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221. Benchmarking Metagenomics Tools for Taxonomic Classification.
Metagenomic sequencing is revolutionizing the detection and characterization of microbial species, and a wide variety of software tools are available to perform taxonomic classification of these data. The fast pace of development of these tools and the complexity of metagenomic data make it important that researchers are able to benchmark their performance. Here, we review current approaches for metagenomic analysis and evaluate the performance of 20 metagenomic classifiers using simulated and experimental datasets. We describe the key metrics used to assess performance, offer a framework for the comparison of additional classifiers, and discuss the future of metagenomic data analysis.
222. Mechanochemical Feedback Loops in Development and Disease.
There is increasing evidence that both mechanical and biochemical signals play important roles in development and disease. The development of complex organisms, in particular, has been proposed to rely on the feedback between mechanical and biochemical patterning events. This feedback occurs at the molecular level via mechanosensation but can also arise as an emergent property of the system at the cellular and tissue level. In recent years, dynamic changes in tissue geometry, flow, rheology, and cell fate specification have emerged as key platforms of mechanochemical feedback loops in multiple processes. Here, we review recent experimental and theoretical advances in understanding how these feedbacks function in development and disease.
223. Autophagy-Independent Functions of the Autophagy Machinery.
Macroautophagy (herein referred to as autophagy) is an evolutionary ancient mechanism that culminates with the lysosomal degradation of superfluous or potentially dangerous cytosolic entities. Over the past 2 decades, the molecular mechanisms underlying several variants of autophagy have been characterized in detail. Accumulating evidence suggests that most, if not all, components of the molecular machinery for autophagy also mediate autophagy-independent functions. Here, we discuss emerging data on the non-autophagic functions of autophagy-relevant proteins.
224. Could iPSCs Enable "Off-the-Shelf" Cell Therapy?
An "off-the-shelf" cell therapy derived from induced pluripotent stem cells (iPSCs) has entered clinical trials in the United States. Other companies are following suit, harnessing iPSCs' self-renewal ability to manufacture cell therapies that don't require customization for each patient. But some experts aren't sure such therapies are a good idea.
225. Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity.
作者: Laurent Gauthier.;Ariane Morel.;Nadia Anceriz.;Benjamin Rossi.;Audrey Blanchard-Alvarez.;Gwendoline Grondin.;Sylvia Trichard.;Cédric Cesari.;Melody Sapet.;Frédéric Bosco.;Hélène Rispaud-Blanc.;Franceline Guillot.;Stéphanie Cornen.;Alain Roussel.;Béatrice Amigues.;Guillaume Habif.;Flavien Caraguel.;Sandrine Arrufat.;Romain Remark.;François Romagné.;Yannis Morel.;Emilie Narni-Mancinelli.;Eric Vivier.
来源: Cell. 2019年177卷7期1701-1713.e16页
Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. VIDEO ABSTRACT.
226. Principles for Integrative Structural Biology Studies.
Integrative structure determination is a powerful approach to modeling the structures of biological systems based on data produced by multiple experimental and theoretical methods, with implications for our understanding of cellular biology and drug discovery. This Primer introduces the theory and methods of integrative approaches, emphasizing the kinds of data that can be effectively included in developing models and using the nuclear pore complex as an example to illustrate the practice and challenges involved. These guidelines are intended to aid the researcher in understanding and applying integrative structural methods to systems of their interest and thus take advantage of this rapidly evolving field.
227. Identifying Epistasis in Cancer Genomes: A Delicate Affair.
作者: Joris van de Haar.;Sander Canisius.;Michael K Yu.;Emile E Voest.;Lodewyk F A Wessels.;Trey Ideker.
来源: Cell. 2019年177卷6期1375-1383页
Recent studies of the tumor genome seek to identify cancer pathways as groups of genes in which mutations are epistatic with one another or, specifically, "mutually exclusive." Here, we show that most mutations are mutually exclusive not due to pathway structure but to interactions with disease subtype and tumor mutation load. In particular, many cancer driver genes are mutated preferentially in tumors with few mutations overall, causing mutations in these cancer genes to appear mutually exclusive with numerous others. Researchers should view current epistasis maps with caution until we better understand the multiple cause-and-effect relationships among factors such as tumor subtype, positive selection for mutations, and gross tumor characteristics including mutational signatures and load.
