The Microevolution and Epidemiology of Staphylococcus aureus Colonization during Atopic Eczema Disease Flare.

Staphylococcus aureus is an opportunistic pathogen and variable component of the human microbiota. A characteristic of atopic eczema (AE) is colonization by S. aureus, with exacerbations associated with an increased bacterial burden of the organism. Despite this, the origins and genetic diversity of S. aureus colonizing individual patients during AE disease flares is poorly understood. To examine the microevolution of S. aureus colonization, we deep sequenced S. aureus populations from nine children with moderate to severe AE and 18 non-atopic children asymptomatically carrying S. aureus nasally. Colonization by clonal S. aureus populations was observed in both AE patients and control participants, with all but one of the individuals carrying colonies belonging to a single sequence type. Phylogenetic analysis showed that disease flares were associated with the clonal expansion of the S. aureus population, occurring over a period of weeks to months. There was a significant difference in the genetic backgrounds of S. aureus colonizing AE cases versus controls (Fisher exact test, P = 0.03). Examination of intra-host genetic heterogeneity of the colonizing S. aureus populations identified evidence of within-host selection in the AE patients, with AE variants being potentially selectively advantageous for intracellular persistence and treatment resistance.CPH was supported by Wellcome Trust (grant number 104241/z/14/z). MTGH, KAP, and KO were supported by the Scottish Infection Research Network and Chief Scientist Office through the Scottish Healthcare Associated Infection Prevention Institute consortium funding (CSO reference: SIRN10). Bioinformatics and computational biology analyses were supported by the University of St Andrews Bioinformatics Unit that is funded by a Wellcome Trust ISSF award (grant 097831/Z/11/Z). JP and MTGH were supported by Wellcome Trust grant 098051. AEM is supported by Biotechnology and Biological Sciences Research Council grant BB/M014088/1. SJB is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (106865/Z/15/Z)

Loss of Biological Diversity: A Global Crisis Requiring International Solutions: A Report to the National Science Board

Executive Summary Biological diversity refers to the variety and variability among living organisms and the ecological complexes in which they occur. Diversity can be defined as the number of different items and their relative frequency. For biological diversity, these items are organized at many levels, ranging from complete ecosystems to the chemical structures that are the molecular basis of heredity. Thus, the term encompasses different ecosystems, species, genes, and their relative abundance (OTA, 1987). There is an ongoing, unprecedented loss of the variety as well as absolute numbers of organisms-from the smallest microorganism to the largest and most spectacular of mammals. Loss of tropical moist forests, which contain over half the total species of organisms, has been well documented by scientists and is now widely reported in the media. Many other ecosystems are also threatened; as human populations and their support systems expand, natural ecosystems at all latitudes are altered or converted. At its meeting on October 15, 1987, the National Science Board concluded that the world\u27s decreasing biological diversity is a critical scientific issue requiring immediate attention. The National Science Board\u27s Committee on International Science was asked to study the scientific and international aspects of the decline of biological diversity and to recommend a course of action. This report describes what the National Science Foundation (NSF) can do to influence the U.S. science and education base, articulates where international scientific cooperation is needed, and suggests roles for other agencies and organizations (both national and international) which have scientific, educational, and management responsibilities. The current disappearance of biota has several causes: the destruction or degradation of entire ecosystems; the accelerating loss of individual species from communities or ecosystems as a result of human disturb;mce; and the loss of genetically distinct parts of populations due to human-induced selective pressures. Although not all parts of the planet are equally affected, the problem is global, and human activities are the primary cause. The loss of biological diversity is important because human existence depends on the biological resources of 1 the earth. Human prosperity is based very largely on the ability to utilize biological diversity: to take advantage of the properties of plants, animals, fungi, and microorganisms for food, clothing, medicine, and shelter. Scientific knowledge about the earth\u27s biological diversity has huge gaps. This lack of information hampers society\u27s ability either to estimate the magnitude of the problem or to prevent further losses. It is impossible to identify all the biological resources at risk, since there is no complete inventory of all the life forms on earth. Approximately 1.4 million species have been given scientific names, but estimates of actual numbers range from 5 million to 80 million species. Although knowledge of some taxa is extensive, the vast majority of groups are largely unknown. The current wave of extinction is destroying both known biotic resources and those still undiscovered. As is proving to be the case with most environmental problems, neither the loss of biological diversity nor its solution is the exclusive province of any one nation. International cooperation is necessary to develop both scientific knowledge and successful mitigation and management strategies. The root causes of the problem include sociological and economic processes which operate on an global scale; a thorough understanding will require investigation and elucidation of both biological and non-biological components. There are several reasons for increasing National Science Foundation (NSF) involvement in biodiversity studies: the economic and social importance of biodiversity (and the risk of opportunity lost due to accelerating extinction); the contributions such leadership can make toward to conservation of biological diversity; the important role of such studies in the international growth of science, especially in tropical countries; the potential impact of such studies on the future course of biology as a whole; and enhancing public awareness of the issues. NSF should assume a scientific leadership position with respect to agencies in the U.S. and throughout the world. By insisting on the central importance of biodiversity, the NSF could encourage collaborative support for the actions recommended below. 1. The Committee believes that the role of the NSF is clear-NSF should, as a matter of National Science Board Policy, provide leadership to undertake the inventory of the world\u27s biodiversity. 2. The scientific basis for conservation biology, restoration ecology, and environmental management must be strengthened. 3. Educational and public awareness programs related to biodiversity need increased support. 4. The economic and social aspects of the biodiversity crisis need additional study. 5. Enhance support for developing country scientists and institutions for biodiversity research and conservation

Growth control of the eukaryote cell: a systems biology study in yeast.

BACKGROUND: Cell growth underlies many key cellular and developmental processes, yet a limited number of studies have been carried out on cell-growth regulation. Comprehensive studies at the transcriptional, proteomic and metabolic levels under defined controlled conditions are currently lacking. RESULTS: Metabolic control analysis is being exploited in a systems biology study of the eukaryotic cell. Using chemostat culture, we have measured the impact of changes in flux (growth rate) on the transcriptome, proteome, endometabolome and exometabolome of the yeast Saccharomyces cerevisiae. Each functional genomic level shows clear growth-rate-associated trends and discriminates between carbon-sufficient and carbon-limited conditions. Genes consistently and significantly upregulated with increasing growth rate are frequently essential and encode evolutionarily conserved proteins of known function that participate in many protein-protein interactions. In contrast, more unknown, and fewer essential, genes are downregulated with increasing growth rate; their protein products rarely interact with one another. A large proportion of yeast genes under positive growth-rate control share orthologs with other eukaryotes, including humans. Significantly, transcription of genes encoding components of the TOR complex (a major controller of eukaryotic cell growth) is not subject to growth-rate regulation. Moreover, integrative studies reveal the extent and importance of post-transcriptional control, patterns of control of metabolic fluxes at the level of enzyme synthesis, and the relevance of specific enzymatic reactions in the control of metabolic fluxes during cell growth. CONCLUSION: This work constitutes a first comprehensive systems biology study on growth-rate control in the eukaryotic cell. The results have direct implications for advanced studies on cell growth, in vivo regulation of metabolic fluxes for comprehensive metabolic engineering, and for the design of genome-scale systems biology models of the eukaryotic cell.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Checks and Balances in Autoimmune Vasculitis

Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system