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  • 09 June

    GT/ Cells reprogrammed to make synthetic polymers

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Wed, Jun 9, 2021 1:38 PM by Paradigm Fund

GT/ Cells reprogrammed to make synthetic polymers

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Genetics biweekly vol.4, 26th May — 9th JuneTL;DRScientists have developed the first cells that can construct artificial polymers from building blocks that are not found in nature, by following instructions the researchers encoded in their genes. The study also found the synthetic genome made the bacteria entirely resistant to infection by viruses.Researchers report how high-speed atomic force microscopy can be used for studying DNA wrapping processes. The technique enables visualizing the dynamics of DNA-protein interactions, which in certain cases resembles the motion of inchworms.The organization of the human genome relies on physics of different states of matter — such as liquid and solid. The new findings reveal how the physical nature of the genome changes as cells transform to serve specific functions and point to new ways to potentially better understand disease and to create improved therapies for cancer and genetic disorders.Scientists replicate the molecular properties of the natural cement used by barnacles and mussels to create a powerful adhesive using silk protein. The new adhesive can work well in both dry and underwater conditions.Researchers have shown that harmful mutations present in the DNA play an important — yet neglected — role in the conservation and translocation programs of threatened species.Scientists have detected Zika virus RNA in free-ranging African bats. RNA, or ribonucleic acid, is a molecule that plays a central role in the function of genes.Clues about molecular changes underlying muscle loss tied to aging. Scientists increased the regeneration of muscle cells in mice by activating the precursors of muscle cells.Researchers have identified a chloride channel involved in cell volume recovery under osmotic stress, and discover how cells can survive in high salt concentrations.The immune system’s attempt to eliminate Salmonella bacteria from the gastrointestinal tract instead facilitates colonization of the intestinal tract and fecal shedding, according to scientists.To describe something as slow and boring we might say it’s ‘like watching grass grow’, but scientists studying the early morning activity of plants have found they make a rapid start to their day — within minutes of dawn.And more!OverviewGenetic technology is defined as the term which includes a range of activities concerned with the understanding of gene expression, advantages of natural genetic variation, modifying genes and transferring genes to new hosts. Genes are found in all living organisms and are transferred from one generation to the next. Gene technology encompasses several techniques including marker-assisted breeding, RNAi and genetic modification. Only some gene technologies produce genetically modified organisms.Modern genetic technologies like genome editing would not be possible without all the previous generations of genetic technologies that have enabled scientists to discover what genes are, what they do and how DNA can be modified to add, remove or replace genes. You can find major genetic technologies development milestones via the link.Gene Technology MarketAccording to Global Genetic Engineering Market Research Report: Product (Biochemical, Genetic Markers), Devices (PCR, Gene Gun, Gel Assemblies), Techniques (Artificial Selection, Gene Splicing), Application (Agriculture, Medical Industry), End-User — Forecast to 2027:The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).North America holds the largest share in the global genetic engineering market, followed by Europe and the Asia Pacific, respectively.Another research provider, MarketsandMarkets, forecasts the genome editing, genome engineering market to grow from USD 3.19 billion in 2017 to USD 6.28 billion by 2022, at a compounded annual growth rate (CAGR) of 14.5% during the forecast period. The key factors propelling market growth are rising government funding and growth in the number of genomics projects, high prevalence of infectious diseases (like COVID-19) and cancer, technological advancements, increasing production of genetically modified (GM) crops, and growing application areas of genomics.Latest News & ResearchesSense codon reassignment enables viral resistance and encoded polymer synthesisby Wesley E. Robertson, Louise F. H. Funke, Daniel de la Torre, Julius Fredens, Thomas S. Elliott, Martin Spinck, Yonka Christova, Daniele Cervettini, Franz L. Böge, Kim C. Liu, Salvador Buse, Sarah Maslen, George P. C. Salmond, Jason W. Chin in ScienceScientists have developed the first cells that can construct artificial polymers from building blocks that are not found in nature, by