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  • Approaches for Understanding the Mechanisms of Long Noncoding RNA Regulation of Gene Expression.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Patrick McDonel,Mitchell Guttman

    SUMMARYMammalian genomes encode tens of thousands of long noncoding RNAs (lncRNAs) that have been implicated in a diverse array of biological processes and human diseases. In recent years, the development of new tools for studying lncRNAs has enabled important progress in defining the mechanisms by which Xist and other lncRNAs function. This collective work provides a framework for how to define the mechanisms by which lncRNAs act. This includes defining lncRNA function, identifying and characterizing lncRNA-protein interactions, and lncRNA localization in the cell. In this review, we discuss various experimental approaches for deciphering lncRNA mechanisms and discuss issues and limitations in interpreting these results. We explore what these data can reveal about lncRNA function and mechanism as well as emerging insights into lncRNA biology that have been derived from these studies.

    更新日期:2019-11-01
  • Structural Biology of Telomerase.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-08-28
    Yaqiang Wang,Lukas Sušac,Juli Feigon

    SUMMARYTelomerase is a DNA polymerase that extends the 3' ends of chromosomes by processively synthesizing multiple telomeric repeats. It is a unique ribonucleoprotein (RNP) containing a specialized telomerase reverse transcriptase (TERT) and telomerase RNA (TER) with its own template and other elements required with TERT for activity (catalytic core), as well as species-specific TER-binding proteins important for biogenesis and assembly (core RNP); other proteins bind telomerase transiently or constitutively to allow association of telomerase and other proteins with telomere ends for regulation of DNA synthesis. Here we describe how nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography of TER and protein domains helped define the structure and function of the core RNP, laying the groundwork for interpreting negative-stain and cryo electron microscopy (cryo-EM) density maps of Tetrahymena thermophila and human telomerase holoenzymes. As the resolution has improved from ∼30 Å to ∼5 Å, these studies have provided increasingly detailed information on telomerase architecture and mechanism.

    更新日期:2019-11-01
  • Ca2+ Signaling and Homeostasis in Mammalian Oocytes and Eggs.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-08-21
    Takuya Wakai,Aujan Mehregan,Rafael A Fissore

    Changes in the intracellular concentration of calcium ([Ca2+]i) represent a vital signaling mechanism enabling communication between and among cells as well as with the environment. Cells have developed a sophisticated set of molecules, "the Ca2+ toolkit," to adapt [Ca2+]i changes to specific cellular functions. Mammalian oocytes and eggs, the subject of this review, are not an exception, and in fact the initiation of embryo devolvement in all species is entirely dependent on distinct [Ca2+]i responses. Here, we review the components of the Ca2+ toolkit present in mammalian oocytes and eggs, the regulatory mechanisms that allow these cells to accumulate Ca2+ in the endoplasmic reticulum, release it, and maintain basal and stable cytoplasmic concentrations. We also discuss electrophysiological and genetic studies that have uncovered Ca2+ influx channels in oocytes and eggs, and we analyze evidence supporting the role of a sperm-specific phospholipase C isoform as the trigger of Ca2+ oscillations during mammalian fertilization including its implication in fertility.

    更新日期:2019-11-01
  • Organellar Calcium Handling in the Cellular Reticular Network.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-07-31
    Wen-An Wang,Luis B Agellon,Marek Michalak

    Ca2+ is an important intracellular messenger affecting diverse cellular processes. In eukaryotic cells, Ca2+ is handled by a myriad of Ca2+-binding proteins found in organelles that are organized into the cellular reticular network (CRN). The network is comprised of the endoplasmic reticulum, Golgi apparatus, lysosomes, membranous components of the endocytic and exocytic pathways, peroxisomes, and the nuclear envelope. Membrane contact sites between the different components of the CRN enable the rapid movement of Ca2+, and communication of Ca2+ status, within the network. Ca2+-handling proteins that reside in the CRN facilitate Ca2+ sensing, buffering, and cellular signaling to coordinate the many processes that operate within the cell.

    更新日期:2019-11-01
  • The Sweet Side of Plant-Specialized Metabolism.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-06-27
    Thomas Louveau,Anne Osbourn

    Glycosylation plays a major role in the structural diversification of plant natural products. It influences the properties of molecules by modifying the reactivity and solubility of the corresponding aglycones, so influencing cellular localization and bioactivity. Glycosylation of plant natural products is usually carried out by uridine diphosphate(UDP)-dependent glycosyltransferases (UGTs) belonging to the carbohydrate-active enzyme glycosyltransferase 1 (GT1) family. These enzymes transfer sugars from UDP-activated sugar moieties to small hydrophobic acceptor molecules. Plant GT1s generally show high specificity for their sugar donors and recognize a single UDP sugar as their substrate. In contrast, they are generally promiscuous with regard to acceptors, making them attractive biotechnological tools for small molecule glycodiversification. Although microbial hosts have traditionally been used for heterologous engineering of plant-derived glycosides, transient plant expression technology offers a potentially disruptive platform for rapid characterization of new plant glycosyltransferases and biosynthesis of complex glycosides.

    更新日期:2019-11-01
  • Sub1 Rice: Engineering Rice for Climate Change.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-06-12
    Kyle Emerick,Pamela C Ronald

    By the year 2100, the number of people on Earth is expected to increase by ∼50%, placing increasing demands on food production in a time when a changing climate is predicted to compromise crop yields. Feeding this future world requires scientifically informed innovations in agriculture. Here, we describe how a rice gene conferring tolerance to prolonged submergence has helped farmers in South and Southeast Asia mitigate rice crop failure during floods. We discuss how planting of this new variety benefited socially disadvantaged groups. This example indicates that investment in agricultural improvement can protect farmers from risks associated with a changing climate.

    更新日期:2019-11-01
  • Functional Amyloids.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-05-16
    Daniel Otzen,Roland Riek

    When protein/peptides aggregate, they usually form the amyloid state consisting of cross β-sheet structure built by repetitively stacked β-strands forming long fibrils. Amyloids are usually associated with disease including Alzheimer's. However, amyloid has many useful features. It efficiently transforms protein from the soluble to the insoluble state in an essentially two-state process, while its repetitive structure provides high stability and a robust prion-like replication mechanism. Accordingly, amyloid is used by nature in multifaceted and ingenious ways of life, ranging from bacteria and fungi to mammals. These include (1) Structure: Templating for small chemical molecules (Pmel17), biofilm formation in bacteria (curli), assisting aerial hyphae formation in streptomycetes (chaplins) or monolayer formation at a surface (hydrophobins). (2) Reservoirs: A storage state for peptide/proteins to protect them from their surroundings or vice versa (storage of peptide hormones in mammalian secretory granules or major basic protein in eosinophils). (3) Information carriers: The fungal immune system (HET-s prion in Podospora anserina, yeast prions) or long-term memory (e.g., mnemons in yeast, cytoplasmic polyadenylation element-binding protein in aplysia). Aggregation is also used to (4) "suppress" the function of the soluble protein (e.g., Cdc19 in yeast stress granules), or (5) "signaling" through formation of oligomers (e.g., HET-s prion, necroptosis-related proteins RIP1/RIP3). This review summarizes current knowledge on functional amyloids with a focus on the amyloid systems curli in bacteria, HET-s prion in P. anserina, and peptide hormone storage in mammals together with an attempt to highlight differences between functional and disease-associated amyloids.

