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Extreme genome diversity in the hyper-prevalent parasitic eukaryote Blastocystis
Blastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%-61% median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane-trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize α-glucans rather than β-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease.
Journal Article
The master builder : how the new science of the cell is rewriting the story of life
What defines who we are? For decades, the biological answer has been our genes. Leading biologist Alfonso Martinez Arias breaks with decades of scientific and popular tradition to make a bold argument: what defines us is our cells. A sweeping revision of both the present and history of life, 'The Master Builder' puts forward a new paradigm for understanding biology, one rooted in cellular cooperation, not selfish genes. Engaging and ambitious, it will transform our understanding of where we come from, what shapes us, and where we are going, as individuals, a species, and the community of life itself.
Book
Stochastic Fluctuations and Distributed Control of Gene Expression Impact Cellular Memory
Despite the stochastic noise that characterizes all cellular processes the cells are able to maintain and transmit to their daughter cells the stable level of gene expression. In order to better understand this phenomenon, we investigated the temporal dynamics of gene expression variation using a double reporter gene model. We compared cell clones with transgenes coding for highly stable mRNA and fluorescent proteins with clones expressing destabilized mRNA-s and proteins. Both types of clones displayed strong heterogeneity of reporter gene expression levels. However, cells expressing stable gene products produced daughter cells with similar level of reporter proteins, while in cell clones with short mRNA and protein half-lives the epigenetic memory of the gene expression level was completely suppressed. Computer simulations also confirmed the role of mRNA and protein stability in the conservation of constant gene expression levels over several cell generations. These data indicate that the conservation of a stable phenotype in a cellular lineage may largely depend on the slow turnover of mRNA-s and proteins.
Journal Article
Experimenting at the boundaries of life : organic vitality in Germany around 1800
\"Attempts to distinguish a science of life at the turn of the nineteenth century faced a number of challenges. A central difficulty was clearly demarcating the living from the nonliving experimentally and conceptually. The more closely the boundaries between organic and inorganic phenomena were examined, the more they expanded and thwarted any clear delineation. Experimenting at the Boundaries of Life traces the debates surrounding the first articulations of a science of life in a variety of texts and practices centered on German contexts. Joan Steigerwald examines the experiments on the processes of organic vitality, such as excitability and generation, undertaken across the fields of natural history, physiology, physics and chemistry. She highlights the sophisticated reflections on the problem of experimenting on living beings by investigators, and relates these epistemic concerns directly to the philosophies of nature of Kant and Schelling. Her book skillfully ties these epistemic reflections to arguments by the Romantic writers Novalis and Goethe for the aesthetic aspects of inquiries into the living world and the figurative languages in which understandings of nature were expressed\"-- Provided by publisher.
Book
The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape
Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.
Journal Article
The healing self : a revolutionary new plan to supercharge your immunity and stay well for life
\"Combining the best current medical knowledge with a new approach grounded in integrative medicine, Chopra and Tanzi offer a groundbreaking new model of healing and the healing system, one of the main mysteries in the mind-body connection\"-- Provided by publisher.
Book
miR-126-5p by direct targeting of JNK-interacting protein-2 (JIP-2) plays a key role in Theileria-infected macrophage virulence
Theileria annulata is an apicomplexan parasite that infects and transforms bovine macrophages that disseminate throughout the animal causing a leukaemia-like disease called tropical theileriosis. Using deep RNAseq of T. annulata-infected B cells and macrophages we identify a set of microRNAs induced by infection, whose expression diminishes upon loss of the hyper-disseminating phenotype of virulent transformed macrophages. We describe how infection-induced upregulation of miR-126-5p ablates JIP-2 expression to release cytosolic JNK to translocate to the nucleus and trans-activate AP-1-driven transcription of mmp9 to promote tumour dissemination. In non-disseminating attenuated macrophages miR-126-5p levels drop, JIP-2 levels increase, JNK1 is retained in the cytosol leading to decreased c-Jun phosphorylation and dampened AP-1-driven mmp9 transcription. We show that variation in miR-126-5p levels depends on the tyrosine phosphorylation status of AGO2 that is regulated by Grb2-recruitment of PTP1B. In attenuated macrophages Grb2 levels drop resulting in less PTP1B recruitment, greater AGO2 phosphorylation, less miR-126-5p associated with AGO2 and a consequent rise in JIP-2 levels. Changes in miR-126-5p levels therefore, underpin both the virulent hyper-dissemination and the attenuated dissemination of T. annulata-infected macrophages.
