The rockefeller university

Polyamines play important roles in a range of cellular processes. In this issue of Cell Host & Microbe, Mounce et al. (2016) link polyamine metabolism to the interferon response and demonstrate proviral effects for polyamines. The study points to the pathway as a potential novel pan-viral therapeutic target.

Tetherin encodes an interferon-inducible antiviral protein that traps a broad spectrum of enveloped viruses at infected cell surfaces. Despite the absence of any clearly related gene or activity, we describe possible scenarios by which tetherin arose that exemplify how protein modularity, evolvability, and robustness can create and preserve new functions. We find that tetherin genes in various organisms exhibit no sequence similarity and share only a common architecture and location in modern genomes. Moreover, tetherin is part of a cluster of three potential sister genes encoding proteins of similar architecture, some variants of which exhibit antiviral activity while others can be endowed with antiviral activity by a simple modification. Only in slowly evolving species (e.g., coelacanths) does tetherin exhibit sequence similarity to one potential sister gene. Neofunctionalization, drift, and genetic conflict appear to have driven a near complete loss of sequence similarity among modern tetherin genes and their sister genes.

Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.

Background: Understanding the relationship between a stimulus and how it is perceived reveals fundamental principles about the mechanisms of sensory perception. While this stimulus-percept problem is mostly understood for color vision and tone perception, it is not currently possible to predict how a given molecule smells. While there has been some progress in predicting the pleasantness and intensity of an odorant, perceptual data for a larger number of diverse molecules are needed to improve current predictions. Towards this goal, we tested the olfactory perception of 480 structurally and perceptually diverse molecules at two concentrations using a panel of 55 healthy human subjects. Results: For each stimulus, we collected data on perceived intensity, pleasantness, and familiarity. In addition, subjects were asked to apply 20 semantic odor quality descriptors to these stimuli, and were offered the option to describe the smell in their own words. Using this dataset, we replicated several previous correlations between molecular features of the stimulus and olfactory perception. The number of sulfur atoms in a molecule was correlated with the odor quality descriptors "garlic," "fish," and "decayed," and large and structurally complex molecules were perceived to be more pleasant. We discovered a number of correlations in intensity perception between molecules. We show that familiarity had a strong effect on the ability of subjects to describe a smell. Many subjects used commercial products to describe familiar odorants, highlighting the role of prior experience in verbal reports of olfactory perception. Nonspecific descriptors like "chemical" were applied frequently to unfamiliar odorants, and unfamiliar odorants were generally rated as neither pleasant nor unpleasant. Conclusions: We present a very large psychophysical dataset and use this to correlate molecular features of a stimulus to olfactory percept. Our work reveals robust correlations between molecular features and perceptual qualities, and highlights the dominant role of familiarity and experience in assigning verbal descriptors to odorants.

A number of studies have shown that CD8+ T cells mediate protective anti-malaria immunity in a mouse model. However, whether human CD8+ T cells play a role in protection against malaria remains unknown. We recently established human immune system (HIS) mice harboring functional human CD8+ T cells (HIS-CD8 mice) by transduction with HLA-A*0201 and certain human cytokines using recombinant adeno-associated virus-based gene transfer technologies. These HIS-CD8 mice mount a potent, antigen-specific HLA-A*0201-restricted human CD8+ T-cell response upon immunization with a recombinant adenovirus expressing a human malaria antigen, the Plasmodium falciparum circumsporozoite protein (PfCSP), termed AdPfCSP. In the present study, we challenged AdPfCSP-immunized HIS-CD8 mice with transgenic Plasmodium berghei sporozoites expressing full-length PfCSP and found that AdPfCSP-immunized (but not naive) mice were protected against subsequent malaria challenge. The level of the HLA-A*0201-restricted, PfCSP-specific human CD8+ T-cell response was closely correlated with the level of malaria protection. Furthermore, depletion of human CD8+ T cells from AdPfCSP-immunized HIS-CD8 mice almost completely abolished the anti -malaria immune response. Taken together, our data show that human CD8+ T cells mediate protective anti-malaria immunity in vivo. (C) 2016 The Author(s). Published by Elsevier Ltd.