    更新日期:2019-11-01
  • Protein Solubility Predictions Using the CamSol Method in the Study of Protein Homeostasis.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-03-06
    Pietro Sormanni,Michele Vendruscolo

    One of the major functions of the protein homeostasis system is to maintain proteins in their soluble states, and indeed several human disorders are associated with the aberrant aggregation of proteins. An active involvement of the protein homeostasis system is necessary to avoid aggregation because proteins are expressed at levels close to their solubility limits, hence being poorly soluble. The mechanisms by which the protein homeostasis system acts to control protein aggregation are, however, still not known in much detail. To facilitate systematic investigations of these mechanisms, we describe here the CamSol method of predicting protein solubility, and illustrate its initial applications. We anticipate that with the advent of powerful proteomics and transcriptomic methods, in combination with the use of the CamSol method and related approaches to predict the solubility and other biophysical properties of proteins, it will become possible to increase our understanding of the principles of protein homeostasis related to the maintenance of the proteome in its soluble form.

    更新日期:2019-11-01
  • Type III Intermediate Filaments Desmin, Glial Fibrillary Acidic Protein (GFAP), Vimentin, and Peripherin.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-12-03
    Elly M Hol,Yassemi Capetanaki

    SummaryType III intermediate filament (IF) proteins assemble into cytoplasmic homopolymeric and heteropolymeric filaments with other type III and some type IV IFs. These highly dynamic structures form an integral component of the cytoskeleton of muscle, brain, and mesenchymal cells. Here, we review the current ideas on the role of type III IFs in health and disease. It turns out that they not only offer resilience to mechanical strains, but, most importantly, they facilitate very efficiently the integration of cell structure and function, thus providing the necessary scaffolds for optimal cellular responses upon biochemical stresses and protecting against cell death, disease, and aging.

    更新日期:2019-11-01
  • Leaving the Bench and Finding Your Foundation.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-12-03
    John E Spiro

    Scientists who leave the laboratory bench to work for biomedical foundations mobilize and focus resources on the most promising research behind a foundation's mission. They acquire a broad view of a field, interact closely with research scientists at meetings and laboratory visits, and often manage proposal review boards and monitor grant progress. Increasingly, scientists at foundations also have a more active role in catalyzing research: They are involved in organizing targeted workshops, setting research priorities, and directly creating and managing resources for a scientific community. They often work closely with patient advocacy groups, contract research organizations, government funders and regulators, and biotech and pharmaceutical companies.Job opportunities in foundations are highly varied, reflecting the diversity of foundations and missions. For example, some foundations have general missions to support broad basic scientific research, whereas others focus specifically on a particular disease and may require different skills. Most scientific positions at foundations require a PhD or MD and often some postdoctoral or other experience, although not all do. Foundations often lack the clear career path that an academic position offers (various levels of professorship, tenure, etc.), although there is often significant potential for growth in responsibilities in terms of managing science, people, and budgets. Jobs in foundations can be challenging yet extremely rewarding, especially for those with broad interests and goal-oriented personalities. Many at foundations feel that they have the potential to have an even greater impact than if they had stayed at the bench.

    更新日期:2019-11-01
  • A 50-Year Personal Journey: Location, Gene Expression, and Circadian Rhythms.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-06-11
    Michael Rosbash

    I worked almost exclusively on nucleic acids and gene expression from the age of 19 as an undergraduate until the age of 38 as an associate professor. Mentors featured prominently in my choice of paths. My friendship with influential Brandeis colleagues then persuaded me that genetics was an important tool for studying gene expression, and I switched my experimental organism to yeast for this reason. Several years later, friendship also played a prominent role in my beginning work on circadian rhythms. As luck would have it, gene expression as well as genetics turned out to be important for circadian timekeeping. As a consequence, background and training put my laboratory in an excellent position to contribute to this aspect of the circadian problem. The moral of the story is, as in real estate, "location, location, location."

    更新日期:2019-11-01
  • Minimal Cells-Real and Imagined.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-30
    John I Glass,Chuck Merryman,Kim S Wise,Clyde A Hutchison,Hamilton O Smith

    A minimal cell is one whose genome only encodes the minimal set of genes necessary for the cell to survive. Scientific reductionism postulates the best way to learn the first principles of cellular biology would be to use a minimal cell in which the functions of all genes and components are understood. The genes in a minimal cell are, by definition, essential. In 2016, synthesis of a genome comprised of only the set of essential and quasi-essential genes encoded by the bacterium Mycoplasma mycoides created a near-minimal bacterial cell. This organism performs the cellular functions common to all organisms. It replicates DNA, transcribes RNA, translates proteins, undergoes cell division, and little else. In this review, we examine this organism and contrast it with other bacteria that have been used as surrogates for a minimal cell.

    更新日期:2019-11-01
  • What Is Wrong with Pertussis Vaccine Immunity? The Problem of Waning Effectiveness of Pertussis Vaccines.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-16
    Nicolas Burdin,Lori Kestenbaum Handy,Stanley A Plotkin

    Pertussis is resurgent in some countries, particularly those in which children receive acellular pertussis (aP) vaccines in early infancy and boosters later in life. Immunologic studies show that, whereas whole-cell pertussis (wP) vaccines orient the immune system toward Th1/Th17 responses, acellular pertussis vaccines orient toward Th1/Th2 responses. Although aP vaccines do provide protection during the first years of life, the change in T-cell priming results in waning effectiveness of aP as early as 2-3 years post-boosters. Although other factors, such as increased virulence of pertussis strains, better diagnosis, and better surveillance may play a role, the increase in pertussis appears to be the result of waning immunity. In addition, studies in baboon models, requiring confirmation in humans, show that aP is less able to prevent nasopharyngeal colonization of Bordetella pertussis than wP or natural infection.