Journal Article
The genesis machine : our quest to rewrite life in the age of synthetic biology
\"Synthetic biology is the promising and controversial technology platform that combines biology and artificial intelligence, opening up the potential to program biological systems much as we program computers. Synthetic biology enables us not just to read and edit DNA - the technique of CRISPR - but also write it. Rather than life being \"a beautiful game of chance\", synthetic biology creates the potential to control our genetic destiny, to say \"no\" to bad genes and build a veritable genetic app store for downloading and adding new capabilities into any cell, microbe, plant, or animal. Amy Webb and Andrew Hessel's riveting stories include: the work of scientists to develop plants that can be grown in sprawling indoor farms capable of feeding millions with a fraction of the usual resources required; a synthetic, self-regulating insulin that doesn't require injections or a pump; life-altering regenerative, personalized medicine; and novel, durable solutions to climate change. There is also whimsy, such as the dream of some geneticists to \"unextinct\" the wooly mammoth. By examining both the science and the ethical, moral, and religious issues surrounding synthetic biology, Webb and Hessel provide the background for preventing its misuse by some to re-engineer their bodies and that of their children, further increasing the disturbing division and polarization of societies into the haves (the enhanced) and the have nots. They provide the background for making wise decisions about issues such as: whether to program novel viruses to fight diseases, what genetic privacy will look like, who will \"own\" living organisms, how companies should earn revenue from engineered cells, and how to contain a synthetic organism in a lab. Whether we approve or disapprove of synthetic biology, it is coming. Now, we need to understand its promise and peril. Webb and Hessel help us understand the science as well as the political and societal issues involved\"-- Provided by publisher.
BOOK
A Novel Nodal Enhancer Dependent on Pluripotency Factors and Smad2/3 Signaling Conditions a Regulatory Switch During Epiblast Maturation
During early development, modulations in the expression of Nodal, a TGFβ family member, determine the specification of embryonic and extra-embryonic cell identities. Nodal has been extensively studied in the mouse, but aspects of its early expression remain unaccounted for. We identified a conserved hotspot for the binding of pluripotency factors at the Nodal locus and called this sequence \"highly bound element\" (HBE). Luciferase-based assays, the analysis of fluorescent HBE reporter transgenes, and a conditional mutation of HBE allowed us to establish that HBE behaves as an enhancer, is activated ahead of other Nodal enhancers in the epiblast, and is essential to Nodal expression in embryonic stem cells (ESCs) and in the mouse embryo. We also showed that HBE enhancer activity is critically dependent on its interaction with the pluripotency factor Oct4 and on Activin/Nodal signaling. Use of an in vitro model of epiblast maturation, relying on the differentiation of ESCs into epiblast stem cells (EpiSCs), revealed that this process entails a shift in the regulation of Nodal expression from an HBE-driven phase to an ASE-driven phase, ASE being another autoregulatory Nodal enhancer. Deletion of HBE in ESCs or in EpiSCs allowed us to show that HBE, although not necessary for Nodal expression in EpiSCs, is required in differentiating ESCs to activate the differentiation-promoting ASE and therefore controls this regulatory shift. Our findings clarify how early Nodal expression is regulated and suggest how this regulation can promote the specification of extra-embryonic precusors without inducing premature differentiation of epiblast cells. More generally, they open new perspectives on how pluripotency factors achieve their function.
Journal Article