228. The Coming Decade of Cell Death Research: Five Riddles.
Active cell death, in its many forms, is a fundamental biological process. Studies over the past several decades have explored the functions and consequences of cellular demise and elucidated several of the key cell death pathways. Here, I pose five questions, or riddles, that might provide a guide to the next decade of cell death research. Focusing mainly on four types of active cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis) mainly in mammals, this Perspective explores the possible research directions that might answer these riddles, or at least prompt new ones.
229. The Lateral Organization and Mobility of Plasma Membrane Components.
Over the last several decades, an impressive array of advanced microscopic and analytical tools, such as single-particle tracking and nanoscopic fluorescence correlation spectroscopy, has been applied to characterize the lateral organization and mobility of components in the plasma membrane. Such analysis can tell researchers about the local dynamic composition and structure of membranes and is important for predicting the outcome of membrane-based reactions. However, owing to the unresolved complexity of the membrane and the structures peripheral to it, identification of the detailed molecular origin of the interactions that regulate the organization and mobility of the membrane has not proceeded quickly. This Perspective presents an overview of how cell-surface structure may give rise to the types of lateral mobility that are observed and some potentially fruitful future directions to elucidate the architecture of these structures in more molecular detail.
230. B Cell Responses: Cell Interaction Dynamics and Decisions.
B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.
231. Integrins and Their Role in Immune Cell Adhesion.
One of the 2019 Canada Gairdner International Awards recognizes Timothy Springer's discovery of the first immune system adhesion molecules involved in lymphocyte homing and the translation of those discoveries into therapeutics for autoimmune disease and cancer.
232. Once and Only Once.
The 2019 Gairdner Prize will be given to John F.X. Diffley and Bruce Stillman for their groundbreaking work on the mechanisms and control of the initiation of eukaryotic DNA replication. No two people have contributed more extensively, or over a longer period of time, to enlighten us on how our genomes replicate themselves once and only once per cell cycle.
233. The Extracellular RNA Communication Consortium: Establishing Foundational Knowledge and Technologies for Extracellular RNA Research.
作者: Saumya Das.; .;K Mark Ansel.;Markus Bitzer.;Xandra O Breakefield.;Alain Charest.;David J Galas.;Mark B Gerstein.;Mihir Gupta.;Aleksandar Milosavljevic.;Michael T McManus.;Tushar Patel.;Robert L Raffai.;Joel Rozowsky.;Matthew E Roth.;Julie A Saugstad.;Kendall Van Keuren-Jensen.;Alissa M Weaver.;Louise C Laurent.
来源: Cell. 2019年177卷2期231-242页
The Extracellular RNA Communication Consortium (ERCC) was launched to accelerate progress in the new field of extracellular RNA (exRNA) biology and to establish whether exRNAs and their carriers, including extracellular vesicles (EVs), can mediate intercellular communication and be utilized for clinical applications. Phase 1 of the ERCC focused on exRNA/EV biogenesis and function, discovery of exRNA biomarkers, development of exRNA/EV-based therapeutics, and construction of a robust set of reference exRNA profiles for a variety of biofluids. Here, we present progress by ERCC investigators in these areas, and we discuss collaborative projects directed at development of robust methods for EV/exRNA isolation and analysis and tools for sharing and computational analysis of exRNA profiling data.
234. Global Genetic Networks and the Genotype-to-Phenotype Relationship.
作者: Michael Costanzo.;Elena Kuzmin.;Jolanda van Leeuwen.;Barbara Mair.;Jason Moffat.;Charles Boone.;Brenda Andrews.