    更新日期:2019-11-01
  • What Is Wrong with Pertussis Vaccine Immunity? Why Immunological Memory to Pertussis Is Failing.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-16
    Dimitri A Diavatopoulos,Kathryn Margaret Edwards

    Memory responses seen after whole-cell pertussis (wP) and acellular pertussis (aP) vaccine priming are different and reflect better long-term protection against pertussis disease seen with the whole-cell vaccines. Although acellular vaccines generate higher levels of antigen-specific IgG to the antigens included in the aP vaccines, there are many more pertussis antigens included in whole-cell vaccines. Acellular vaccine priming is associated with skewing of the immune response to a more Th2-like response, whereas whole-cell priming is associated with a Th1/Th17 response. Repeated booster doses of acellular vaccine in children primed with acellular vaccine has been shown to result in progressively shorter duration of protection against disease. This may be explained by the generation of higher levels of antigen-specific IgG4, which does not bind complement and leads to a suboptimal inflammatory response and impaired phagocytosis and antimicrobial defense. In contrast, whole-cell priming followed by aP vaccine boosters results in better opsonization, phagocytosis, and complement mediated killing through the preferential induction of IgG1.

    更新日期:2019-11-01
  • What Is Wrong with Pertussis Vaccine Immunity? Inducing and Recalling Vaccine-Specific Immunity.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-16
    Christiane S Eberhardt,Claire-Anne Siegrist

    The high incidence of pertussis in vaccinated adolescents suggests the failing of immune memory. We argue that acellular pertussis vaccines generate memory cells that are effectively reactivated by boosters better than by Bordetella pertussis exposure. We propose that there are two main causes. One is the induction of vaccine-specific immunity rather than pathogen-specific immunity. The second is that strictly mucosal infections such as B. pertussis poorly reactivate memory B and T cells residing deep in lymph nodes or tissues. Developing new vaccines for infants or adolescents will be immunologically and economically challenging. Let us hope that maternal and infant immunization, to date the most effective strategies against pertussis death, will remain so.

    更新日期:2019-11-01
  • Polarized Exocytosis.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-02
    Jingwen Zeng,Shanshan Feng,Bin Wu,Wei Guo

    Polarized exocytosis is generally considered as the multistep vesicular trafficking process in which membrane-bounded carriers are transported from the Golgi or endosomal compartments to specific sites of the plasma membrane. Polarized exocytosis in cells is achieved through the coordinated actions of membrane trafficking machinery and cytoskeleton orchestrated by signaling molecules such as the Rho family of small GTPases. Elucidating the molecular mechanisms of polarized exocytosis is essential to our understanding of a wide range of pathophysiological processes from neuronal development to tumor invasion.

    更新日期:2019-11-01
  • TGF-β Family Signaling in Tumor Suppression and Cancer Progression.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-02
    Joan Seoane,Roger R Gomis

    Transforming growth factor-β (TGF-β) induces a pleiotropic pathway that is modulated by the cellular context and its integration with other signaling pathways. In cancer, the pleiotropic reaction to TGF-β leads to a diverse and varied set of gene responses that range from cytostatic and apoptotic tumor-suppressive ones in early stage tumors, to proliferative, invasive, angiogenic, and oncogenic ones in advanced cancer. Here, we review the knowledge accumulated about the molecular mechanisms involved in the dual response to TGF-β in cancer, and how tumor cells evolve to evade the tumor-suppressive responses of this signaling pathway and then hijack the signal, converting it into an oncogenic factor. Only through the detailed study of this complexity can the suitability of the TGF-β pathway as a therapeutic target against cancer be evaluated.

    更新日期:2019-11-01
  • Signaling Networks in Epithelial Tube Formation.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-02
    Ilenia Bernascone,Mariam Hachimi,Fernando Martin-Belmonte

    Epithelial tubes are crucial to the function of organ systems including the excretory, gastrointestinal, cardiovascular, and pulmonary. Studies in the last two decades using in vitro organotypic systems and a variety of animal models have substantiated a large number of the morphogenetic mechanisms required to form epithelial tubes in development and regeneration. Many of these mechanisms modulate the differentiation and proliferation events necessary for generating the cell movements and changes in cell shape to delineate the wide variety of epithelial tube sizes, lengths, and conformations. For instance, when coupled with oriented cell division, proliferation itself plays a role in changes in tube shape and their directed expansion. Most of these processes are regulated in response to signaling inputs from adjacent cells or soluble factors from the environment. Despite the great deal of recent investigation in this direction, the knowledge we have about the signaling pathways associated with all epithelial tubulogenesis in development and regeneration is still very limited.

    更新日期:2019-11-01
  • Direct Lineage Reprogramming: Harnessing Cell Plasticity between Liver and Pancreas.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Silvia Ruzittu,David Willnow,Francesca M Spagnoli

    Direct lineage reprogramming of abundant and accessible cells into therapeutically useful cell types holds tremendous potential in regenerative medicine. To date, a number of different cell types have been generated by lineage reprogramming methods, including cells from the neural, cardiac, hepatic, and pancreatic lineages. The success of this strategy relies on developmental biology and the knowledge of cell-fate-defining transcriptional networks. Hepatocytes represent a prime target for β cell conversion for numerous reasons, including close developmental origin, accessibility, and regenerative potential. We present here an overview of pancreatic and hepatic development, with a particular focus on the mechanisms underlying the divergence between the two cell lineages. Additionally, we discuss to what extent this lineage relationship can be exploited in efforts to reprogram one cell type into the other and whether such an approach may provide a suitable strategy for regenerative therapies of diabetes.

    更新日期:2019-11-01
  • The First Heartbeat-Origin of Cardiac Contractile Activity.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Richard C V Tyser,Shankar Srinivas

    The amniote embryonic heart starts as a crescent of mesoderm that transitions through a midline linear heart tube in the course of developing into the four chambered heart. It is unusual in having to contract rhythmically while still undergoing extensive morphogenetic remodeling. Advances in imaging have allowed us to determine when during development this contractile activity starts. In the mouse, focal regions of contractions can be detected as early as the cardiac crescent stage. Calcium transients, required to trigger contraction, can be detected even earlier, prior to contraction. In this review, we outline what is currently known about how this early contractile function is initiated and the impact early contractile function has on cardiac development.

    更新日期:2019-11-01
  • Capturing Stem Cell Behavior Using Intravital and Live Cell Microscopy.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Arianna Fumagalli,Lotte Bruens,Colinda L G J Scheele,Jacco van Rheenen

    Stem cells maintain tissue homeostasis by driving cellular turnover and regeneration upon damage. They reside within specialized niches that provide the signals required for stem cell maintenance. Stem cells have been identified in many tissues and cancer types, but their behavior within the niche and their reaction to microenvironmental signals were inferred from limited static observations. Recent advances in live imaging techniques, such as live cell imaging and intravital microscopy, have allowed the visualization of stem cell behavior and dynamics over time in their (near) native environment. Through these recent technological advances, it is now evident that stem cells are much more dynamic than previously anticipated, resulting in a model in which stemness is a state that can be gained or lost over time. In this review, we will highlight how live imaging and intravital microscopy have unraveled previously unanticipated stem cell dynamics and plasticity during development, homeostasis, regeneration, and tumor formation.

