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Lin S.,Cell and Developmental Biology | Lin S.,Center for Environmental Implications of Nanotechnology | Lin S.,Center for Environmental Implications of Nanotechnology | Zhao Y.,Cell and Developmental Biology | Nel A.E.,University of California at Los Angeles
Small | Year: 2013

To assure a responsible and sustainable growth of nanotechnology, the environmental health and safety (EHS) aspect of engineered nanomaterials and nano-related products needs to be addressed at a rate commensurate with the expansion of nanotechnology. Zebrafish has been demonstrated as a correlative in vivo vertebrate model for such task, and the current advances of using zebrafish for nano EHS studies are summarized here. In addition to morphological and histopathological observations, the accessibility of gene manipulation would greatly empower such a model for detailed mechanistic studies of any nanoparticles of interest. The potential for establishing high-throughput screening platforms to facilitate the nano EHS studies is highlighted, and a discussion is presented on how toxicogenomics approaches represent a future direction to guide the identification of toxicity pathways. Zebrafish, an in vivo model, possesses great potential for facilitating nano EHS studies. With its high fecundity, embryo transparency, highly conserved cellular and metabolic activities etc., zebrafish offers higher biological relevance and complexities compared to in vitro cellular assays, while maintaining high throughput and high volume data generation capabilities. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Willis M.S.,McAllister Heart Institute | Willis M.S.,Laboratory Medicine | Townley-Tilson W.H.D.,Cell and Developmental Biology | Kang E.Y.,McAllister Heart Institute | And 4 more authors.
Circulation Research | Year: 2010

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease. © 2010 American Heart Association, Inc. Source