来源: Cell. 2019年177卷1期85-100页
Genetic interactions identify combinations of genetic variants that impinge on phenotype. With whole-genome sequence information available for thousands of individuals within a species, a major outstanding issue concerns the interpretation of allelic combinations of genes underlying inherited traits. In this Review, we discuss how large-scale analyses in model systems have illuminated the general principles and phenotypic impact of genetic interactions. We focus on studies in budding yeast, including the mapping of a global genetic network. We emphasize how information gained from work in yeast translates to other systems, and how a global genetic network not only annotates gene function but also provides new insights into the genotype-to-phenotype relationship.
235. A Tumor-Agnostic NTRK (TRK) Inhibitor.
Larotrectinib is a small-molecule kinase inhibitor that targets NTRK fusions that occur in multiple types of cancer. Its FDA approval represents the first instance of a treatment indication being designated "tumor-agnostic" from the outset, being based on actionable genomic insights. To view this Bench to Bedside, open or download the PDF.
236. Genomic Analysis in the Age of Human Genome Sequencing.
Affordable genome sequencing technologies promise to revolutionize the field of human genetics by enabling comprehensive studies that interrogate all classes of genome variation, genome-wide, across the entire allele frequency spectrum. Ongoing projects worldwide are sequencing many thousands-and soon millions-of human genomes as part of various gene mapping studies, biobanking efforts, and clinical programs. However, while genome sequencing data production has become routine, genome analysis and interpretation remain challenging endeavors with many limitations and caveats. Here, we review the current state of technologies for genetic variant discovery, genotyping, and functional interpretation and discuss the prospects for future advances. We focus on germline variants discovered by whole-genome sequencing, genome-wide functional genomic approaches for predicting and measuring variant functional effects, and implications for studies of common and rare human disease.
237. Personalized Medicine and the Power of Electronic Health Records.
Personalized medicine has largely been enabled by the integration of genomic and other data with electronic health records (EHRs) in the United States and elsewhere. Increased EHR adoption across various clinical settings and the establishment of EHR-linked population-based biobanks provide unprecedented opportunities for the types of translational and implementation research that drive personalized medicine. We review advances in the digitization of health information and the proliferation of genomic research in health systems and provide insights into emerging paths for the widespread implementation of personalized medicine.
238. Genomic Medicine-Progress, Pitfalls, and Promise.
In the wake of the Human Genome Project (HGP), strong expectations were set for the timeline and impact of genomics on medicine-an anticipated transformation in the diagnosis, treatment, and prevention of disease. In this Perspective, we take stock of the nascent field of genomic medicine. In what areas, if any, is genomics delivering on this promise, or is the path to success clear? Where are we falling short, and why? What have been the unanticipated developments? Overall, we argue that the optimism surrounding the transformational potential of genomics on medicine remains justified, albeit with a considerably different form and timescale than originally projected. We also argue that the field needs to pivot back to basics, as understanding the entirety of the genotype-to-phenotype equation is a likely prerequisite for delivering on the full potential of the human genome to advance the human condition.
239. The Genetics of Aging: A Vertebrate Perspective.
Aging negatively impacts vitality and health. Many genetic pathways that regulate aging were discovered in invertebrates. However, the genetics of aging is more complex in vertebrates because of their specialized systems. This Review discusses advances in the genetic regulation of aging in vertebrates from work in mice, humans, and organisms with exceptional lifespans. We highlight challenges for the future, including sex-dependent differences in lifespan and the interplay between genes and environment. We also discuss how the identification of reliable biomarkers of age and development of new vertebrate models can be leveraged for personalized interventions to counter aging and age-related diseases.
240. Human Immunology through the Lens of Evolutionary Genetics.
Pathogen-imposed selection pressures have been paramount during human evolution. Detecting such selection signatures in ancient and modern human genomes can thus help us to identify genes of temporal and spatial immunological relevance. Admixture with ancient hominins and between human populations has been a source of genetic diversity open to selection by infections. Furthermore, cultural transitions, such as the advent of agriculture, have exposed humans to new microbial threats, with impacts on host defense mechanisms. The integration of population genetics and systems immunology holds great promise for the increased understanding of the factors driving immune response variation between individuals and populations.
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