    更新日期:2019-11-01
  • The Chicken as a Model Organism to Study Heart Development.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Johannes G Wittig,Andrea Münsterberg

    Heart development is a complex process and begins with the long-range migration of cardiac progenitor cells during gastrulation. This culminates in the formation of a simple contractile tube with multiple layers, which undergoes remodeling into a four-chambered heart. During this morphogenesis, additional cell populations become incorporated. It is important to unravel the underlying genetic and cellular mechanisms to be able to identify the embryonic origin of diseases, including congenital malformations, which impair cardiac function and may affect life expectancy or quality. Owing to the evolutionary conservation of development, observations made in nonamniote and amniote vertebrate species allow us to extrapolate to human. This review will focus on the contributions made to a better understanding of heart development through studying avian embryos-mainly the chicken but also quail embryos. We will illustrate the classic and recent approaches used in the avian system, give an overview of the important discoveries made, and summarize the early stages of cardiac development up to the establishment of the four-chambered heart.

    更新日期:2019-11-01
  • Brain Organoids: Human Neurodevelopment in a Dish.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Silvia Benito-Kwiecinski,Madeline A Lancaster

    The human brain is often described as the most complex organ in our body. Because of the limited accessibility of living brain tissue, human-specific features of neurodevelopment and disease remain largely unknown. The ability of induced pluripotent stem cells to self-organize into 3D brain organoids has revolutionized approaches to studying brain development in vitro. This review will first look at the history of studying neural development in a dish and how organoids came to be. We evaluate the ability of brain organoids to recapitulate key developmental events, focusing on the generation of various regional identities, cytoarchitecture, cell diversity, features of neuronal maturation, and circuit formation. We also consider the limitations of the model and review recent approaches to improve reproducibility and the healthy maturation of brain organoids.

    更新日期:2019-11-01
  • Xenopus: Experimental Access to Cardiovascular Development, Regeneration Discovery, and Cardiovascular Heart-Defect Modeling.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Stefan Hoppler,Frank L Conlon

    Xenopus has been used to study a wide array of developmental processes, benefiting from vast quantities of relatively large, externally developing eggs. Xenopus is particularly amenable to examining the cardiac system because many of the developmental processes and genes involved in cardiac specification, differentiation, and growth are conserved between Xenopus and human and have been characterized in detail. Furthermore, compared with other higher vertebrate models, Xenopus embryos can survive longer without a properly functioning heart or circulatory system, enabling investigation of later consequences of early embryological manipulations. This biology is complemented by experimental technology, such as embryonic explants to study the heart, microinjection of overexpression constructs, and, most recently, the generation of genetic mutations through gene-editing technologies. Recent investigations highlight Xenopus as a powerful experimental system for studying injury/repair and regeneration and for congenital heart disease (CHD) modeling, which reinforces why this model system remains ideal for studying heart development.

    更新日期:2019-11-01
  • Neutrophil Extracellular Traps in Host Defense.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Sabrina Sofia Burgener,Kate Schroder

    Neutrophils are produced in the bone marrow and then patrol blood vessels from which they can be rapidly recruited to a site of infection. Neutrophils bind, engulf, and efficiently kill invading microbes via a suite of defense mechanisms. Diverse extracellular and intracellular microbes induce neutrophils to extrude neutrophil extracellular traps (NETs) through the process of NETosis. Here, we review the signaling mechanisms and cell biology underpinning the key NETosis pathways during infection and the antimicrobial functions of NETs in host defense.

    更新日期:2019-11-01
  • Modeling Brain Disorders Using Induced Pluripotent Stem Cells.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Krishna C Vadodaria,Jeffrey R Jones,Sara Linker,Fred H Gage

    Brain disorders, from neurodegenerative to psychiatric disorders, are among the most challenging conditions to study because of the intricate nature of the human brain and the limitations of existing model systems in recapitulating all these intricacies. However, innovations in stem cell technologies now allow us to reprogram patient somatic cells to induced pluripotent stem cells (iPSCs), which can then be differentiated to disease-relevant neural and glial cells. iPSCs are a valuable tool to model brain disorders, as they can be derived from patients with known symptom histories, genetics, and drug-response profiles. Here, we discuss the premise and validity of the iPSC-based in vitro model system and highlight key findings from the most commonly studied neurodegenerative and psychiatric disorders.

    更新日期:2019-11-01
  • The RNA Base-Pairing Problem and Base-Pairing Solutions.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-12-05
    Zhipeng Lu,Howard Y Chang

    RNA molecules are folded into structures and complexes to perform a wide variety of functions. Determination of RNA structures and their interactions is a fundamental problem in RNA biology. Most RNA molecules in living cells are large and dynamic, posing unique challenges to structure analysis. Here we review progress in RNA structure analysis, focusing on methods that use the "cross-link, proximally ligate, and sequence" principle for high-throughput detection of base-pairing interactions in living cells. Beginning with a comparison of commonly used methods in structure determination and a brief historical account of psoralen cross-linking studies, we highlight the important features of cross-linking methods and new biological insights into RNA structures and interactions from recent studies. Further improvement of these cross-linking methods and application to previously intractable problems will shed new light on the mechanisms of the "modern RNA world."

    更新日期:2019-11-01
  • Working for a Scientific Society.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-12-05
    Martin Frank

    Opportunities for employment of PhD scientists exist within the world of scientific societies. Societies exist to serve the needs of their scientific or engineering constituencies. As membership organizations, they provide their constituents with access to meetings, publications (both books and journals), educational programs, and advocacy assistance. Within many of these societies, leadership positions and associated coordinator/analyst positions can be filled by someone with a PhD. Examples of positions in societies include science policy/government relations, education, publications, communications, and executive departments. Interested PhDs should demonstrate their interest by volunteering to participate in society outreach or committee activities. The critical element is to remember that as a PhD you have the critical thinking and problem-solving ability to succeed in whatever career you pursue. The key is to demonstrate that these abilities are applicable to the available positions in the association.

    更新日期:2019-11-01
  • Imaging the Life and Death of mRNAs in Single Cells.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-12-05
    Jeffrey A Chao,Timothée Lionnet

    RNA plays a central role in gene expression from its transcription in the nucleus through translation and degradation in the cytoplasm. Technological advances in fluorescent microscopy and labeling methodologies have made it possible to detect single molecules of RNA in both fixed and living cells. Here, we focus on the recent developments in RNA imaging that have allowed quantitatively measuring the lives of individual transcripts from birth to death and all the events in between in single cells and tissues. Direct observation of RNAs within their native cellular environment has revealed a complex layer of spatial and temporal regulation that has profoundly impacted our understanding of RNA biology.