News Article
Site: http://phys.org/biology-news/

Epigenetics is the study of stable, or persistent, changes in gene expression that occur without changes in DNA sequence. Epigenetic regulation has been observed to affect a variety of distinct traits in animals, including body size, aging, and behavior. However, there is an enormous gap in knowledge about the epigenetic mechanisms that regulate social behavior. Ants provide ideal models to study social behavior, because each colony is comprised of thousands of individual sisters—famously, the queen and all workers are female—with nearly identical genetic makeup, much like human twins. However, these sisters possess stereotypically distinct physical traits and behaviors based on caste. In a previous study, the authors created the first genome-wide epigenetic maps in ants. This revealed that epigenetic regulation is key to distinguishing majors as the "brawny" soldiers of carpenter ant colonies, compared to minors, their smaller, "brainier" sisters. Major ants have large heads and powerful mandibles that help to defeat enemies and process and transport large food items. Minor ants are much smaller, outnumber majors two to one, and assume the important responsibility of searching for food and recruiting other ants to help with the harvest. Compared to majors, these foraging minors have genes involved in brain development and neurotransmission that are over expressed. In the new findings, an interdisciplinary research team led by senior author Shelley Berger, PhD, from the Perelman School of Medicine at the University of Pennsylvania, in collaboration with teams led by Juergen Liebig from Arizona State University and Danny Reinberg from New York University, found that caste-specific foraging behavior can be directly altered, by changing the balance of epigenetic chemicals called acetyl groups attached to histone protein complexes, around which DNA strands are wrapped in a cell nucleus. To reveal this exquisite control, the team demonstrated that foraging behavior could be reprogrammed using compounds that inhibit the addition or removal of these acetyl groups on histones (histone acetylation), in turn changing the expression of nearby genes. Berger is the Daniel S. Och University Professor in the Departments of Cell & Developmental Biology, Biology, and Genetics. She is also the director of the Penn Epigenetics Program. "The results suggest that behavioral malleability in ants, and likely other animals, may be regulated in an epigenetic manner via histone modification," said lead author Daniel F. Simola, PhD, a postdoctoral researcher in the Penn Department of Cell and Developmental Biology. Simola is co-lead author with Riley Graham, a doctoral student in the Berger lab. It's All About the Histone The almost decade-long collaboration between the Berger, Liebig, and Reinberg labs, supported by the Howard Hughes Medical Institute, blends molecular biology with observations of animal behavior to understand how caste-based differences arise in ants. Ants, as well as termites, and some bees and wasps, are eusocial (or "truly social") species. Previous work suggested that histone acetylation could create dramatic differences in gene expression between genetically identical individuals, contributing to the physical differences in body size and reproductive ability between ant castes. The current study expands on this narrative by showing that caste behaviors are also regulated by epigenetic changes in histone acetylation. To do so, the team used the fact that chromatin structure—the coiling of the DNA around histone proteins—can be altered by the addition of acetyl groups, which ultimately changes the compaction of the genome. Modifications like histone acetylation allow DNA to uncoil, whereas others cause DNA to become tightly compact and inaccessible to the proteins that regulate gene expression. Knowing that histone modifications are used to establish specific features of different tissues within an individual led the team to ask whether histone modifications might also be used to create differences in traits like social behavior between individuals, notably the brawny majors and the brainy minors. In the Science paper, the team fed foraging minors a chemical inhibitor that prevents cells from removing acetyl groups from histones. This treatment enhanced foraging and scouting for food, and correspondingly, led to increased histone acetylation near genes involved in neuronal activity. Conversely, inhibiting the addition of acetyl groups led to decreased foraging activity. In contrast to the dramatic boost in foraging seen in minors, feeding mature major workers these inhibitors caused little to no increase in foraging. However, the team found that directly injecting these epigenetic inhibitors into the brains of very young majors immediately increased foraging, reaching levels normally only observed in minors. Additionally, a single treatment with these inhibitors was sufficient to induce and sustain minor-like foraging in the majors for up to 50 days. These results suggest that there is an "epigenetic window of vulnerability" in young ant brains, which confers increased susceptibility to environmental manipulations, such as with histone-modifying inhibitors. Berger observes that all of the genes known to be major epigenetic regulators in mammals are also present in ants, which makes ants "a fantastic model for studying principles of epigenetic modulation of behavior and even longevity, because queens have a much longer lifespan compared to the major and minor workers. Because of the remarkable window we have uncovered, ants also provide an extraordinary opportunity to explore and understand the epigenetic processes that come into play to establish behavioral patterns at a young age. This is a topic of increasing research interest in humans, owing to the growing prevalence of behavioral disorders and diseases and the appreciation that diet may influence behavior." One important gene implicated in the ant study is CBP, which is an epigenetic "writer" enzyme that alters chromatin by adding acetyl groups to histones. CBP had already been implicated as a critical enzyme facilitating learning and memory in mice and is mutated in certain human cognitive disorders, notably Rubinstein-Taybi syndrome. Hence, the team's findings suggest that CBP-mediated histone acetylation may also facilitate complex social interactions found in vertebrate species. The authors suspect that CBP's role as an epigenetic writer enzyme contributes to patterns of histone acetylation that enhance memory pathways related to learned behaviors such as foraging. Differences in CBP activity between minor and major castes may guide unique patterns of gene expression that fine tune neuronal functions for each caste. "From mammalian studies, it's clear this is an important protein involved in learning and memory," Berger noted. "The finding that CBP plays a key role in establishing distinct social behaviors in ants strongly suggests that the discoveries made in ants may have broad implications for understanding social organization." The Berger team is now focused on precisely defining the "epigenetic window of vulnerability" and its key molecular features. She explains that "understanding the mechanisms of when and how this window is opened and how changes are sustained—and why the window closes as the major ant ages—may have profound implications for explaining human vulnerability to early life exposures." Explore further: The first ant methylomes uncover the relationship between DNA methylation and caste differentiation More information: "Epigenetic (re)programming of caste-specific behavior in the ant Camponotus floridanus," DOI: 10.1126/science.aac6633

