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News Article | May 17, 2017
Site: www.eurekalert.org

Chemists, materials scientists and nanoengineers at UC San Diego have created what may be the ultimate natural sunscreen. In a paper published in the American Chemical Society journal ACS Central Science, they report the development of nanoparticles that mimic the behavior of natural melanosomes, melanin-producing cell structures that protect our skin, eyes and other tissues from the harmful effects of ultraviolet radiation. "Basically, we succeeded in making a synthetic version of the nanoparticles that our skin uses to produce and store melanin and demonstrated in experiments in skin cells that they mimic the behavior of natural melanosomes," said Nathan Gianneschi, a professor of chemistry and biochemistry, materials science and engineering and nanoengineering at UC San Diego, who headed the team of researchers. The achievement has practical applications. "Defects in melanin production in humans can cause diseases such as vitiligo and albinism that lack effective treatments," Gianneschi added. Vitiligo develops when the immune system wrongly attempts to clear normal melanocytes from the skin, effectively stopping the production of melanocytes. Albinism is due to genetic defects that lead to either the absence or a chemical defect in tyrosinase, a copper-containing enzyme involved in the production of melanin. Both of these diseases lack effective treatments and result in a significant risk of skin cancer for patients. "The widespread prevalence of these melanin-related diseases and an increasing interest in the performance of various polymeric materials related to melanin prompted us to look for novel synthetic routes for preparing melanin-like materials," Gianneschi said. Melanin particles are produced naturally in many different sizes and shapes by animals--for iridescent feathers in birds or the pigmented eyes and skin of some reptiles. But scientists have discovered that extracting melanins from natural sources is a difficult and potentially more complex process than producing them synthetically. Gianneschi and his team discovered two years ago that synthetic melanin-like nanoparticles could be developed in a precisely controllable manner to mimic the performance of natural melanins used in bird feathers. "We hypothesized that synthetic melanin-like nanoparticles would mimic naturally occurring melanosomes and be taken up by keratinocytes, the predominant cell type found in the epidermis, the outer layer of skin," said Gianneschi. In healthy humans, melanin is delivered to keratinocytes in the skin after being excreted as melanosomes from melanocytes. The UC San Diego scientists prepared melanin-like nanoparticles through the spontaneous oxidation of dopamine--developing biocompatible, synthetic analogues of naturally occurring melanosomes. Then they studied their update, transport, distribution and ultraviolet radiation-protective capabilities in human keratinocytes in tissue culture. The researchers found that these synthetic nanoparticles were not only taken up and distributed normally, like natural melanosomes, within the keratinocytes, they protected the skin cells from DNA damage due to ultraviolet radiation. "Considering limitations in the treatment of melanin-defective related diseases and the biocompatibility of these synthetic melanin-like nanoparticles in terms of uptake and degradation, these systems have potential as artificial melanosomes for the development of novel therapies, possibly supplementing the biological functions of natural melanins," the researchers said in their paper. The other co-authors of the study were Yuran Huang and Ziying Hu of UC San Diego's Materials Science and Engineering Program, Yiwen Li and Maria Proetto of the Department of Chemistry and Biochemistry; Xiujun Yue of the Department of Nanoengineering; and Ying Jones of the Electron Microscopy Core Facility. The UC San Diego Office of Innovation and Commercialization has filed a patent application on the use of polydopamine-based artificial melanins as an intracellular UV-shield. Companies interested in commercializing this invention should contact Skip Cynar at invent@ucsd.edu The study was supported by a grant from the Air Force Office of Scientific Research (FA9550-11-1-0105).