    更新日期:2019-11-01
  • Cell-Cycle Cross Talk with Caspases and Their Substrates.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Patrick Connolly,Irmina Garcia-Carpio,Andreas Villunger

    Caspases play central roles in mediating both cell death and inflammation. It has more recently become evident that caspases also drive other biological processes. Most prominently, caspases have been shown to be involved in differentiation. Several stem and progenitor cell types rely on caspases to initiate and execute their differentiation processes. These range from neural and glial cells, to skeletal myoblasts and osteoblasts, and several cell types of the hematopoietic system. Beyond differentiation, caspases have also been shown to play roles in other "noncanonical" processes, including cell proliferation, arrest, and senescence, thereby contributing to the mechanisms that regulate tissue homeostasis at multiple levels. Remarkably, caspases directly influence the course of the cell cycle in both a positive and negative manner. Caspases both cleave elements of the cell-cycle machinery and are themselves substrates of cell-cycle kinases. Here we aim to summarize the breadth of interactions between caspases and cell-cycle regulators. We also highlight recent developments in this area.

    更新日期:2019-11-01
  • Coming Together: RNAs and Proteins Assemble under the Single-Molecule Fluorescence Microscope.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-04-03
    Ameya P Jalihal,Paul E Lund,Nils G Walter

    SUMMARYRNAs, across their numerous classes, often work in concert with proteins in RNA-protein complexes (RNPs) to execute critical cellular functions. Ensemble-averaging methods have been instrumental in revealing many important aspects of these RNA-protein interactions, yet are insufficiently sensitive to much of the dynamics at the heart of RNP function. Single-molecule fluorescence microscopy (SMFM) offers complementary, versatile tools to probe RNP conformational and compositional changes in detail. In this review, we first outline the basic principles of SMFM as applied to RNPs, describing key considerations for labeling, imaging, and quantitative analysis. We then sample applications of in vitro and in vivo single-molecule visualization using the case studies of pre-messenger RNA (mRNA) splicing and RNA silencing, respectively. After discussing specific insights single-molecule fluorescence methods have yielded, we briefly review recent developments in the field and highlight areas of anticipated growth.

    更新日期:2019-11-01
  • Protocells and RNA Self-Replication.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-09-06
    Gerald F Joyce,Jack W Szostak

    The general notion of an "RNA world" is that, in the early development of life on the Earth, genetic continuity was assured by the replication of RNA, and RNA molecules were the chief agents of catalytic function. Assuming that all of the components of RNA were available in some prebiotic locale, these components could have assembled into activated nucleotides that condensed to form RNA polymers, setting the stage for the chemical replication of polynucleotides through RNA-templated RNA polymerization. If a sufficient diversity of RNAs could be copied with reasonable rate and fidelity, then Darwinian evolution would begin with RNAs that facilitated their own reproduction enjoying a selective advantage. The concept of a "protocell" refers to a compartment where replication of the primitive genetic material took place and where primitive catalysts gave rise to products that accumulated locally for the benefit of the replicating cellular entity. Replication of both the protocell and its encapsulated genetic material would have enabled natural selection to operate based on the differential fitness of competing cellular entities, ultimately giving rise to modern cellular life.

    更新日期:2019-11-01
  • Careers in Science and Grant Administration: View from the National Institutes of Health.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-09-06
    Marion Zatz,Sherry Dupere

    Scientist administrators at the National Institutes of Health fall into two categories: program officers and scientific review officers. Program officers provide advice to applicants and grantees, make funding recommendations, oversee grantees' research progress, and facilitate research opportunities in emerging areas of science. Scientific review officers oversee all aspects of the initial (peer) review of grant applications.

    更新日期:2019-11-01
  • Infectious (Non)tolerance--frustrated commensalism gone awry?
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2012-03-30
    Jesse C Nussbaum,Richard M Locksley

    Despite advances in medicine, infectious diseases remain major causes of death and disability worldwide. Acute or chronic infectious agents mediate host tissue damage and cause a spectrum of disease as diverse as overwhelming sepsis and shock within hours to persistent tissue inflammation causing organ failure or even cancer over years. Although pathogen exposure can cause disease via host-derived inflammation, pathogens share recognized elements with harmless human commensals. Mouse models and organisms with simpler flora are revealing the dialogue between multicellular hosts and commensal flora. In some instances the persistent inflammation associated with pathogens can be interpreted within a framework of frustrated commensalism in which the host and pathogen cannot complete the requisite dialogue that establishes homeostasis. In contrast, coevolved commensals interact cooperatively with the host immune system, resulting in immunotolerance. Attempts to more thoroughly understand the molecular nature of the dialogue may uncover novel approaches to the control of inflammation and tissue damage.

    更新日期:2019-11-01
  • The Killer Pseudokinase Mixed Lineage Kinase Domain-Like Protein (MLKL).
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    James M Murphy

    Whereas the apoptosis cell death pathway typically enables cells to undergo death in an immunologically silent manner, cell death by necroptosis induces cell lysis and release of cellular constituents known to elicit an immune response. Consequently, the origins of necroptosis likely originated in host defense against pathogens, although recently it has emerged that dysregulation of the pathway underlies many human pathologies. The past decade has seen a rapid advance in our understanding of the molecular mechanisms underlying necroptotic cell death, including the implication of the pseudokinase, mixed lineage kinase domain-like protein (MLKL), as the terminal effector in the pathway. Here, I review our current understanding of how MLKL is activated by the upstream receptor interacting protein kinase (RIPK)3, the proposed mechanism(s) by which MLKL kills cells, and recently described layers of regulation that tune MLKL's killing activity.

    更新日期:2019-11-01
  • Reptiles as a Model System to Study Heart Development.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Bjarke Jensen,Vincent M Christoffels

    A chambered heart is common to all vertebrates, but reptiles show unparalleled variation in ventricular septation, ranging from almost absent in tuataras to full in crocodilians. Because mammals and birds evolved independently from reptile lineages, studies on reptile development may yield insight into the evolution and development of the full ventricular septum. Compared with reptiles, mammals and birds have evolved several other adaptations, including compact chamber walls and a specialized conduction system. These adaptations appear to have evolved from precursor structures that can be studied in present-day reptiles. The increase in the number of studies on reptile heart development has been greatly facilitated by sequencing of several genomes and the availability of good staging systems. Here, we place reptiles in their phylogenetic context with a focus on features that are primitive when compared with the homologous features of mammals. Further, an outline of major developmental events is given, and variation between reptile species is discussed.

    更新日期:2019-11-01
  • At the Crossroads of Science and Society: Careers in Science Policy.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-10-03
    Amy P Patterson,Mary E Groesch,Allan C Shipp,Christopher J Viggiani

    Science policy offers a challenging and rewarding career path for scientists interested in the social, ethical, and legal implications of their field. This topic encompasses a broad spectrum of activities all in support of advancing the scientific enterprise. Science policy spans various sectors, and policy careers are found in many different organizations, including the federal government, scientific societies, and professional organizations. Although their specific duties may vary greatly, science policy professionals generally apply their scientific training to ensure that the scientific enterprise advances in a responsible and ethical manner and to solve challenges with broad scientific and societal implications.

