Interferon-Induced Guanylate Binding Protein-1 (GBP-1) Mediates an Antiviral Effect against Vesicular Stomatitis Virus and Encephalomyocarditis Virus

AbstractA cDNA encoding the human guanylate binding protein-1 (hGBP-1) was expressed in HeLa cells using a constitutive expression vector. Stably transfected clones expressing hGBP-1 exhibited resistance to the cytopathic effect mediated by both vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) and produced less viral progeny than control cells following infection with these viruses. To study the role hGBP-1 plays in the IFN-mediated antiviral effect, cells were stably transfected with a construct expressing antisense RNA for hGBP-1. VSV infection of IFN-α-treated antisense RNA-expressing cells produced an amount of virus comparable to that produced in the parental cell line, while EMCV infection of the IFN-α-treated transfected cells and VSV and EMCV infection of the IFN-γ-treated transfected cells produced far more virus than was produced in the parental cell line. These results demonstrate that GBP-1 mediates an antiviral effect against VSV and EMCV and plays a role in the IFN-mediated antiviral response against these viruses

Exposure and infection to Plasmodium knowlesi in case study communities in Northern Sabah, Malaysia and Palawan, The Philippines.

BACKGROUND: Primarily impacting poor, rural populations, the zoonotic malaria Plasmodium knowlesi is now the main cause of human malaria within Malaysian Borneo. While data is increasingly available on symptomatic cases, little is known about community-level patterns of exposure and infection. Understanding the true burden of disease and associated risk factors within endemic communities is critical for informing evidence-based control measures. METHODOLOGY/PRINCIPAL FINDINGS: We conducted comprehensive surveys in three areas where P. knowlesi transmission is reported: Limbuak, Pulau Banggi and Matunggung, Kudat, Sabah, Malaysia and Bacungan, Palawan, the Philippines. Infection prevalence was low with parasites detected by PCR in only 0.2% (4/2503) of the population. P. knowlesi PkSERA3 ag1 antibody responses were detected in 7.1% (95% CI: 6.2-8.2%) of the population, compared with 16.1% (14.6-17.7%) and 12.6% (11.2-14.1%) for P. falciparum and P. vivax. Sero-prevalence was low in individuals <10 years old for P. falciparum and P. vivax consistent with decreased transmission of non-zoonotic malaria species. Results indicated marked heterogeneity in transmission intensity between sites and P. knowlesi exposure was associated with agricultural work (OR 1.63; 95% CI 1.07-2.48) and higher levels of forest cover (OR 2.40; 95% CI 1.29-4.46) and clearing (OR 2.14; 95% CI 1.35-3.40) around houses. Spatial patterns of P. knowlesi exposure differed from exposure to non-zoonotic malaria and P. knowlesi exposed individuals were younger on average than individuals exposed to non-zoonotic malaria. CONCLUSIONS/SIGNIFICANCE: This is the first study to describe serological exposure to P. knowlesi and associated risk factors within endemic communities. Results indicate community-level patterns of infection and exposure differ markedly from demographics of reported cases, with higher levels of exposure among women and children. Further work is needed to understand these variations in risk across a wider population and spatial scale

Environmental risk factors and exposure to the zoonotic malaria parasite Plasmodium knowlesi across northern Sabah, Malaysia: a population-based cross-sectional survey.