following instructions the researchers encoded in their genes.The study, led by scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology, in Cambridge, UK, also found the synthetic genome made the bacteria entirely resistant to infection by viruses.The scientists say their research could lead to the development of new polymers — large molecules made of many repeating units, such as proteins, plastics, and many drugs including antibiotics — and make it easier to manufacture drugs reliably using bacteria.The research builds on previous ground-breaking work by the team when, in 2019, they developed new techniques to create the biggest ever synthetic genome — constructing the entire genome of the bacterium Escherichia coli (E.coli) from scratch.The scientists’ goal was to utilise their new technology to create the first cell that can assemble polymers entirely from building blocks that are not found in nature.Proteins are a type of polymer, so the scientists aimed to make artificial polymers by exploiting cells’ natural protein-making processes. The genetic code instructs a cell how to make proteins, which are constructed by joining together strings of natural building blocks, called amino acids. The genetic code in DNA is made up of four bases, represented by the letters: A, T, C and G. The four letters in DNA are ‘read’ in groups of three letters — for example ‘TCG’ — which are called a ‘codon’. Each codon tells the cell to add a specific amino acid to the chain — it does this via molecules called ‘tRNA’. Each codon has a specific tRNA that recognises it and adds the corresponding amino acid, for example: the tRNA that recognises the codon ‘TCG’, brings the amino acid serine. With four letters in groups of three, there are 64 possible combinations of letters; however, there are only 20 different natural amino acids that cells commonly use. So, several different codons can be synonymous — they all code for the same amino acid — for example: TCG, TCA, AGC and AGT all code for serine. There are also codons which tell a cell when to stop making a protein, such as TAG and TAA.When, in 2019, the team at the MRC Laboratory of Molecular Biology created the first entire genome synthesised from scratch for the commonly studied bacteria, E. coli, they also took the opportunity to simplify its genome. They replaced some of the codons with their synonyms: they removed every instance of TCG and TCA and replaced them with the synonyms AGC and AGT. They also removed every instance of the ‘stop’ codon TAG and replaced it with its synonym TAA. The modified bacteria no longer had the codons TCG, TCA and TAG in their genome, but they could still make normal proteins and live and grow.Now, in their latest research, the scientists have further modified the bacteria to remove the tRNA molecules that recognise the codons TCG and TCA. This means that — even if there are TCG or TCA codons in the genetic code — the cell no longer has the molecule that can read those codons.This is fatal for any virus that tries to infect the cell, because viruses replicate by injecting their genome into a cell and hijacking the cell’s machinery. Virus genomes still contain lots of the TCG, TCA and TAG codons, but the modified bacteria are missing the tRNAs to read these codons.When the machinery in the modified bacteria tries to read the virus genome, it fails every time it reaches a TCG, TCA or TAG codon.In this study, the researchers infected their bacteria with a cocktail of viruses. Unmodified normal bacteria were killed by the viruses, but the modified bacteria were resistant to infection and survived.Making bacteria resistant to viruses could make manufacturing certain types of drugs more reliable and cheaper. Many drugs — for example, protein drugs, such as insulin, and polysaccharide and protein subunit vaccines — are manufactured by growing bacteria which contain instructions to produce the drug.Professor Jason Chin, from the MRC Laboratory of Molecular Biology, who led the study, said: “If a virus gets into the vats of bacteria used to manufacture certain drugs then it can destroy the whole batch. Our modified bacterial cells could overcome this problem by being completely resistant to viruses. Because viruses use the full genetic code, the modified bacteria won’t be able to read the viral genes.”By creating bacteria with synthetic genomes that do not use certain codons, the researchers had freed up those codons to be available to be used for other purposes, such as coding for synthetic building blocks, called monomers.Professor Chin said: “This system allows us to write a gene that encodes the instructions to make polymers out of monomers that don’t occur in nature.“These bacteria may be turned into renewable and programmable factories that produce a wide range of new molecules with novel properties, which could have benefits for biotechnology and medicine, including making new drugs, such as new antibiotics.”