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The small-subunit processome represents the earliest stable precursor of the eukaryotic small ribosomal subunit. Here we present the cryo-EM structure of the Saccharomyces cerevisiae small-subunit processome at an overall resolution of 3.8 angstrom, which provides an essentially complete near-atomic model of this assembly. In this nucleolar superstructure, 51 ribosome-assembly factors and two RNAs encapsulate the 18S rRNA precursor and 15 ribosomal proteins in a state that precedes pre-rRNA cleavage at site A1. Extended flexible proteins are employed to connect distant sites in this particle. Molecular mimicry and steric hindrance, as well as protein-and RNA-mediated RNA remodeling, are used in a concerted fashion to prevent the premature formation of the central pseudoknot and its surrounding elements within the small ribosomal subunit.

To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type-specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.

In addition to storing and mobilizing energy, adipocytes secrete circulating factors to signal to other tissues and coordinate energy metabolism. These functions can become disrupted in the setting of obesity, contributing to the development of diabetes, cardiovascular disease, and cancer. Since the discovery of leptin and adiponectin, an increasing number of adipokines have been identified and their functions elucidated. More recent studies have highlighted other modes by which adipose tissue can participate in crosstalk with other cell types and tissues. These modes of communication, which are reviewed here, include the secretion of enzymes, lipid species, and exosomes. Advances in profiling technology suggest that a substantial number of adipose-derived factors remain to be characterized. Further advances in this growing field are likely to provide important basic insights into the molecular control of metabolism.

A measurement of the inclusive production cross section of isolated prompt photons in proton-antiproton collisions at center-of-mass energy root s = 1.96 TeV is presented. The results are obtained using the full Run II data sample collected with the Collider Detector at the Fermilab Tevatron, which corresponds to an integrated luminosity of 9.5 fb(-1). The cross section is measured as a function of photon transverse energy, E-T(gamma), in the range 30 < E-T(gamma) < 500 GeV and in the pseudorapidity region |eta(gamma)| < 1.0. The results are compared with predictions from parton-shower Monte Carlo models at leading order in QCD and from next-to-leading-order perturbative QCD calculations. The latter show good agreement with the measured cross section.

Enzymatic proteolysis of cell surface proteins and extracellular matrix (ECM) is critical for tissue homeostasis and cell signaling. These proteolytic activities are mediated predominantly by a family of proteases termed matrix metalloproteinases (MMPs). The growing evidence in recent years that ECM and non-ECM bioactive molecules (e.g., growth factors, cytokines, chemokines, on top of matrikines and matricryptins) have versatile functions redefines our view on the roles matrix remodeling enzymes play in many physiological and pathological processes, and underscores the notion that ECM proteolytic reaction mechanisms represent master switches in the regulation of critical biological processes and govern cell behavior. Accordingly, MMPs are not only responsible for direct degradation of ECM molecules but are also key modulators of cardinal bioactive factors. Many attempts were made to manipulate ECM degradation by targeting MMPs using small peptidic and organic inhibitors. However, due to the high structural homology shared by these enzymes, the majority of the developed compounds are broad-spectrum inhibitors affecting the proteolytic activity of various MMPs and other zinc-related proteases. These inhibitors, in many cases, failed as therapeutic agents, mainly due to the bilateral role of MMPs in pathological conditions such as cancer, in which MMPs have both pro-and anti-tumorigenic effects. Despite the important role of MMPs in many human diseases, none of the broad-range synthetic MMP inhibitors that were designed have successfully passed clinical trials. It appears that, designing highly selective MMP inhibitors that are also effective in vivo, is not trivial. The challenges related to designing selective and effective metalloprotease inhibitors, are associated in part with the aforesaid high structural homology and the dynamic nature of their protein scaffolds. Great progress was achieved in the last decade in understanding the biochemistry and biology of MMPs activity. This knowledge, combined with lessons from the past has drawn new "boundaries" for the development of the next-generation MMP inhibitors. These novel agents are currently designed to be highly specific, capable to discriminate between the homologous MMPs and ideally administered as a short-term topical treatment. In this review we discuss the latest progress in the fields of MMP inhibitors in terms of structure, function and their specific activity. The development of novel highly specific inhibitors targeting MMPs paves the path to study complex biological processes associated with ECM proteolysis in health and disease. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.

Tissues have a natural capacity to replace dying cells and to heal wounds. This ability resides in resident stem cells, which self-renew, preserve, and repair their tissue during homeostasis and following injury. The skin epidermis and its appendages are subjected to daily assaults from the external environment. A high demand is placed on renewal and regeneration of the skin's barrier in order to protect the body from infection and dehydration and to heal wounds. This review focuses on the epithelial stem cells of skin, where they come from, where they reside, and how they function in normal homeostasis and wound repair.

