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1.  Cytokines in chronic respiratory diseases 
Cytokines are small, secreted proteins that control immune responses. Within the lung, they can control host responses to injuries or infection, resulting in clearance of the insult, repair of lung tissue, and return to homeostasis. Problems can arise when this response is over exuberant and/or cytokine production becomes dysregulated. In such cases, chronic and repeated inflammatory reactions and cytokine production can be established, leading to airway remodeling and fibrosis with unintended, maladaptive consequences. In this report, we describe the cytokines and molecular mechanisms behind the pathology observed in three major chronic diseases of the lung: asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. Overlapping mechanisms are presented as potential sites for therapeutic intervention.
PMCID: PMC3564216  PMID: 23413371
2.  PKM and the maintenance of memory 
How can memories outlast the molecules from which they are made? Answers to this fundamental question have been slow coming but are now emerging. A novel kinase, an isoform of protein kinase C (PKC), PKMzeta, has been shown to be critical to the maintenance of some types of memory. Inhibiting the catalytic properties of this kinase can erase well-established memories without altering the ability of the erased synapse to be retrained. This article provides an overview of the literature linking PKMzeta to memory maintenance and identifies some of the controversial issues that surround the bold implications of the existing data. It concludes with a discussion of the future directions of this domain.
PMCID: PMC3564217  PMID: 23413372
3.  Protein flexibility, not disorder, is intrinsic to molecular recognition 
An ‘intrinsically disordered protein’ (IDP) is assumed to be unfolded in the cell and perform its biological function in that state. We contend that most intrinsically disordered proteins are in fact proteins waiting for a partner (PWPs), parts of a multi-component complex that do not fold correctly in the absence of other components. Flexibility, not disorder, is an intrinsic property of proteins, exemplified by X-ray structures of many enzymes and protein-protein complexes. Disorder is often observed with purified proteins in vitro and sometimes also in crystals, where it is difficult to distinguish from flexibility. In the crowded environment of the cell, disorder is not compatible with the known mechanisms of protein-protein recognition, and, foremost, with its specificity. The self-assembly of multi-component complexes may, nevertheless, involve the specific recognition of nascent polypeptide chains that are incompletely folded, but then disorder is transient, and it must remain under the control of molecular chaperones and of the quality control apparatus that obviates the toxic effects it can have on the cell.
PMCID: PMC3542771  PMID: 23361309
4.  The case for intrinsically disordered proteins playing contributory roles in molecular recognition without a stable 3D structure 
The classical ‘lock-and-key’ and ‘induced-fit’ mechanisms for binding both originated in attempts to explain features of enzyme catalysis. For both of these mechanisms and for their recent refinements, enzyme catalysis requires exquisite spatial and electronic complementarity between the substrate and the catalyst. Thus, binding models derived from models originally based on catalysis will be highly biased towards mechanisms that utilize structural complementarity. If mere binding without catalysis is the endpoint, then the structural requirements for the interaction become much more relaxed. Recent observations on specific examples suggest that this relaxation can reach an extreme lack of specific 3D structure, leading to molecular recognition with biological consequences that depend not only upon structural and electrostatic complementarity between the binding partners but also upon kinetic, entropic, and generalized electrostatic effects. In addition to this discussion of binding without fixed structure, examples in which unstructured regions carry out important biological functions not involving molecular recognition will also be discussed. Finally, we discuss whether ‘intrinsically disordered protein’ (IDP) represents a useful new concept.
PMCID: PMC3542772  PMID: 23361308
5.  Molecular evolution and genetics of postzygotic reproductive isolation in plants 
In just the last few years, plant geneticists have made tremendous progress in identifying the molecular genetic basis of postzygotic reproductive isolation. With more than a dozen genes now cloned, it is clear that plant hybrid incompatibilities usually evolve via two or more mutational steps, as is predicted by the Dobzhansky-Muller model. There is evidence that natural selection or random genetic drift can be responsible for these incompatibilities.
PMCID: PMC3515857  PMID: 23236340
6.  Is perceptual learning associated with changes in a sensory region? 
Perceptual learning is defined as long-term improvement in perceptual abilities as a result of perceptual experiences. It is controversial as to whether perceptual learning is associated with changes in a sensory region of the brain or not. Here, we review research that supports, or otherwise, the sensory change hypothesis and discuss what needs to be done in the future to answer this question more definitively.