BACKGROUND: Land use changes disrupt ecosystems, altering the transmission of vector-borne diseases. These changes have been associated with increasing incidence of zoonotic malaria caused by Plasmodium knowlesi; however, the population-level distributions of infection and exposure remain unknown. We aimed to measure prevalence of serological exposure to P knowlesi and assess associated risk factors. METHODS: We did an environmentally stratified, population-based, cross-sectional survey across households in the Kudat, Kota Marudu, Pitas, and Ranau districts in northern Sabah, Malaysia, encompassing a range of ecologies. Using blood samples, the transmission intensity of P knowlesi and other malaria species was measured by specific antibody prevalence and infection detected using molecular methods. Proportions and configurations of land types were extracted from maps derived from satellite images; a data-mining approach was used to select variables. A Bayesian hierarchical model for P knowlesi seropositivity was developed, incorporating questionnaire data about individual and household-level risk factors with selected landscape factors. FINDINGS: Between Sept 17, 2015, and Dec 12, 2015, 10 100 individuals with a median age of 25 years (range 3 months to 105 years) were sampled from 2849 households in 180 villages. 5·1% (95% CI 4·8-5·4) were seropositive for P knowlesi, and marked historical decreases were observed in the transmission of Plasmodium falciparum and Plasmodium vivax. Nine Plasmodium spp infections were detected. Age, male sex, contact with macaques, forest use, and raised house construction were positively associated with P knowlesi exposure, whereas residing at higher geographical elevations and use of insecticide were protective. Agricultural and forest variables, such as proportions and fragmentation of land cover types, predicted exposure at different spatial scales from households. INTERPRETATION: Although few infections were detected, P knowlesi exposure was observed in all demographic groups and was associated with occupational factors. Results suggest that agricultural expansion and forest fragmentation affect P knowlesi exposure, supporting linkages between land use change and P knowlesi transmission. FUNDING: UK Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council

How Treatment Partners Help: Social Analysis of an African Adherence Support Intervention

Treatment partnering is an adherence intervention developed in sub-Saharan Africa. This paper describes the additional social functions that treatment partners serve and shows how these functions contribute to health and survival for patients with HIV/AIDS. Ninety-eight minimally structured interviews were conducted with twenty pairs of adult HIV/AIDS patients (N = 20) and treatment partners (N = 20) treated at a public HIV-care setting in Tanzania. Four social functions were identified using inductive, category construction and interpretive methods of analysis: (1) encouraging disclosure; (2) combating stigma; (3) restoring hope; and (4) reducing social difference. These functions work to restore social connections and reverse the isolating effects of HIV/AIDS, strengthening access to essential community safety nets. Besides encouraging ARV adherence, treatment partners contribute to the social health of patients. Social health as well as HIV treatment success is essential to survival for persons living with HIV/AIDS in sub-Saharan Africa

Ligation Tunes Protein Reactivity in an Ancient Haemoglobin: Kinetic Evidence for an Allosteric Mechanism in Methanosarcina acetivorans Protoglobin

Protoglobin from Methanosarcina acetivorans (MaPgb) is a dimeric globin with peculiar structural properties such as a completely buried haem and two orthogonal tunnels connecting the distal cavity to the solvent. CO binding to and dissociation from MaPgb occur through a biphasic kinetics. We show that the heterogenous kinetics arises from binding to (and dissociation from) two tertiary conformations in ligation-dependent equilibrium. Ligation favours the species with high binding rate (and low dissociation rate). The equilibrium is shifted towards the species with low binding (and high dissociation) rates for the unliganded molecules. A quantitative model is proposed to describe the observed carbonylation kinetics

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study.

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The conversion of previtamin D2 to vitamin D2 in white button mushrooms and baby bella mushrooms, and in organic solvent

Thesis (M.A.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [email protected]. Thank you.Vitamin D is essential for maintaining bone metabolism, calcium homeostasis, the immune system, and much more. Upon exposure to sunlight, 7-dehydrocholestrol in the skin converts to previtamin D3, which undergoes a temperature-dependent isomerization in the plasma membrane to form the more stable vitamin D3. Many species of plants and fungi, including mushrooms, produce vitamin D2 from ergosterol upon exposure to ultraviolet-B radiation. To determine whether the vitamin D formation in mushrooms is more similar to that in human skin or in organic solvent, this study compares the rate of thermal isomerization of previtamin D2 to vitamin D2 in white button mushrooms and baby bella mushrooms with the isomerization in methanol under identical conditions. At 25°C, the rate of isomerization is enhanced by approximately 400% in button mushrooms and in baby bella mushrooms compared to that in methanol. Therefore, the formation of vitamin D2 in mushrooms from previtamin D2 is enhanced, similar to that in lizard and human skin. As a result, it is possible that a membrane enhanced conversion for previtamin D2 to vitamin D2 played an important role in the evolution of mushrooms and still aids in some unknown function in mushrooms