The exclusive deep inelastic electroproduction of psi(2S) and J/psi (1S) at an ep centre-of-mass energy of 317 GeV has been studied with the ZEUS detector at HERA in the kinematic range 2 < Q(2) < 80 GeV2, 30 < W < 210 GeV and vertical bar t vertical bar < 1 GeV2, where Q(2) is the photon virtuality, W is the photon-proton centre-of-mass energy and t is the squared four-momentum transfer at the proton vertex. The data for 2 < Q(2) < 5 GeV2 were taken in the HERA I running period and correspond to an integrated luminosity of 114 pb(-1). The data for 5 < Q(2) < 80 GeV2 are from both HERA I and HERA II periods and correspond to an integrated luminosity of 468 pb(-1). The decay modes analysed were mu(+)mu(-) and J/psi(1S)pi(+)pi(-) for the psi(2S) and mu(+)mu(-) for the J/psi(1S). The cross-section ratio sigma(psi(2S))/sigma(J/psi(1S)) has been measured as a function of Q(2), W and t. The results are compared to predictions of QCD-inspired models of exclusive vector-meson production. (C) 2016 The Author(s). Published by Elsevier B.V.

The impact of alpha linolenic acid (ALA), EPA, and DHA on obesity and metabolic complications was studied in mice fed a high-fat, high-sucrose (HF) diet. HF diets were supplemented with ALA, EPA, or DHA (1% w/w) and given to C57BL/6J mice for 16 weeks and to Ob/Ob mice for 6 weeks. In C57BL/6J mice, EPA reduced plasma cholesterol (-20%), limited fat mass accumulation (-23%) and adipose cell hypertrophy (-50%), and reduced plasma leptin concentration (-60%) compared with HF-fed mice. Furthermore, mice supplemented with EPA exhibited a higher insulin sensitivity (+24%) and glucose tolerance (+20%) compared with HF-fed mice. Similar effects were observed in EPA-supplemented Ob/Ob mice, although fat mass accumulation was not prevented. By contrast, in comparison with HF-fed mice, DHA did not prevent fat mass accumulation, increased plasma leptin concentration (+128%) in C57BL/6J mice, and did not improve glucose homeostasis in C57BL/6J and Ob/Ob mice. In 3T3-L1 adipocytes, DHA stimulated leptin expression whereas EPA induced adiponectin expression, suggesting that improved leptin/adiponectin balance may contribute to the protective effect of EPA.(jlr) In conclusion, supplementation with EPA, but not ALA and DHA, could preserve glucose homeostasis in an obesogenic environment and limit fat mass accumulation in the early stage of weight gain.-Pinel, A., E. Pitois, J-P. Rigaudiere, C. Jouve, S. De Saint-Vincent, B. Laillet, C. Montaurier, A. Huertas, B. Morio, and F. Capel. EPA prevents fat mass expansion and metabolic disturbances in mice fed with a Western diet.

Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-bedefined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor alpha-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.

The APOBEC3 (A3) cytidine deaminases are antiretroviral proteins, whose targets include human immunodeficiency virus type-1 (HIV-1). Their incorporation into viral particles is critical for antiviral activity and is driven by interactions with the RNA molecules that are packaged into virions. However, it is unclear whether A3 proteins preferentially target RNA molecules that are destined to be packaged and if so, how. Using cross-linking immunoprecipitation sequencing (CLIP-seq), we determined the RNA binding preferences of the A3F, A3G and A3H proteins. We found that A3 proteins bind preferentially to RNA segments with particular properties, both in cells and in virions. Specifically, A3 proteins target RNA sequences that are G-rich and/or A-rich and are not scanned by ribosomes during translation. Comparative analyses of HIV-1 Gag, nucleocapsid (NC) and A3 RNA binding to HIV-1 RNA in cells and virions revealed the striking finding that A3 proteins partially mimic the RNA binding specificity of the HIV-1 NC protein. These findings suggest a model for A3 incorporation into HIV-1 virions in which an NC-like RNA binding specificity is determined by nucleotide composition rather than sequence. This model reconciles the promiscuity of A3 RNA binding that has been observed in previous studies with a presumed advantage that would accompany selective binding to RNAs that are destined to be packaged into virions.

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (PMCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.