“We’d like to use these bacteria to discover and build long synthetic polymers that fold up into structures and may form new classes of materials and medicines. We will also investigate applications of this technology to develop novel polymers, such as biodegradable plastics, which could contribute to a circular bioeconomy.”They engineered the bacteria to produce tRNAs coupled with artificial monomers, which recognised the newly available codons (TCG and TAG).They inserted genetic sequences with strings of TCG and TAG codons into the bacteria’s DNA. These were read by the altered tRNAs, which assembled chains of synthetic monomers in the sequence defined by the sequence of codons in the DNA.The cells were programmed to string together monomers in different orders by changing the order of TCG and TAG codons in the genetic sequence.Polymers composed of different monomers were also made by changing which monomers were coupled to the tRNAs.The researchers were able to create polymers made of up to eight monomers strung together. They joined the ends of these polymers together to make macrocycles — a type of molecule that form the basis of some drugs, such as certain antibiotics and cancer drugs.In the study, the synthetic monomers were linked together by the same chemical bonds that join together amino acids in proteins, but the researchers are investigating how to expand the range of linkages that can be used in the new polymers.Dr Megan Dowie, head of molecular and cellular medicine at the Medical Research Council, which funded the study, said: “Dr Chin’s pioneering work into genetic code expansion is a really exciting example of the value of the MRC’s long-term commitment to discovery science. Research like this, in synthetic and engineering biology, has huge potential for major impact in biopharma and other industrial settings.”In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell nicheby Chao Wang, Ruben Rabadan Ros, Paloma Martinez-Redondo, Zaijun Ma, Lei Shi, Yuan Xue, Isabel Guillen-Guillen, Ling Huang, Tomoaki Hishida, Hsin-Kai Liao, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Pedro Guillen-Garcia, Pradeep Reddy, Juan Carlos Izpisua Belmonte in Nature CommunicationsOne of the many effects of aging is loss of muscle mass, which contributes to disability in older people. To counter this loss, scientists at the Salk Institute are studying ways to accelerate the regeneration of muscle tissue, using a combination of molecular compounds that are commonly used in stem-cell research.The investigators showed that using these compounds increased the regeneration of muscle cells in mice by activating the precursors of muscle cells, called myogenic progenitors. Although more work is needed before this approach can be applied in humans, the research provides insight into the underlying mechanisms related to muscle regeneration and growth and could one day help athletes as well as aging adults regenerate tissue more effectively.“Loss of these progenitors has been connected to age-related muscle degeneration,” says Salk Professor Juan Carlos Izpisua Belmonte, the paper’s senior author. “Our study uncovers specific factors that are able to accelerate muscle regeneration, as well as revealing the mechanism by which this occurred.”RNA-seq analysis of slow-twitch and fast-twitch muscles with myofiber-specific OSKM inductionThe compounds used in the study are often called Yamanaka factors after the Japanese scientist who discovered them. Yamanaka factors are a combination of proteins (called transcription factors) that control how DNA is copied for translation into other proteins. In lab research, they are used to convert specialized cells, like skin cells, into more stem-cell-like cells that are pluripotent, which means they have the ability to become many different types of cells.“Our laboratory previously showed that these factors can rejuvenate cells and promote tissue regeneration in live animals,” says first author Chao Wang, a postdoctoral fellow in the Izpisua Belmonte lab. “But how this happens was not previously known.”Muscle regeneration is mediated by muscle stem cells, also called satellite cells. Satellite cells are located in a niche between a layer of connective tissue (basal lamina) and muscle fibers (myofibers). In this study, the team used two different mouse models to pinpoint the muscle stem-cell-specific or niche-specific changes following addition of Yamanaka factors. They focused on younger mice to study the effects of the factors independent of age.In the myofiber-specific model, they found that adding the Yamanaka factors accelerated muscle regeneration in mice by reducing the levels of a protein called Wnt4 in the niche, which in turn activated the satellite cells. By contrast, in the satellite-cell-specific model, Yamanaka factors did not activate satellite cells and did not improve muscle regeneration, suggesting that Wnt4 plays a vital role in muscle regeneration.According to Izpisua Belmonte, who holds the Roger Guillemin Chair, the observations from this study could eventually lead to new treatments by targeting Wnt4.CasRx-mediated cyclic Wnt4 knockdown accelerates muscle regeneration.