46 research outputs found

    The evolution of the actin binding NET superfamily

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    The Arabidopsis Networked (NET) superfamily are plant-specific actin binding proteins which specifically label different membrane compartments and identify specialized sites of interaction between actin and membranes unique to plants. There are 13 members of the superfamily in Arabidopsis, which group into four distinct clades or families. NET homologs are absent from the genomes of metazoa and fungi; furthermore, in plantae, NET sequences are also absent from the genome of mosses and more ancient extant plant clades. A single family of the NET proteins is found encoded in the club moss genome, an extant species of the earliest vascular plants. Gymnosperms have examples from families 4 and 3, with a hybrid form of NET1 and 2 which shows characteristics of both NET1 and NET2. In addition to NET3 and 4 families, the NET1 and pollen-expressed NET2 families are found only as independent sequences in Angiosperms. This is consistent with the divergence of reproductive actin. The four families are conserved across Monocots and Eudicots, with the numbers of members of each clade expanding at this point, due, in part, to regions of genome duplication. Since the emergence of the NET superfamily at the dawn of vascular plants, they have continued to develop and diversify in a manner which has mirrored the divergence and increasing complexity of land-plant species

    Considerations for designing and implementing combination HIV cure trials: findings from a qualitative in-depth interview study in the United States

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    Background: An increasing number of HIV cure trials involve combining multiple potentially curative interventions. Until now, considerations for designing and implementing complex combination HIV cure trials have not been thoroughly considered. Methods: We used a purposive method to select key informants for our study. Informants included biomedical HIV cure researchers, regulators, policy makers, bioethicists, and community members. We used in-depth interviews to generate ethical and practical considerations to guide the design and implementation of combination HIV cure research. We analyzed the qualitative data using conventional content analysis focused on inductive reasoning. Results: We interviewed 11 biomedical researchers, 4 community members, 2 regulators, 1 policy researcher, and 1 bioethicist. Informants generated considerations for designing and implementing combination interventions towards an HIV cure, focused on ethical aspects, as well as considerations to guide trial design, benefit/risk determinations, regulatory requirements, prioritization and sequencing and timing of interventions, among others. Informants also provided considerations related to combining specific HIV cure research modalities, such as broadly neutralizing antibodies (bNAbs), cell and gene modification products, latency-reversing agents and immune-based interventions. Finally, informants provided suggestions to ensure meaningful therapeutic improvements over standard antiretroviral therapy, overcome challenges of designing combination approaches, and engage communities around combination HIV cure research. Conclusion: The increasing number of combination HIV cure trials brings with them a host of ethical and practical challenges. We hope our paper will inform meaningful stakeholder dialogue around the use of combinatorial HIV cure research approaches. To protect the public trust in HIV cure research, considerations should be periodically revisited and updated with key stakeholder input as the science continues to advance

    Operationalizing Human Immunodeficiency Virus Cure-related Trials with Analytic Treatment Interruptions During the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pandemic: A Collaborative Approach

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    Efforts to recognize and minimize the risk to study participants will be necessary to safely and ethically resume scientific research in the context of the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. These efforts are uniquely challenging in the context of human immunodeficiency virus (HIV) cure clinical trials, which often involve complex experimental therapy regimens and perhaps analytic treatment interruption, in which participants pause antiretroviral therapy. In this viewpoint, we discuss our approach to reopening an HIV cure trial in this context, with a focus on key considerations regarding study design, informed consent and participant education, and study implementation. These recommendations might be informative to other groups seeking to resume HIV cure research in settings similar to ours

    SARS-CoV-2 Vaccination in the Context of Ongoing HIV Cure-Related Research Studies

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    To the Editors: The SARS-CoV-2 pandemic has affected research efforts worldwide. Previously, we described our strategy to mitigate COVID-19 transmission risk during an ongoing HIV cure-related clinical trial. SARS-CoV-2 vaccines recently have been authorized for emergency use and will become available to people with HIV imminently. As a result, researchers must determine how to adjust study protocols to incorporate the likelihood that participants may be vaccinated

    Association of Immunosuppression and Human Immunodeficiency Virus (HIV) Viremia with Anal Cancer Risk in Persons Living with HIV in the United States and Canada

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    Background: People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. Methods: We studied 102 777 PLWH during 1996-2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. Results: Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for <50 vs ≥500 cells/μL, 13.4; 95% confidence interval [CI], 3.5-51.0) and proportion of time CD4 <200 cells/μL from approximately 8.5 to 4.5 years in the past (a cumulative measure; HR for 100% vs 0%, 3.1; 95% CI, 1.5-6.6). Conclusions: Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk

    Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals

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    Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen?. We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the “no direct effect†assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/μl compared with 500 cells/μl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The “no direct effect†assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size

    Bio-analytical Assay Methods used in Therapeutic Drug Monitoring of Antiretroviral Drugs-A Review

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    Control of the actin cytoskeleton in plant cell growth

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    Plant cells grow through increases in volume and cell wall surface area. The mature morphology of a plant cell is a product of the differential rates of expansion between neighboring zones of the cell wall during this process. Filamentous actin arrays are associated with plant cell growth, and the activity of actin-binding proteins is proving to be essential for proper cell morphogenesis. Actin-nucleating proteins participate in cell expansion and cell plate formation whereas the recycling of actin monomers is required to maintain actin dynamics and controlled growth. Coordination of actin-binding protein activity and other aspects of cytoskeletal behavior during cell development maintains cohesive cell expansion. Emerging plant signaling networks are proving to be powerful regulators of morphology-shaping cytoskeletal activity, and in this review we highlight current research in actin network regulatio

    Arp2/3 and scar: Plants move to the fore

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    Arp2/3 and 'The Shape of things to come'

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