A statistical combination of searches is presented for massive resonances decaying to WW, WZ, ZZ, WH, and ZH boson pairs in proton-proton collision data collected by the CMS experiment at the LHC. The data were taken at centre-of-mass energies of 8 and 13TeV, corresponding to respective integrated luminosities of 19.7 and up to 2.7 fb(-1). The results are interpreted in the context of heavy vector triplet and singlet models that mimic properties of composite-Higgs models predicting W' and Z' bosons decaying to WZ, WW, WH, and ZH bosons. A model with a bulk graviton that decays into WW and ZZ is also considered. This is the first combined search for WW, WZ, WH, and ZH resonances and yields lower limits on masses at 95% confidence level for W' and Z' singlets at 2.3 TeV, and for a triplet at 2.4TeV. The limits on the production cross section of a narrow bulk graviton resonance with the curvature scale of the warped extra dimension (K)over-tilde = 0.5, in the mass range of 0.6 to 4.0TeV, are the most stringent published to date. (c) 2017 The Author(s). Published by Elsevier B.V.

Background-Low-density lipoprotein cholesterol (LDL-C) control is higher among insured than uninsured adults, but data on time trends and contributing factors are incomplete and important for improving health equity. Methods and Results-Awareness, treatment, and control of elevated LDL-C were compared among insured versus uninsured and publicly versus privately insured adults, aged 21 to 64 years, in National Health and Nutrition Examination Surveys from 2001 to 2004, 2005 to 2008, and 2009 to 2012 using Adult Treatment Panel-3 criteria. Compared with insured adults, uninsured adults were younger; were more often minority; reported lower incomes, less education, and fewer healthcare encounters; and had lower awareness and treatment of elevated LDL-C (P<0.0001). LDL-C control was higher among insured than uninsured adults in 2001 to 2004 (mean +/- SEM, 21.4 +/- 1.6% versus 10.5 +/- 2.6%; P<0.01), and the gap widened by 2009 to 2012 (35.1 +/- 1.9% versus 11.3 +/- 2.2%; P<0.0001). Despite more minorities (P<0.01), greater poverty, and less education (P<0.001), publicly insured adults had more healthcare visits/year than privately insured adults (P<0.001) and similar awareness, treatment, and control of LDL-C from 2001 to 2012. In multivariable logistic regression, significant positive predictors of cholesterol awareness, treatment, and control included more frequent health care (strongest), increasing age, private healthcare insurance versus uninsured, and hypertension. Public insurance (versus uninsured) was a significant positive predictor of LDL-C control, whereas income <200% versus >= 200% of federal poverty was a significant negative predictor. Conclusions-LDL-C control improved similarly over time in publicly and privately insured adults but was stagnant among the uninsured. Healthcare insurance largely addresses socioeconomic barriers to effective LDL-C management, yet poverty retains an independent adverse effect.

Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic load and overload. Allostatic overload, which can occur during chronic stress, can reshape the hypothalamic-pituitary-adrenal axis through epigenetic modification of genes in the hippocampus, hypothalamus and other stress-responsive brain regions. Glucocorticoids exert their effects on the brain through genomic mechanisms that involve both glucocorticoid receptors and mineralocorticoid receptors directly binding to DNA, as well as by non-genomic mechanisms. Furthermore, glucocorticoids synergize both genomically and non-genomically with neurotransmitters, neurotrophic factors, sex hormones and other stress mediators to shape an organism's present and future responses to a stressful environment. Here, we discuss the mechanisms of glucocorticoid action in the brain and review how glucocorticoids interact with stress mediators in the context of allostasis, allostatic load and stress-induced neuroplasticity.

Tuberculosis is a major worldwide problem, and protection from it is achieved mainly by live attenuated bacille Calmette-Guerin vaccine, which is capable of causing disease in immunocompromised host. Oral thrush is abnormal in healthy children, which suggests an underlying immunodeficiency. Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by a selective predisposition to weakly virulent Mycobacteria and Salmonella and also predisposition to chronic mucocutaneous candidiasis. Interleukin 12 receptor beta 1 ( IL-12R beta 1) deficiency is the most common disease of Mendelian susceptibility to mycobacterial disease, and to date only 50 IL-12R beta 1 deficient patients with clinical signs of chronic mucocutaneous candidiasis have been reported. We report a 2.5-year-old daughter of consanguineous parents with both regional bacille Calmette-Guerin lymphadenitis and recurrent oral candidiasis carrying biallelic R175W mutation in the IL12R beta 1 gene, resulting in complete loss of expression of IL-12R beta 1. To our knowledge, this is the first report of bacille Calmette-Guerin lymphadenitis with concurrent oral candidiasis displaying such a mutation. New mutations and wide clinical diversities are the indisputable fact of populations with a high rate of consanguineous marriages.