PMCID: PMC3516464  PMID: 23236341
7.  Evolving concepts of sensory adaptation 
Sensory systems constantly adapt their responses to match the current environment. These adjustments occur at many levels of the system and increasingly appear to calibrate even for highly abstract perceptual representations of the stimulus. The similar effects of adaptation across very different stimulus domains point to common design principles but also continue to raise questions about the purpose of adaptation.
PMCID: PMC3501690  PMID: 23189092
8.  On the spot: very local chromosomal rearrangements 
Over the last decade, the detection of chromosomal abnormalities has shifted from conventional karyotyping under a light microscope to molecular detection using microarrays. The latter technology identified copy number variation as a major source of variation in the human genome; moreover, copy number variants were found responsible for 10-20% of cases of intellectual disability. Recent technological advances in microarray technology have also enabled the detection of very small local chromosomal rearrangements, sometimes affecting the function of only a single gene. Here, we illustrate how high resolution microarray analysis has led to increased insights into the contribution of specific genes in disease.
PMCID: PMC3505860  PMID: 23189093
9.  Can we vaccinate against Type 1 diabetes? 
Vaccination is the administration of antigenic material to stimulate the immune system to develop adaptive immunity to a disease. As the most successful prophylactic in medical history, there is now an emerging interest as to whether vaccination can be applied in autoimmune and inflammatory conditions. These are diseases of failed immune regulation; vaccination in this context aims to exploit the power of antigenic material to stimulate immune homeostasis in the form of active, adaptive, regulatory immune responses. Type 1 diabetes is an autoimmune disease that could benefit from the therapeutic potential of vaccination. The major conditions necessary to make prophylaxis feasible are in place; the self antigens are known, the failure of existing immune regulation has been demonstrated, early studies of vaccine approaches have proved safe, and the preclinical prodrome of the disease can be easily detected by simple blood tests. Challenges for future implementation include finding the best mode of delivery and the best blend of adjunctive therapies that create the favorable conditions required for a vaccine to be effective.
PMCID: PMC3463895  PMID: 23112807
10.  An emerging concept of vascular salt sensitivity 
Excessive amounts of salt in food, as usually consumed worldwide, affect the vascular system, leading to high blood pressure and premature disabilities. Salt entering the vascular bed after a salty meal is transiently bound to the endothelial glycocalyx, a negatively charged biopolymer lining the inner surface of the blood vessels. This barrier protects the endothelium against salt overload. A poorly-developed glycocalyx increases the salt permeability of the vascular system and the amount of salt being deposited in the body, which affects organ function. A simple test system is now available that evaluates vascular salt sensitivity in humans and identifies individuals who are at risk of salt-induced hypertension. This short review aims to discuss how the underlying basic research can be translated into medical practice and, thus, meaningful health outcomes.
PMCID: PMC3463896  PMID: 23112808
11.  Ocean viruses and their effects on microbial communities and biogeochemical cycles 
Viruses are the most abundant life forms on Earth, with an estimated 1031 total viruses globally. The majority of these viruses infect microbes, whether bacteria, archaea or microeukaryotes. Given the importance of microbes in driving global biogeochemical cycles, it would seem, based on numerical abundances alone, that viruses also play an important role in the global cycling of carbon and nutrients. However, the importance of viruses in controlling host populations and ecosystem functions, such as the regeneration, storage and export of carbon and other nutrients, remains unresolved. Here, we report on advances in the study of ecological effects of viruses of microbes. In doing so, we focus on an area of increasing importance: the role that ocean viruses play in shaping microbial population sizes as well as in regenerating carbon and other nutrients.
PMCID: PMC3434959  PMID: 22991582
12.  Epigenetic synthesis: a need for a new paradigm for evolution in a contaminated world 
Epigenetics is a perspective, not a set of techniques. Molecular biology and genetics are the dominant disciplines in biology today, but practitioners of these fields have only recently ‘rediscovered’ the importance of the environment. This has led to increasing research into molecular epigenetics and the interface between the environment and gene regulation. Beyond the study of epigenetic mechanisms at the level of the gene, more investigation of epigenetic outcomes at the level of both the individual organism and the evolution of the population is needed.