PubMed | Biosciences and Biotechnology Institute of Grenoble BIG, Bip Institute Of Microbiologie Of La Mediterranee, Microscopy core facility, French National Institute for Agricultural Research and IBPC
Type: | Journal: The Journal of biological chemistry | Year: 2016

Aldehyde/alcohol dehydrogenases (ADHEs) are bifunctional enzymes that commonly produce ethanol from acetyl-CoA with acetaldehyde as intermediate, and play a key role in anaerobic redox balance in many fermenting bacteria. ADHEs are also present in photosynthetic unicellular eukaryotes, where their physiological role and regulation are however largely unknown. Herein we provide the first molecular and enzymatic characterization of the ADHE from the photosynthetic microalga Chlamydomonas reinhardtii. Purified recombinant ADHE catalyzed the reversible NADH-mediated interconversions of acetyl-CoA, acetaldehyde and ethanol, but seemed to be poised towards the production of ethanol from acetaldehyde. Phylogenetic analysis of the algal fermentative enzyme supports a vertical inheritance from a cyanobacterial-related ancestor. ADHE was located in the chloroplast where it associated in dimers and higher order oligomers. Electron microscopy analysis of ADHE-enriched stromal fractions revealed fine spiral structures, similar to bacterial ADHE spirosomes. Protein blots showed that ADHE is regulated under oxic conditions. Upregulation is observed in cells exposed to diverse physiological stresses, including zinc deficiency, nitrogen starvation, and inhibition of carbon concentration/fixation capacity. Analyses of the overall proteome and fermentation profiles revealed that cells with increased ADHE abundance exhibit better survival under dark anoxia. This likely relates to the fact that greater ADHE abundance appeared to coincide with enhanced starch accumulation, which might reflect ADHE-mediated anticipation of anaerobic survival.


News Article | November 21, 2016
Site: www.eurekalert.org

Type-1 diabetes occurs when immune cells attack the pancreas. EPFL scientists have now discovered what may trigger this attack, opening new directions for treatments. Type-1 diabetes is the rarest but most aggressive form of diabetes, usually affecting children and adolescents. The patient's own immune cells begin to attack the cells in the pancreas that make insulin, eventually eliminating its production in the body. The immune cells target certain proteins inside the insulin-producing cells. However, it is unclear how this actually happens. EPFL scientists have now discovered that the immune attack in type-1 diabetes may be triggered by the release of proteins from the pancreas itself, as well as the package they come in. The work, which has significant implications for therapy strategies, is published in Diabetes. Diabetes is a disease in which the body produces inadequate or no amounts of the hormone insulin, which regulates sugar levels in the blood. Insulin is produced by a group of cells in the pancreas called beta cells. In type-1 diabetes, the patient's immune cells specifically attack beta cells, thereby disrupting the production of insulin. However, we don't actually know what causes the immune cells to attack in the first place. Scientists from EPFL's Institute of Bioengineering, led by Steinunn Baekkeskov, have now discovered that pancreatic beta cells actually secrete proteins that are targeted by the immune attack. But it's not only the proteins that cause problems; the researchers found that it is also their packaging. That packaging comes in the form of small vesicles called exosomes, which are secreted by all cell types to distribute various molecules with different functions. But previous studies have shown that exosomes can also activate the immune system. Building on this, the EPFL researchers looked at exosomes from human and animal pancreatic beta cells. The results showed that rat and human pancreatic beta cells release three proteins known to be associated with type-1 diabetes, and are in fact used by clinicians to diagnose its onset in people. The researchers might have also discovered why the immune attack on the pancreas begins in the first place: When insulin-making beta cells were exposed to stress, they released high amounts of exosomes, which they also "decorated" with proteins that activate immune cells. These powerfully inflammatory proteins may be involved in induction of autoimmunity in the disease. The hope is that this will lead to new directions in developing more effective treatments that focus on developing exosome mimics that contain molecules inhibiting rather than stimulating immune cells. These synthetic molecules would be taken up by the patient's immune cells and would block them from attacking beta cells. This work was carried out at the EPFL's Institute of Bioengineering (IBI), by lead authors Chiara Cianciaruso and Edward A. Phelps, with contributions from EPFL's Proteomics Core Facility, Bio-Electron Microscopy Core Facility, Bio-Imaging Core Facility, the Swiss Institute for Experimental Cancer Research. It involves a collaboration with the European Consortium on Islet Transplantation (ECIT) Islets for Basic Research Program at the University Hospital of Geneva and at the San Raffaele Scientific Institute of Milan. It was funded by JDRF and EPFL. Chiara Cianciaruso, Edward A. Phelps, Miriella Pasquier, Romain Hamelin, Davide Demurtas, Mohamed Alibashe Ahmed, Lorenzo Piemonti, Sachiko Hirosue, Melody A. Swartz, Michele De Palma, Jeffrey A. Hubbell, Steinunn Baekkeskov. Primary human and rat beta cells release the intracellular autoantigens GAD65, IA-2 and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 21 November 2016. DOI: 10.2337/db16-0671