    更新日期:2019-11-01
  • The Story of RNA Folding, as Told in Epochs.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-10-03
    Daniel Herschlag,Steve Bonilla,Namita Bisaria

    The past decades have witnessed tremendous developments in our understanding of RNA biology. At the core of these advances have been studies aimed at discerning RNA structure and at understanding the forces that influence the RNA folding process. It is easy to take the present state of understanding for granted, but there is much to be learned by considering the path to our current understanding, which has been tortuous, with the birth and death of models, the adaptation of experimental tools originally developed for characterization of protein structure and catalysis, and the development of novel tools for probing RNA. In this review we tour the stages of RNA folding studies, considering them as "epochs" that can be generalized across scientific disciplines. These epochs span from the discovery of catalytic RNA, through biophysical insights into the putative primordial RNA World, to characterization of structured RNAs, the building and testing of models, and, finally, to the development of models with the potential to yield generalizable predictive and quantitative models for RNA conformational, thermodynamic, and kinetic behavior. We hope that this accounting will aid others as they navigate the many fascinating questions about RNA and its roles in biology, in the past, present, and future.

    更新日期:2019-11-01
  • Technique Development for Probing RNA Structure In Vivo and Genome-Wide.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-10-03
    Philip C Bevilacqua,Sarah M Assmann

    How organisms perceive and respond to their surroundings is one of the great questions in biology. It is clear that RNA plays key roles in sensing. Cellular and environmental cues that RNA responds to include temperature, ions, metabolites, and biopolymers. Recent advances in next-generation sequencing and in vivo chemical probing have provided unprecedented insights into RNA folding in vivo and genome-wide. Patterns of chemical reactivity have implicated control of gene expression by RNA and aided prediction of RNA structure. Central to these advances has been development of molecular biological and chemical techniques. Key advances are improvements in the quality, cost, and throughput of library preparation; availability of a wider array of chemicals for probing RNA structure in vivo; and robustness and user friendliness of data analysis. Insights from probing transcriptomes and future directions are provided.

    更新日期:2019-11-01
  • NAADP Receptors.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-06-12
    Antony Galione

    Of the established Ca2+-mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations, and its receptors undergo dramatic desensitization. Recent studies have identified a new class of calcium-release channel, the two-pore channels (TPCs), as the likely targets for NAADP regulation, even though the effect may be indirect. These channels localized at endolysosomes, where they mediate local Ca2+ release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca2+ mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca2+ release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca2+-induced Ca2+-release (CICR) channels at lysosomal-endoplasmic reticulum (ER) junctions. The third is to regulate plasma membrane excitability by the targeting of Ca2+ release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca2+-activated channels. In this review, I discuss the role of nicotinic acid adenine nucleotide diphosphate (NAADP)-mediated Ca2+ release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca2+ signaling.

    更新日期:2019-11-01
  • The Proteasome and Its Network: Engineering for Adaptability.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-03-06
    Daniel Finley,Miguel A Prado

    The proteasome, the most complex protease known, degrades proteins that have been conjugated to ubiquitin. It faces the unique challenge of acting enzymatically on hundreds and perhaps thousands of structurally diverse substrates, mechanically unfolding them from their native state and translocating them vectorially from one specialized compartment of the enzyme to another. Moreover, substrates are modified by ubiquitin in myriad configurations of chains. The many unusual design features of the proteasome may have evolved in part to endow this enzyme with a robust ability to process substrates regardless of their identity. The proteasome plays a major role in preserving protein homeostasis in the cell, which requires adaptation to a wide variety of stress conditions. Modulation of proteasome function is achieved through a large network of proteins that interact with it dynamically, modify it enzymatically, or fine-tune its levels. The resulting adaptability of the proteasome, which is unique among proteases, enables cells to control the output of the ubiquitin-proteasome pathway on a global scale.

    更新日期:2019-11-01
  • Principles and Practices of Hybridization Capture Experiments to Study Long Noncoding RNAs That Act on Chromatin.
    CSH Perspect. Biol. (IF 9.110) Pub Date : null
    Matthew D Simon,Martin Machyna

    SUMMARYThe diverse roles of cellular RNAs can be studied by purifying RNAs of interest together with the biomolecules they bind. Biotinylated antisense oligonucleotides that hybridize specifically to the RNA of interest provide a general approach to develop affinity reagents for these experiments. Such oligonucleotides can be used to enrich endogenous RNAs from cross-linked chromatin extracts to study the genomic binding sites of RNAs. These hybridization capture protocols are evolving modular experiments that are compatible with a range of cross-linkers and conditions. This review discusses the principles of these hybridization capture experiments as well as considerations and controls necessary to interpret the resulting data without being misled by artifactual signals.

    更新日期:2019-11-01
  • The Role of Dwarfing Traits in Historical and Modern Agriculture with a Focus on Rice.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-07-31
    Ángel Ferrero-Serrano,Christian Cantos,Sarah M Assmann

    Semidwarf stature is a valuable agronomic trait in grain crops that reduces lodging and increases harvest index. A fundamental advance during the 1960s Green Revolution was the introduction of semidwarf cultivars of rice and wheat. Essentially, all semidwarf varieties of rice under cultivation today owe their diminished stature to a specific null mutation in the gibberellic acid (GA) biosynthesis gene, SD1 However, it is now well-established that, in addition to GAs, brassinosteroids and strigolactones also control plant height. In this review, we describe the synthesis and signaling pathways of these three hormones as understood in rice and discuss the mutants and transgenics in these pathways that confer semidwarfism and other valuable architectural traits. We propose that such genes offer underexploited opportunities for broadening the genetic basis and germplasm in semidwarf rice breeding.

    更新日期:2019-11-01
  • Ca2+ Signaling and Regeneration.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-07-17
    Jonathan S Marchant

    Regeneration is the process by which lost or damaged tissue is replaced in adult organisms. Some organisms exhibit robust regenerative capabilities, while others, including humans, do not. Understanding the molecular principles governing the regenerative malleability of different organisms is of fundamental biological interest. Further, this problem has clear impact for the field of "regenerative medicine," which aspires to understand how human cells, tissues, and organs may be restored to normal function in scenarios of disease, damage, or age-related decline. This review will focus on the planarian flatworm as a powerful model system for studying the role of Ca2+ signals in regeneration. These invertebrate animals display an astounding innate regenerative capacity capable of regenerating complete organisms from tiny, excised fragments. New knowledge and methodological capabilities in this system highlight the potential for studying the role of Ca2+ signaling at multiple stages of the regenerative blueprint that controls stem cell behavior in vivo.