PMCID: PMC3434969  PMID: 22991583
13.  Metagenomics and its connection to microbial community organization 
Microbes dominate most global biogeochemical cycles, and microbial metagenomics (studying the collective microbial genomes) provides invaluable new insights into microbial systems, independent of cultivation. Metagenomic approaches targeting specific genes, e.g. small subunit (ssu) ribosomal RNA (rRNA), can be used to investigate microbial community organization by efficiently showing which taxa of organisms are present, while shotgun approaches show all genes and can indicate what functions the organisms are capable of. But collecting and organizing comprehensive shotgun data is extremely challenging and costly, and, in theory, predicting functionalities from microbial identities alone would save immense effort. However, we don’t yet know to what extent such predictions are applicable.
PMCID: PMC3410722  PMID: 22912649
14.  Spatial regulation of translation through RNA localization 
RNA localization is a mechanism to post-transcriptionally regulate gene expression. Eukaryotic organisms ranging from fungi to mammals localize mRNAs to spatially restrict synthesis of specific proteins to distinct regions of the cytoplasm. In this review, we provide a general summary of RNA localization pathways in Saccharomyces cerevisiae, Xenopus, Drosophila and mammalian neurons.
PMCID: PMC3412389  PMID: 22912650
15.  Crosstalk between metabolic and neuropsychiatric disorders 
Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.
PMCID: PMC3388805  PMID: 22802875
16.  Leukocyte set points in metabolic disease 
Vertebrate tissues comprise precise admixtures of parenchymal and hematopoietic cells, whose interactions are vital to proper tissue function. By regulating this interaction, vertebrates are able to mitigate environmental stress and coordinate dramatic physiologic adaptations. For instance, under conditions of chronic nutrient excess, leukocyte recruitment and activation increase in an effort to decrease excess nutrient storage and alleviate adipocyte stress. While basal equilibria may be reestablished upon normalization of nutrient intake, a new set point characterized by insulin resistance and chronic inflammation is established if the stress persists. Consequently, although this response is adaptive in settings of acute overfeeding and infection, it has catastrophic health consequences in the modern context of obesity. Understanding how leukocyte set points (numbers and activation status) are established, maintained, and regulated in tissues is, thus, critical to our understanding of, and intervention in, chronic metabolic diseases, such as obesity and diabetes.
PMCID: PMC3388849  PMID: 22802874
17.  Controlling animal growth and body size – does fruit fly physiology point the way? 
The question of how growth and size are controlled has fascinated generations of biologists. However, the underlying mechanisms still remain unclear. The last year or so has seen a flurry of reports on the control of growth and body size in Drosophila, and a central theme to these papers is the idea of signaling between organs as a control mechanism for overall body growth and development. While this concept is obviously not new, these fly studies now open up the possibility of using a genetically tractable system to dissect in detail how organ-to-organ communication dictates body size.
PMCID: PMC3369236  PMID: 22685490
18.  Advances in embryo selection methods 
Despite many recent advances in the field of reproductive biology and medicine, the efficiency of in vitro fertilization procedures remains relatively low. There is a need for a reliable and non-invasive method of embryo selection to ensure that only embryos with the highest developmental potential are chosen for transfer to mothers-to-be. Here, we compare various methods currently used for assessing embryonic viability, such as examination of embryonic morphology, quality of the genetic material, or metabolism. Additionally, we discuss novel procedures for embryonic assessment based on advanced time-lapse imaging techniques, which show great promise and may lead to increased in vitro fertilization efficiencies.
PMCID: PMC3369238  PMID: 22685489
19.  Development of feedstocks for cellulosic biofuels 
The inclusion of cellulosic ethanol in the Energy Independence and Security Act (EISA) of 2007 and the revised Renewable Fuel Standard (RFS2) has spurred development of the first commercial scale cellulosic ethanol biorefineries. These efforts have also revived interest in the development of dedicated energy crops selected for biomass productivity and for properties that facilitate conversion of biomass to liquid fuels. While many aspects of developing these feedstocks are compatible with current agricultural activities, improving biomass productivity may provide opportunities to expand the potential for biofuel production beyond the classical research objectives associated with improving traditional food and feed crops.
PMCID: PMC3342825  PMID: 22615716
20.  The immune diet: meeting the metabolic demands of lymphocyte activation 
During the adaptive immune response, lymphocytes undergo dramatic changes in metabolism that accompany the proliferative burst and differentiation into functional subsets. This brief overview focuses on recent advances in understanding the mechanisms of this metabolic reprogramming in T lymphocytes.
