GO) annotation to identify biological processes, cellular components, or molecular functions that favor the incorporation of multi-domain proteins. Using this approach, we identified multiple GO terms that favor the incorporation of multi-domain proteins; interestingly, several of the GO terms with elevated domain counts were not restricted to a single gene family. The findings presented here represent an important step in resolving the complex relationship between protein length, function, and domain content. The comparison of the data presented in this work to data from other kingdoms is likely to reveal additional differences in the regulation of protein length.
Covering extensive parts of China, Karst landscapes are exceptional because rapid and intensive land use change has caused severe ecosystem degradation within only the last 50 years. The twentieth ...century intensification in food production through agriculture has led to a rapid deterioration of soil quality, evidenced in reduced crop production and rapid loss of soil. In many areas, a tipping point appears to have been passed as basement rock is exposed and ＇rocky desertification＇ dominates. Through the establishment of the ＂Soil processes and ecological services in the karst critical zone of SW China＂（SPECTRA）Critical Zone Observatory（CZO） we will endevaour to understand the fundmental processes involved in soil production and erosion, and investigate the integrated geophysical-geochemical-ecological responses of the CZ to perturbations. The CZ spans a gradient from undisturbed natural vegetation through human perturbed landscapes.We seek to understand the importance of heterogeneity insurface and below-ground morphology and flow pathways in determining the spatial distribution of key stocks（soil,C, vegetation, etc.） and their control on ecosystem service delivery. We will assess the extent to which the highly heterogeneous critical zone resources can be restored to enable sustainable delivery of ecosystem services. This paper presents the CZO design and initial assessment of soil and soil organic carbon stocks and evidence for their stability based on caesium-137（^137 Cs） data.
This thesis seeks to investigate the effects of the No Child Left Behind Act (NCLB) on U.S. student achievement and teacher effectiveness. By combining the results from various data sources, I am ...able to indicate the levels of student preparedness, school spending, and specific classroom practices. After an analysis of my results, I suggest that NCLB has found moderate success in increasing the level of math preparedness for younger students from historically disadvantaged backgrounds. On the other hand, the data also suggests that there have been no statistically significant gains in reading achievement after the implementation of NCLB. Additionally, spending by school districts increased a significant amount and NCLB raised teacher pay and the number of teachers entering the profession with graduate degrees. Within schools, NCLB appears to have directed instruction towards math and reading and away from other subjects as teachers strove to achieve proficiency on the new accountability measures implemented by NCLB.
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