“Our laboratory has recently developed novel gene-editing technologies that could be used to accelerate muscle recovery after injury and improve muscle function,” he says. “We could potentially use this technology to either directly reduce Wnt4 levels in skeletal muscle or to block the communication between Wnt4 and muscle stem cells.”The investigators are also studying other ways to rejuvenate cells, including using mRNA and genetic engineering. These techniques could eventually lead to new approaches to boost tissue and organ regeneration.High-Speed Atomic Force Microscopy Reveals Spatiotemporal Dynamics of Histone Protein H2A Involution by DNA Inchwormingby Goro Nishide, Keesiang Lim, Mahmoud Shaaban Mohamed, Akiko Kobayashi, Masaharu Hazawa, Takahiro Watanabe-Nakayama, Noriyuki Kodera, Toshio Ando, Richard W. Wong in The Journal of Physical Chemistry LettersThe genetic material of most organisms is carried by DNA, a complex organic molecule. DNA is very long — for humans, the molecule is estimated to be about 2 m in length. In cells, DNA occurs in a densely packed form, with strands of the molecule coiled up in a complicated but efficient space-filling way. A key role in DNA’s compactification is played by histones, structural-support proteins around which a part of a DNA molecule can wrap. The DNA-histone wrapping process is reversible — the two molecules can unwrap and rewrap — but little is known about the mechanisms at play. Now, by applying high-speed atomic-force microscopy (HS-AFM), Richard Wong and colleagues from Kanazawa University (NanoLSI WPI) provide valuable insights into the spatiotemporal dynamics of DNA-histone interactions.Nanotopology of plasmid dsDNA, long-linearized dsDNA and short-linearized dsDNA in neutral physiological buffer captured using HS-AFM.The researchers looked at the interaction between DNA and a histone called H2A, one of the five main histones. To check the applicability of HS-AFM as a viable tool for imaging the DNA-histone interaction, they first focused on H2A in its native state. Wong and colleagues were able to image the topology of the molecule, and how it changes over time. Importantly, they showed that the HS-AFM process, during which a tapping force is constantly exerted on the molecule, does not lead to conformational changes or actual damage.For real-time observation of the DNA-H2A interaction with HS-AFM, the scientists prepared DNA samples with different lengths and forms: plasmid (long and circular), long-linearized and short-linearized DNA, with the latter having the highest motility. The experiments showed that the choice of substrate on which to put the DNA for AFM imaging is crucial; a particular type of lipid layer was found to be good as it does not strongly absorb DNA strands.The observations of the interaction of H2A with short-linearized DNA, which the researchers nicknamed ‘inchworm DNA’, led to the most notable results. Specifically, four different interaction situations could be distinguished: touching, sliding, sandwiching and wrapping, with the associated motions indeed resembling the movements of inchworms.Wong and colleagues also investigated the effect of ionic strength on the DNA-histone binding affinity, by changing the salt concentration of the liquid containing the DNA-histone aggregate. When increasing the liquid’s salinity, the aggregate was found to dissolve. When diluting the liquid again — and so reducing the salt content — the aggregate reformed. This result shows that varying the ionic strength (i.e., the salt concentration) of the environment of the DNA-H2A complex provides a way to mimic the variations in the strength of DNA-histone interactions as they happen in living organisms.The report of Wong and colleagues represents the first real-time observation of DNA-histone interactions, and convincingly shows the applicability of HS-AFM for studying this kind of biological process, also in the context of diseases. Quoting the researchers: “[Our work] demonstrates … the potential to study protein aggregation and protein-nucleic acid aggregate formation in various human diseases.”Direct real-time visualization of histone H2A-DNA complex aggregation, dissolution, and re-aggregation using HS-AFMBackground: Atomic force microscopy (AFM) is an imaging technique in which the image is formed by scanning a surface with a very small tip. Horizontal scanning motion of the tip is controlled by piezoelectric elements, while vertical motion is converted into a height profile, resulting in a height distribution of the sample’s surface. As the technique does not involve lenses, its resolution is not restricted by the so-called diffraction limit as in X-ray