PMCID: PMC3342832  PMID: 22615715
21.  The Protein Structure Initiative: achievements and visions for the future 
The Protein Structure Initiative (PSI) was established in 2000 by the National Institutes of General Medical Sciences with the long-term goal of providing 3D (three-dimensional) structural information for most proteins in nature. As advances in genomic sequencing, bioinformatics, homology modelling, and methods for rapid determination of 3D structures of proteins by X-ray crystallography and nuclear magnetic resonance (NMR) converged, it was proposed that our understanding of the biology of protein structure and evolution could be greatly enabled by ‘genomic-scale’ protein structure determination. Over the past 12 years, the PSI has evolved from a testing bed for new methods of sample and structure production to a core component of a wide range of biology programs.
PMCID: PMC3318194  PMID: 22500193
22.  The context of gene expression regulation 
Recent advances in sequencing technologies have uncovered a world of RNAs that do not code for proteins, known as non-protein coding RNAs, that play important roles in gene regulation. Along with histone modifications and transcription factors, non-coding RNA is part of a layer of transcriptional control on top of the DNA code. This layer of components and their interactions specifically enables (or disables) the modulation of three-dimensional folding of chromatin to create a context for transcriptional regulation that underlies cell-specific transcription. In this perspective, we propose a structural and functional hierarchy, in which the DNA code, proteins and non-coding RNAs act as context creators to fold chromosomes and regulate genes.
PMCID: PMC3318259  PMID: 22500194
23.  Cellular networks controlling Th2 polarization in allergy and immunity 
In contrast to the development of Th1 (type 1 T helper cells), Th17 and Treg (regulatory T cells), little is known of the mechanisms governing Th2 development, which is important for immunity to helminths and for us to understand the pathogenesis of allergy. A picture is emerging in which mucosal epithelial cells instruct dendritic cells to promote Th2 responses in the absence of IL-12 (interleukin 12) production and provide instruction through thymic stromal lymphopoieitin (TSLP) or granulocyte-macrophage colony stimulating factor (GM-CSF). At the same time, allergens, helminths and chemical adjuvants elicit the response of innate immune cells like basophils, which provide more polarizing cytokines and IL-4 and reinforce Th2 immunity. This unique communication between cells will only be fully appreciated if we study Th2 immunity in vivo and in a tissue-specific context, and can only be fully understood if we compare several models of Th2 immune response induction.
PMCID: PMC3292286  PMID: 22403589
24.  New Antiviral Agents for Hepatitis C 
Approximately 120-130 million individuals are chronically infected with hepatitis C virus (HCV) worldwide, although it is curable by therapy. Until recently, treatment of chronic hepatitis C was based on the combination of pegylated interferon-α and ribavirin. A number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors. They led to the development of antiviral agents that specifically target a viral function (direct acting antivirals), and host-targeted agents that inhibit HCV replication. Direct acting antivirals in clinical development include NS3-4A protease inhibitors (two of which, telaprevir and boceprevir, have recently been approved for treatment of HCV genotype 1 infection in combination with pegylated interferon-α and ribavirin), nucleoside/nucleotide analogue and non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, and NS5A inhibitors. Host-targeted agents include cyclophilin inhibitors. This article describes the direct acting antivirals and host-targeted agents that have recently been approved or have been tested in HCV-infected patients and discusses their two current paths of clinical development: with or without interferon-α.
PMCID: PMC3292288  PMID: 22403588
25.  microRNA induced transdifferentiation 
Recent months have seen rapid advances in the field of transdifferentiation, specifically in the conversion of fibroblasts to neurons. Most surprising is the observation that the ability to drive these transitions is not limited to transcription factors, but that they can be promoted by microRNAs as well. Indeed, in one case, microRNAs alone induced the transdifferentiation of fibroblasts to neuron-like cells, albeit at a low efficiency. Here, we review this rapidly advancing field, discuss possible mechanisms underlying microRNA-induced transdifferentiation and the potential for microRNAs to drive such transitions to any cell type of interest in vitro and in vivo.
PMCID: PMC3270586  PMID: 22312415

Résultats 1-25 (264)