News Article
Site: http://phys.org/biology-news/

Programmed cell death – also known as apoptosis – is universal among higher organisms, and is a tightly regulated process that results in the disposal of damaged or unwanted cells. The latter variant is particularly important in the course of embryonic development, during which many more cells are produced than are ultimately required. Now researchers led by Barbara Conradt, Professor of Cell and Developmental Biology at LMU, have uncovered one mechanism that induces apoptosis in the nematode Caenorhabditis elegans (C. elegans). In this case, the mother cell actively determines the fate of the daughter destined to die. The new findings appear in the journal Nature Communications. During the embryonic development of C. elegans, precisely 1090 cells are generated by cell division, of which 131 undergo programmed cell death. Since the entire schedule of cell division and cell death is known for this organism, it has become a favorite system for the investigation of apoptosis. – And because essentially the same process is observed in all higher organisms, the insights gained from C. elegans can be applied to other animals, including humans. Apoptosis involves a precisely defined series of steps. The first step determines which cells are to be eliminated, and the second carries out the sentence by forcing the cells to commit suicide. "When a cell is dying, it goes through a characteristic series of morphological alterations and, in the end, it is engulfed and digested by neighboring cells," Conradt explains. "It has been known for the past 15 years or so that the cellular pathways that initiate and mediate engulfment are involved not only in the disposal of the dead cell, but also play a role in the actual killing. We have now discovered how they do this." The researchers focused on a particular cell lineage in the C. elegans embryo, the so-called NSM lineage. The NSM mother cell divides asymmetrically, giving rise to two daughter cells of unequal size, of which the smaller one survives for only a very short time. "Up until now, it was believed that the apoptotic machinery is activated only in the smaller daughter cell after the division of the mother cell," says Conradt. "But we found that it is already activated – at least to a certain degree - in the mother cell. Moreover, in this pre-activated state, the apoptotic machinery produces a signal that activates the engulfment pathways in specific neighboring cells. And these adjacent cells then help the mother cell to polarize and to concentrate the cell-death protein CED-3 (a proteolytic enzyme of the caspase family) in the portion of the cytoplasm destined for the smaller of the two daughter cells. Thus, the mother cell determines the cell death fate of the smaller daughter by asymmetric segregation of CED-3." CED-3 is known to function as a killer factor, which activates the apoptotic program. "So, prior to cell division, the mother cell is already actively engaged in "assisting" the smaller daughter cell to kill itself, by supplying it with an overdose of cell-death-promoting factors," says Conradt. She and her colleagues now plan to analyze this process further and to ask whether it also takes place in mammalian tissues or stem cells. "Unequal segregation of resources may be especially important in stem cells, which also divide asymmetrically , as factors that may be deleterious to the surviving cell can be disposed of by loading them into the daughter cell that is fated to die," Conradt explains. Apoptosis also plays a crucial role in health maintenance, as errors in the process can be deleterious for the whole organism, irrespective of whether they lead to the death of essential cells or the survival of cells that would otherwise have been eliminated. Indeed, many disorders have been linked to errors in the control of apoptosis, such as cancer, neurodegenerative disorders and autoimmune diseases. Thus a better understanding of the mechanisms underlying apoptosis could in the future help to identify targets for the development of new therapeutics. More information: Sayantan Chakraborty et al. Engulfment pathways promote programmed cell death by enhancing the unequal segregation of apoptotic potential, Nature Communications (2015). DOI: 10.1038/ncomms10126

Angus A.A.,Cell and Developmental Biology | Hirsch A.M.,Cell and Developmental Biology | Hirsch A.M.,University of California at Los Angeles
Molecular Ecology | Year: 2010

The interaction between legumes and rhizobia has been well studied in the context of a mutualistic, nitrogen-fixing symbiosis. The fitness of legumes, including important agricultural crops, is enhanced by the plants' ability to develop symbiotic associations with certain soil bacteria that fix atmospheric nitrogen into a utilizable form, namely, ammonia, via a chemical reaction that only bacteria and archaea can perform. Of the bacteria, members of the alpha subclass of the protebacteria are the best-known nitrogen-fixing symbionts of legumes. Recently, members of the beta subclass of the proteobacteria that induce nitrogen-fixing nodules on legume roots in a species-specific manner have been identified. In this issue, Bontemps et al. reveal that not only are these newly identified rhizobia novel in shifting the paradigm of our understanding of legume symbiosis, but also, based on symbiotic gene phylogenies, have a history that is both ancient and stable. Expanding our understanding of novel plant growth promoting rhizobia will be a valuable resource for incorporating alternative strategies of nitrogen fixation for enhancing plant growth. © 2010 Blackwell Publishing Ltd. Source

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