    更新日期:2019-11-01
  • Engineering Disease-Resistant Cassava.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-06-12
    Z J Daniel Lin,Nigel J Taylor,Rebecca Bart

    Manihot esculenta Crantz (cassava) is a food crop originating from South America grown primarily for its starchy storage roots. Today, cassava is grown in the tropics of South America, Africa, and Asia with an estimated 800 million people relying on it as a staple source of calories. In parts of sub-Saharan Africa, cassava is particularly crucial for food security. Cassava root starch also has use in the pharmaceutical, textile, paper, and biofuel industries. Cassava has seen strong demand since 2000 and production has increased consistently year-over-year, but potential yields are hampered by susceptibility to biotic and abiotic stresses. In particular, bacterial and viral diseases can cause severe yield losses. Of note are cassava bacterial blight (CBB), cassava mosaic disease (CMD), and cassava brown streak disease (CBSD), all of which can cause catastrophic losses for growers. In this article, we provide an overview of the major microbial diseases of cassava, discuss current and potential future efforts to engineer new sources of resistance, and conclude with a discussion of the regulatory hurdles that face biotechnology.

    更新日期:2019-11-01
  • Chaperone Interactions at the Ribosome.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-03-06
    Elke Deuerling,Martin Gamerdinger,Stefan G Kreft

    The continuous refreshment of the proteome is critical to maintain protein homeostasis and to adapt cells to changing conditions. Thus, de novo protein biogenesis by ribosomes is vitally important to every cellular system. This process is delicate and error-prone and requires, besides cytosolic chaperones, the guidance by a specialized set of molecular chaperones that bind transiently to the translation machinery and the nascent protein to support early folding events and to regulate cotranslational protein transport. These chaperones include the bacterial trigger factor (TF), the archaeal and eukaryotic nascent polypeptide-associated complex (NAC), and the eukaryotic ribosome-associated complex (RAC). This review focuses on the structures, functions, and substrates of these ribosome-associated chaperones and highlights the most recent findings about their potential mechanisms of action.

    更新日期:2019-11-01
  • Recognition and Degradation of Mislocalized Proteins in Health and Disease.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-03-06
    Ramanujan S Hegde,Eszter Zavodszky

    A defining feature of eukaryotic cells is the segregation of complex biochemical processes among different intracellular compartments. The protein targeting, translocation, and trafficking pathways that sustain compartmentalization must recognize a diverse range of clients via degenerate signals. This recognition is imperfect, resulting in polypeptides at incorrect cellular locations. Cells have evolved mechanisms to selectively recognize mislocalized proteins and triage them for degradation or rescue. These spatial quality control pathways maintain cellular protein homeostasis, become especially important during organelle stress, and might contribute to disease when they are impaired or overwhelmed.

    更新日期:2019-11-01
  • Structural Insights into Nuclear pre-mRNA Splicing in Higher Eukaryotes.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-02-16
    Berthold Kastner,Cindy L Will,Holger Stark,Reinhard Lührmann

    SUMMARYThe spliceosome is a highly complex, dynamic ribonucleoprotein molecular machine that undergoes numerous structural and compositional rearrangements that lead to the formation of its active site. Recent advances in cyroelectron microscopy (cryo-EM) have provided a plethora of near-atomic structural information about the inner workings of the spliceosome. Aided by previous biochemical, structural, and functional studies, cryo-EM has confirmed or provided a structural basis for most of the prevailing models of spliceosome function, but at the same time allowed novel insights into splicing catalysis and the intriguing dynamics of the spliceosome. The mechanism of pre-mRNA splicing is highly conserved between humans and yeast, but the compositional dynamics and ribonucleoprotein (RNP) remodeling of the human spliceosome are more complex. Here, we summarize recent advances in our understanding of the molecular architecture of the human spliceosome, highlighting differences between the human and yeast splicing machineries.

    更新日期:2019-11-01
  • Mechanical Properties of the Cytoskeleton and Cells.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-11-03
    Adrian F Pegoraro,Paul Janmey,David A Weitz

    SUMMARYThe cytoskeleton is the major mechanical structure of the cell; it is a complex, dynamic biopolymer network comprising microtubules, actin, and intermediate filaments. Both the individual filaments and the entire network are not simple elastic solids but are instead highly nonlinear structures. Appreciating the mechanics of biopolymer networks is key to understanding the mechanics of cells. Here, we review the mechanical properties of cytoskeletal polymers and discuss the implications for the behavior of cells.

    更新日期:2019-11-01
  • TGF-β Family Signaling in Connective Tissue and Skeletal Diseases.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-02
    Elena Gallo MacFarlane,Julia Haupt,Harry C Dietz,Eileen M Shore

    The transforming growth factor β (TGF-β) family of signaling molecules, which includes TGF-βs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-β family members play different roles in these tissues, and their activities are often balanced with those of other TGF-β family members and by interactions with other signaling pathways. Perturbations in TGF-β family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-β family of signaling mediators and the extracellular matrix in connective tissues.

    更新日期:2019-11-01
  • Neurodegenerative Disease Transmission and Transgenesis in Mice.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-02-15
    Brittany N Dugger,Daniel P Perl,George A Carlson

    Although the discovery of the prion protein (PrP) resulted from its co-purification with scrapie infectivity in Syrian hamsters, work with genetically defined and genetically modified mice proved crucial for understanding the fundamental processes involved not only in prion diseases caused by PrP misfolding, aggregation, and spread but also in other, much more common, neurodegenerative brain diseases. In this review, we focus on methodological and conceptual approaches used to study scrapie and related PrP misfolding diseases in mice and how these approaches have advanced our understanding of related disorders including Alzheimer's and Parkinson's disease.

    更新日期:2019-11-01
  • Drugging the RNA World.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2018-11-06
    Matthew D Disney,Brendan G Dwyer,Jessica L Childs-Disney

    Although we live in the remnants of an RNA world, the world of drug discovery and chemical probes is firmly protein-centric. Developing highly selective small molecules targeting RNA is often considered to be an insurmountable challenge. Our goal is to demystify the design of such compounds. In this review, we describe various approaches to design small molecules that target RNA from sequence and the application of these compounds in RNA biology, with a focus on inhibition of human RNA-protein complexes. We have developed a library-versus-library screening approach to define selective RNA-small-molecule binding partners and applied them to disease-causing RNAs, in particular noncoding oncogenic RNAs and expanded RNA repeats, to modulate their biology in cells and animals. We also describe the design of new types of small-molecule probes that could broadly decipher the mysteries of RNA in cells.

