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The aesthetics and concepts of modern art have influenced American television ever since its inception in the 1930s. In return, early television introduced the public to the latest trends in art and design. This engaging catalogue is the first book to comprehensively examine the way avant-garde art shaped the look and content of network television in its formative years, from the 1940s through the mid-1970s. -- Page [4] of cover.

Genes induced by inflammatory stimuli are expressed in a precise temporal order. Baltimore and colleagues show that mRNA stability exerts strong influence over the kinetics of the induction of genes encoding inflammatory molecules. The inflammatory response plays out over time in a reproducible and organized way after an initiating stimulus. Here we show that genes activated in cultured mouse fibroblasts in response to the cytokine tumor necrosis factor could be categorized into roughly three groups, each with different induction kinetics. Although differences in transcription were important in determining the grouping of these genes, differences in mRNA stability also exerted a strong influence on the temporal order of gene expression, in some cases overriding that of transcriptional control elements. Transcripts of mRNA expressed early had abundant AU-rich elements in their 3′ untranslated regions, whereas those expressed later had fewer. Thus, mRNA stability and transcriptional control, two intrinsic characteristics of genes, control the kinetics of gene expression induced by proinflammatory cytokines.

The His²⁷⁴[rightward arrow]Tyr²⁷⁴ (H274Y) mutation confers oseltamivir resistance on N1 influenza neuraminidase but had long been thought to compromise viral fitness. However, beginning in 2007-2008, viruses containing H274Y rapidly became predominant among human seasonal H1N1 isolates. We show that H274Y decreases the amount of neuraminidase that reaches the cell surface and that this defect can be counteracted by secondary mutations that also restore viral fitness. Two such mutations occurred in seasonal H1N1 shortly before the widespread appearance of H274Y. The evolution of oseltamivir resistance was therefore enabled by \"permissive\" mutations that allowed the virus to tolerate subsequent occurrences of H274Y. An understanding of this process may provide a basis for predicting the evolution of oseltamivir resistance in other influenza strains.

When cells are induced to express inflammatory genes by treatment with TNF, the mRNAs for the induced genes appear in three distinct waves, defining gene groups I, II, and III, or early, intermediate, and late genes. To examine the basis for these different kinetic classes, we have developed a PCR-based procedure to distinguish pre-mRNAs from mRNAs. It shows that the three groups initiate transcription virtually simultaneously but that delays in splicing characterize groups II and III. We also examined the elongation times, concluding that pre-mRNA synthesis is coordinate but splicing differences directly regulate the timing of mRNA production.

A fetus is inherently antigenic to its mother and yet is not rejected. The T regulatory (Treg) subset of CD4⁺ T cells can limit immune responses and has been implicated in maternal tolerance of the fetus. Using virgin inbred mice undergoing a first syngenic pregnancy, in which only the male fetuses are antigenic, we demonstrate a maternal splenocyte proliferative response to the CD4⁺ T cell restricted epitope of the male antigen (H-Y) in proportion to the fetal antigen load. A portion of the maternal immune response to fetal antigens is Treg in nature. The bystander suppressive function of pregnancy-generated Tregs requires the presence of the fetal antigen, demonstrating their inherent antigen specificity. In vivo targeting of diphtheria toxin to kill Tregs leads to a lower fraction of live male offspring and a selective reduction in mass of the surviving males. Thus, Tregs generated in the context of pregnancy function in an antigen-specific manner to limit the maternal immune response to the fetus in a successful pregnancy.

The innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-κB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-κB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-κB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-κB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-κB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity. MicroRNAs (miR) are important regulators of gene transcription, with miR-155 and miR-146a both implicated in macrophage activation. Here the authors show that NF-κB signalling, miR-155 and miR-146a form a complex network of cross-regulations to control gene transcription in macrophages for modulating inflammatory responses.

Key Points MicroRNAs (miRNAs) are expressed by cells that constitute the immune system, and they function by repressing specific mRNA targets at the post-transcriptional level. The biosynthesis of miRNAs involves several levels of regulation, some of which are influenced by inflammation. Specific miRNAs modulate haematopoietic cell development. miRNAs regulate both innate and adaptive immune responses. miRNA expression levels are dysregulated in diseases of immunological origin, such as cancer and autoimmunity. Altered miRNA expression can subsequently exacerbate disease severity. Research into miRNA is a recent development, and therefore many aspects of miRNA biology remain unexplored. Here, the authors review the fast-moving field of gene expression regulation by microRNAs. They describe how microRNAs influence many stages of innate and adaptive immune responses and how they might precipitate cancer and autoimmune disease if dysregulated. Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.

A single injection of a viral vector that encodes antibodies able to neutralize most HIV strains protects humanized mice from HIV infection. Anti-HIV vaccination The identification of broadly neutralizing antibodies against HIV has stimulated a search for vaccine immunogens that can elicit similar antibodies. This paper presents an alternative approach to boosting immunity against infectious diseases for which neutralizing antibodies are available. David Baltimore and colleagues have engineered adenovirus-associated vectors expressing a human antibody against HIV. A single injection of the vector induced lifelong expression of HIV-neutralizing antibodies that protect humanized mice from infection with a high dose of HIV. Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains 1 , 2 , 3 , 4 , 5 . These antibodies all exhibit an unusually high level of somatic mutation 6 , presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen 7 . Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes 8 , 9 , 10 , it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.

NF-κB is a key activator of inflammatory and immune responses with important pathological roles in cancer, heart disease, and autoimmune diseases. Transcriptional activity of NF-κB is regulated by different posttranslational modifications. Here, we report a novel mechanism of NF-κB regulation through lysine monomethylation by SET9 methyltransferase. Set9 specifically methylates p65 at lysine 37. Both TNFα and IL-1β treatments induced methylation of p65. Methylated p65 is restricted to the nucleus and this modification regulates the promoter binding of p65. Moreover, Set9 mediated methylation of p65 is required for the expression of a subset of NF-κB target genes in response to TNFα stimulation.

HIV persists through continued transmission Antiretroviral therapy suppresses, but does not eradicate, HIV infection. Low-level viraemia continues for life because of the persistence of treatment-resistant reservoirs of the virus. Various different types of reservoir are thought to exist. David Baltimore and colleagues use a combination of mathematical modelling and a cell culture model of HIV infection and drug treatment to propose that ongoing HIV replication can occur in the presence of drugs if the cells become infected through cell-to-cell transmission. They propose that cell-to-cell spread of virus could be a source of localized and intermittent ongoing replication, which may show little evolution, and which could contribute to replenishment of the virus reservoir and virus persistence. Latency and ongoing replication 1 have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections 2 , 3 per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV 4 , 5 , 6 , 7 , a mode of HIV transmission that can lead to multiple infection events per target cell 8 , 9 , 10 . Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo , it may have adverse consequences for the immune system 11 , 12 , 13 , lead to therapy failure in individuals with risk factors 14 , and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.