The gene product Murr1 restricts HIV-1 replication in resting CD4(+) lymphocytes

Although human immunodeficiency virus-1 (HIV-1) infects quiescent and proliferating CD4(+) lymphocytes, the virus replicates poorly in resting T cells(1-6). Factors that block viral replication in these cells might help to prolong the asymptomatic phase of HIV infection(7); however, the molecular mechanisms that control this process are not fully understood. Here we show that Murr1, a gene product known previously for its involvement in copper regulation(8,9), inhibits HIV-1 growth in unstimulated CD4(+) T cells. This inhibition was mediated in part through its ability to inhibit basal and cytokine-stimulated nuclear factor (NF)-kappaB activity. Knockdown of Murr1 increased NF-kappaB activity and decreased IkappaB-alpha concentrations by facilitating phospho-IkappaB-alpha degradation by the proteasome. Murr1 was detected in CD4(+) T cells, and RNA-mediated interference of Murr1 in primary resting CD4(+) lymphocytes increased HIV-1 replication. Through its effects on the proteasome, Murr1 acts as a genetic restriction factor that inhibits HIV-1 replication in lymphocytes, which could contribute to the regulation of asymptomatic HIV infection and the progression of AIDS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62709/1/nature02171.pd

Embryo movement is more frequent in avian brood parasites than birds with parental reproductive strategies.

Funder: Tanzanian Commission for Science and TechnologyFunder: Tanzania Wildlife Research InstituteFunder: NERCFunder: National Science FoundationFunder: Ministry of EducationFunder: German Academic Exchange ServiceFunder: University of Cape TownFunder: Max-Planck-GesellschaftMovement of the embryo is essential for musculoskeletal development in vertebrates, yet little is known about whether, and why, species vary. Avian brood parasites exhibit feats of strength in early life as adaptations to exploit the hosts that rear them. We hypothesized that an increase in embryonic movement could allow brood parasites to develop the required musculature for these demands. We measured embryo movement across incubation for multiple brood-parasitic and non-parasitic bird species. Using a phylogenetically controlled analysis, we found that brood parasites exhibited significantly increased muscular movement during incubation compared to non-parasites. This suggests that increased embryo movement may facilitate the development of the stronger musculoskeletal system required for the demanding tasks undertaken by young brood parasites

Understanding the Impacts of Research Synthesis

Research synthesis is the integration of existing knowledge and research findings pertinent to an issue. The aim of synthesis is to increase the generality and applicability of those findings and to develop new knowledge through the process of integration. Synthesis is promoted as an approach that deals with the challenge of öinformation overload’, delivering products that further our understanding of problems and distil relevant evidence for decision-making. However, despite the increasing prominence of synthesis efforts in the science and policy landscape, we know very little about the impacts these initiatives have on research, policy and practice and the assumptions underpinning how they will lead to change. This paper presents a framework for considering the conceptual, strategic, instrumental and network-based impacts of research synthesis on policy. This framework provides insight into the range of underlying assumptions and impacts on policy and practice from 10 case studies of research synthesis related to contemporary sustainability challenges. Findings suggest that research synthesis is having diverse impacts on research, policy and practice including creating a new understanding of problems, establishing new networks, and contributing to changes in policy and practice. These impacts emerged across a range of contexts, synthesis methods, assumptions and operating models. This suggests that there is no single öcorrect way’ to design research synthesis for impact, but rather a need to tailor the approach for the context of intended use

An agenda for research and action towards diverse and just futures for life on Earth

Decades of research and policy interventions on biodiversity have insufficiently addressed the dual issues of biodiversity degradation and social justice. New approaches are therefore needed. This essay outlines a research and action agenda that calls for a collective task of 'revisiting biodiversity' towards the goal of sustaining diverse and just futures for life on Earth. The agenda was developed through a two-year dialogue process that involved close to 300 experts from diverse disciplines and geographies. This process was informed by social science insights that have shown that biodiversity research and action is underpinned by choices about how problems are conceptualized. Recognizing knowledge, action, and ethics as inseparable, we synthesize a set of principles that help navigate the task of 'revisiting biodiversity'. The agenda articulates four thematic areas for future research. First, the need to revisit biodiversity narratives by challenging conceptualizations that exclude diversity and entrench the separation of humans, cultures, economies, and societies from nature. Second, embracing a focus on the relationships between the anthropocene, biodiversity, and culture by considering humanity and biodiversity as tied together in specific contexts. Third, focusing on nature and economy by better accounting for the interacting structures of economic and financial systems as core drivers of biodiversity loss. Finally, enabling transformative biodiversity research and action by re-configuring relationships between human and non-human communities in and through science, policy, and practice. Revisiting biodiversity necessitates a renewed focus on dialogue among biodiversity communities and beyond that critically reflects on the past to channel research and action towards fostering just and diverse futures for human and non-human life on Earth. Article impact statement: Placing diversity and justice at the heart of transformative change for biodiversity offers important new directions for research and action. This article is protected by copyright

SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity1. This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy

Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

A preventive HIV-1 vaccine should induce HIV-1–specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs

Structure and immune recognition of trimeric pre-fusion HIV-1 Env.

CAPRISA, 2014.The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation

Dense sampling of bird diversity increases power of comparative genomics (vol 587, pg 252, 2020)

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