    更新日期:2019-11-01
  • Careers at Biotech Start-Ups and in Entrepreneurship.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-11-03
    Susan Froshauer

    The world of biotechnology "start-ups" and entrepreneurship offers exciting new avenues for driving state-of-the-art research using an arsenal of multidisciplinary skills, whether your role is as part of a team or as a leader. Although traditionally these positions may not be as secure as those offered by some of the larger companies, the small start-up culture provides opportunities for contributing at many levels to a wide range of responsibilities: from scientific discovery to delivery of proof of concept and intellectual property; from analysis of market opportunities and competitive intelligence to creation of time lines and business plans for a first product. Often, if you get in on the ground level, you get to validate your own concept, pitch to potential investors, argue value, build a team, engage advisors, and then, with funding in hand, launch an entirely new research and development (R&D) enterprise. Many of the skills and much of the experience gained while pursuing a graduate degree can be put to good use in these arenas as well. This path, however, is not for the faint of heart; it requires not only a strong scientific background and organizational skills, but also the ability to work well on a team, excellent communication skills, and persistence when faced with delays or disappointment. With increasing responsibilities in the small company come the requirements for aptitudes for leadership, strategic and financial planning, networking, negotiating, and managing both projects and personnel.

    更新日期:2019-11-01
  • Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-23
    Ming Ma,Anna-Rachel Gallagher,Stefan Somlo

    Autosomal-dominant polycystic kidney disease (ADPKD) is a disease of defective tissue homeostasis resulting in active remodeling of nephrons and bile ducts to form fluid-filled sacs called cysts. The causal genes PKD1 and PKD2 encode transmembrane proteins polycystin 1 (PC1) and polycystin 2 (PC2), respectively. Together, the polycystins localize to the solitary primary cilium that protrudes from the apical surface of most kidney tubule cells and is thought to function as a privileged compartment that the cell uses for signal integration of sensory inputs. It has been proposed that PC1 and PC2 form a receptor-channel complex that detects external stimuli and transmit a local calcium-mediated signal, which may control a multitude of cellular processes by an as-yet unknown mechanism. Genetic studies using mouse models of cilia and polycystin dysfunction have shown that polycystins regulate an unknown cilia-dependent signal that is normally part of the homeostatic maintenance of nephron structure. ADPKD ensues when this pathway is dysregulated by absence of polycystins from intact cilia, but disruption of cilia also disrupts this signaling mechanism and ameliorates ADPKD even in the absence of polycystins. Understanding the role of cilia and ciliary signaling in ADPKD is challenging, but success will provide saltatory advances in our understanding of how tubule structure is maintained in healthy kidneys and how disruption of polycystin or cilia function leads to the pathological tissue remodeling process underlying ADPKD.

    更新日期:2019-11-01
  • Regulation of Transporters and Channels by Membrane-Trafficking Complexes in Epithelial Cells.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-02
    Curtis T Okamoto

    The vectorial secretion and absorption of fluid and solutes by epithelial cells is dependent on the polarized expression of membrane solute transporters and channels at the apical and basolateral membranes. The establishment and maintenance of this polarized expression of transporters and channels are affected by divers protein-trafficking complexes. Moreover, regulation of the magnitude of transport is often under control of physiological stimuli, again through the interaction of transporters and channels with protein-trafficking complexes. This review highlights the value in utilizing transporters and channels as cargo to characterize core trafficking machinery by which epithelial cells establish and maintain their polarized expression, and how this machinery regulates fluid and solute transport in response to physiological stimuli.

    更新日期:2019-11-01
  • Making Heads or Tails of It: Cell-Cell Adhesion in Cellular and Supracellular Polarity in Collective Migration.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-03-02
    Jan-Hendrik Venhuizen,Mirjam M Zegers

    Collective cell migration is paramount to morphogenesis and contributes to the pathogenesis of cancer. To migrate directionally and reach their site of destination, migrating cells must distinguish a front and a rear. In addition to polarizing individually, cell-cell interactions in collectively migrating cells give rise to a higher order of polarity, which allows them to move as a supracellular unit. Rather than just conferring adhesion, emerging evidence indicates that cadherin-based adherens junctions intrinsically polarize the cluster and relay mechanical signals to establish both intracellular and supracellular polarity. In this review, we discuss the various functions of adherens junctions in polarity of migrating cohorts.

    更新日期:2019-11-01
  • What Are the Most Powerful Immunogen Design Vaccine Strategies? A Structural Biologist's Perspective.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2017-02-06
    Peter D Kwong

    The ability of structure-based design to control the shape and reactivity-the atomic-level chemistry-of an immunogen argues for it being one of the "most powerful" immunogen-design strategies. But antigenic reactivity is only one of the properties required to induce a protective immune response. Here, a multidimensional approach is used to exemplify the enabling role atomic-level information can play in the development of immunogens against three viral pathogens, respiratory syncytial virus, influenza A virus, and human immunodeficiency virus (HIV), which have resisted standard approaches to vaccine development. Overall, structure-based strategies incorporating B-cell ontogenies and viral evasion mechanisms appear exceptionally powerful.

    更新日期:2019-11-01
  • Golgi during development.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2011-07-20
    Weimin Zhong

    The Golgi is essential for processing proteins and sorting them, as well as plasma membrane components, to their final destinations. Not surprisingly, this organelle, a major compartment of the secretory pathway, is an important venue for regulating many aspects of development in both invertebrates and vertebrates. Through its role as a site for protein cleavage and glycosylation as well as through changes in its spatial organization and secretory trafficking, the Golgi exerts highly specific effects on cellular differentiation and morphogenesis by spatially and temporally constraining developmental pathways.

    更新日期:2019-11-01
  • Holliday junction resolvases.
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2014-09-04
    Haley D M Wyatt,Stephen C West

    Four-way DNA intermediates, called Holliday junctions (HJs), can form during meiotic and mitotic recombination, and their removal is crucial for chromosome segregation. A group of ubiquitous and highly specialized structure-selective endonucleases catalyze the cleavage of HJs into two disconnected DNA duplexes in a reaction called HJ resolution. These enzymes, called HJ resolvases, have been identified in bacteria and their bacteriophages, archaea, and eukaryotes. In this review, we discuss fundamental aspects of the HJ structure and their interaction with junction-resolving enzymes. This is followed by a brief discussion of the eubacterial RuvABC enzymes, which provide the paradigm for HJ resolvases in other organisms. Finally, we review the biochemical and structural properties of some well-characterized resolvases from archaea, bacteriophage, and eukaryotes.

    更新日期:2019-11-01
  • Medical Communications: The "Write" Career Path for You?
    CSH Perspect. Biol. (IF 9.110) Pub Date : 2019-01-04
    Yfke Hager

    The pharmaceutical industry spends billions each year on the clinical development of new medicines. Getting those products to the patients who will benefit from them requires an ability to convey the results of extensive clinical research programs to regulatory authorities, physicians, and payers. Employed by medical communications agencies, contract research organizations, and pharmaceutical companies, medical writers distill and translate complex clinical and scientific data to develop documentation spanning the entire pharmaceutical-product life cycle, from clinical development to registration and marketing. Despite being a relatively new career, the market for medical communications professionals has doubled in recent years and future job prospects look promising.

    更新日期:2019-11-01
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