News Article | February 15, 2017
Site: www.eurekalert.org

LOGAN, UTAH, USA - Unlocking the geologic past of Utah's mighty Wasatch Fault and its earthquake history, requires a zoomed-in, nanoscale pursuit clues left over millions of years, says Utah State University geologist Alexis Ault. And what better detectives to assist her in the task than energetic youngsters, whose curiosity fuels Ault's enthusiasm. "I'm so excited about the research, but I also have a passion and fire to explore this work with middle school students," says the assistant professor in USU's Department of Geology. "We have a lot of science before us and this is a very real and challenging opportunity." Ault is a 2017 recipient of a prestigious Faculty Early Career Development 'CAREER' Award from the National Science Foundation. The NSF's highly competitive grant program for junior faculty, CAREER awards recognize demonstrated excellence in research, teaching and the integration of education and research. Ault's award provides a five-year grant of $631,000. "When an earthquake occurs, the primary byproduct is heat," says Ault, who joined USU's faculty in 2014. "Each event imparts a distinct textural and thermochronologic signature on the fault rocks." The Wasatch Fault provides an accessible natural laboratory for Utah's residents, including students at Perry, Utah's Promontory School for Expeditionary Learning. Ault began working with teachers and students from the public charter school about a year ago. "Middle school is a time when students form their 'STEM identity,'" she says. "It's important they have role models, who can instill a passion for science that will grow. Providing field and lab broadens their horizons by helping them understand how science works and the role of technology in our everyday lives." Technological developments students will experience first-hand are USU's scanning electron microscope in the university's Microscopy Core Facility and the USTAR Nanofab Facility at the University of Utah. "This CAREER research provides a new window into processes that cause earthquakes in the Wasatch Fault down to the nano-scale," Ault says. "These middle schoolers will be participating in cutting-edge research relevant to their daily lives." To pursue this project, she's assembled a team of interdisciplinary experts, including researchers from the U.S. Geological Survey and multiple universities across the country. Graduate student Rob McDermott, a USU Presidential Doctoral Research Fellow, provided pilot data for the project. David Feldon and Colby Tofel-Grehl, faculty members in USU's Emma Eccles Jones College of Education and Human Services, will assist in instructional and learning assessment efforts. Rock mechanics experts from Brown University and the University of Pennsylvania will guide students in rock deformation experiments and earthquake simulations in the lab. Collaborations will also continue with the Arizona Radiogenic Helium Dating Laboratory at the University of Arizona. "None of this happens in a vacuum," Ault says. "We're pushing the intellectual and educational boundaries for these young students, as well as ourselves, and that's what our mission as scientists and citizens is all about."


Remijsen Q.,Catholic University of Leuven | Remijsen Q.,Molecular Signaling and Cell Death Unit | Remijsen Q.,Ghent University | Berghe T.V.,Molecular Signaling and Cell Death Unit | And 12 more authors.
Cell Research | Year: 2011

Neutrophil extracellular traps (NETs) are extracellular chromatin structures that can trap and degrade microbes. They arise from neutrophils that have activated a cell death program called NET cell death, or NETosis. Activation of NETosis has been shown to involve NADPH oxidase activity, disintegration of the nuclear envelope and most granule membranes, decondensation of nuclear chromatin and formation of NETs. We report that in phorbol myristate acetate (PMA)-stimulated neutrophils, intracellular chromatin decondensation and NET formation follow autophagy and superoxide production, both of which are required to mediate PMA-induced NETosis and occur independently of each other. Neutrophils from patients with chronic granulomatous disease, which lack NADPH oxidase activity, still exhibit PMA-induced autophagy. Conversely, PMA-induced NADPH oxidase activity is not affected by pharmacological inhibition of autophagy. Interestingly, inhibition of either autophagy or NADPH oxidase prevents intracellular chromatin decondensation, which is essential for NETosis and NET formation, and results in cell death characterized by hallmarks of apoptosis. These results indicate that apoptosis might function as a backup program for NETosis when autophagy or NADPH oxidase activity is prevented. © 2011 IBCB, SIBS, CAS All rights reserved.


Guerfal M.,Unit for Medical Biotechnology | Guerfal M.,Ghent University | Claes K.,Unit for Medical Biotechnology | Claes K.,Ghent University | And 6 more authors.
Microbial Cell Factories | Year: 2013

Background: Membrane protein research is frequently hampered by the low natural abundance of these proteins in cells and typically relies on recombinant gene expression. Different expression systems, like mammalian cells, insect cells, bacteria and yeast are being used, but very few research efforts have been directed towards specific host cell customization for enhanced expression of membrane proteins. Here we show that by increasing the intracellular membrane production by interfering with a key enzymatic step of lipid synthesis, enhanced expression of membrane proteins in yeast is achieved. Results: We engineered the oleotrophic yeast, Yarrowia lipolytica, by deleting the phosphatidic acid phosphatase, PAH1, which led to massive proliferation of endoplasmic reticulum (ER) membranes. For all eight tested representatives of different integral membrane protein families, we obtained enhanced protein accumulation levels and in some cases enhanced proteolytic integrity in the {increment}pah1 strain. We analysed the adenosine A2AR G-protein coupled receptor case in more detail and found that concomitant induction of the unfolded protein response in the {increment}pah1 strain enhanced the specific ligand binding activity of the receptor. These data indicate an improved quality control mechanism for membrane proteins accumulating in yeast cells with proliferated ER. Conclusions: We conclude that redirecting the metabolic flux of fatty acids away from triacylglycerol- and sterylester-storage towards membrane phospholipid synthesis by PAH1 gene inactivation, provides a valuable approach to enhance eukaryotic membrane protein production. Complementary to this improvement in membrane protein quantity, UPR co-induction further enhances the quality of the membrane protein in terms of its proper folding and biological activity. Importantly, since these pathways are conserved in all eukaryotes, it will be of interest to investigate similar engineering approaches in other cell types of biotechnological interest, such as insect cells and mammalian cells. © 2013 Guerfal et al.; licensee BioMed Central Ltd.


Kozjak-Pavlovic V.,Max Planck Institute for Infection Biology | Kozjak-Pavlovic V.,University of Würzburg | Ross K.,Max Planck Institute for Infection Biology | Gotz M.,University of Würzburg | And 3 more authors.
Journal of Molecular Biology | Year: 2010

β-Barrel proteins are found in the outer membranes of bacteria, chloroplasts and mitochondria. The evolutionary conserved sorting and assembly machinery (SAM complex) assembles mitochondrial β-barrel proteins, such as voltage-dependent anion-selective channel 1 (VDAC1), into complexes in the outer membrane by recognizing a sorting β-signal in the carboxy-terminal part of the protein. Here we show that in mammalian mitochondria, masking of the C-terminus of β-barrel proteins by a tag leads to accumulation of soluble misassembled protein in the intermembrane space, which causes mitochondrial fragmentation and loss of membrane potential. A similar phenotype is observed if the β-signal is shortened, removed or when the conserved hydrophobic residues in the β-signal are mutated. The length of the tag at the C-terminus is critical for the assembly of VDAC1, as well as the amino acid residues at positions 130, 222, 225 and 251 of the protein. We propose that if the recognition of the β-signal or the folding of the β-barrel proteins is inhibited, the nonassembled protein will accumulate in the intermembrane space, aggregate and damage mitochondria. This effect offers easy tools for studying the requirements for the membrane assembly of β-barrel proteins, but also advises caution when interpreting the outcome of the β-barrel protein overexpression experiments. © 2010 Elsevier Ltd. All rights reserved.

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