diffraction, for example. In a high-speed setup (HS-AFM), the method can be used to produce movies of a sample’s structural evolution in real time, as a typical biomolecule can be scanned in 100 ms or less. Now, Richard Wong and colleagues from Kanazawa University have successfully applied the HS-AFM technique to study the wrapping of DNA around structural proteins.Comment on “Individual heterozygosity predicts translocation success in threatened desert tortoises”by Bengt Hansson, Hernán E. Morales, Cock van Oosterhout in ScienceResearchers in Lund, Copenhagen and Norwich have shown that harmful mutations present in the DNA play an important — yet neglected — role in the conservation and translocation programs of threatened species.Individual-based simulations show that alternative translocation regimes can have differential effects on genetic variation and fitness.“Many species are threatened by extinction, both locally and globally. For example, we have lost about ten vertebrate species in Sweden in the last century. However, all these species occur elsewhere in Europe, which means that they could be reintroduced into Sweden. Our computer simulations show how we could theoretically maximize the success of such reestablishments,” says Bengt Hansson, biologist at Lund University.In a new study, the researchers investigated which individuals might be most suited for translocation to new populations. To date, conservation geneticists have opted to select the most genetically variable individuals. However, the authors argue that is important to consider what type of genetic variation is being move around. Using computer simulations, they showed that harmful mutations present in the genome of translocated individuals can cause problems in future generations. This so called “mutation load” could jeopardize the viability of the new population in the long run and eventually led to extinction.According to Hansson and van Oosterhout, geneticist at University of East Anglia, Norwich, who led the study, the best choice is to exclude individuals with many harmful mutations, whilst at the same time, selecting individuals from multiple different source populations.“Active translocation of animals between localities is sometimes the last option available to conservation biologists. By carefully selecting individuals based on their low mutation load, we can minimize the loss of fitness that is normally associated with inbreeding in small populations,” says Bengt Hansson.Huge advances have been made in DNA sequencing technologies, and the whole genomes of individuals can now be sequenced for relatively little costs. This opens up new possibilities to improve the conservation management of threatened species.“For many species of mammals and birds, we now know which mutations are harmful. Similar mutations are also found in humans, so we understand what they do, and hence, we know what to look out for when analyzing the sequence data of those species. The advantage of using DNA sequencing is that we can see these mutations in the genome, even if an individual carries just a single copy of the mutant gene. This means we can select against those bad mutations even before they cause a problem. Our computer model shows that at least theoretically, this ensures the best probability for population survival. This could help conservation managers in picking the optimal individuals of a threatened species for translocation into a new habitat,” says van Oosterhout.Cytosolic replication in epithelial cells fuels intestinal expansion and chronic fecal shedding of Salmonella Typhimuriumby Audrey Chong, Kendal G. Cooper, Laszlo Kari, Olof R. Nilsson, Chad Hillman, Brittany A. Fleming, Qinlu Wang, Vinod Nair, Olivia Steele-Mortimer in Cell Host & MicrobeThe immune system’s attempt to eliminate Salmonella bacteria from the gastrointestinal (GI) tract instead facilitates colonization of the intestinal tract and fecal shedding, according to National Institutes of Health scientists. The study was conducted by National Institute of Allergy and Infectious Diseases (NIAID) scientists at Rocky Mountain Laboratories in Hamilton, Montana.Salmonella Typhimurium bacteria (hereafter Salmonella) live in the gut and often cause gastroenteritis in people. The Centers for Disease Control and Prevention estimates Salmonella bacteria cause about 1.35 million infections, 26,500 hospitalizations and 420 deaths in the United States every year. Contaminated food is the source for most of these illnesses. Most people who get ill from Salmonella have diarrhea, fever and stomach cramps but recover without specific treatment. Antibiotics typically are used only to treat people who have severe illness or who are at risk for it.Salmonella bacteria also can infect a wide variety of animals, including cattle, pigs and chickens. Although clinical disease usually resolves within a few days, the bacteria can persist in the GI tract for much longer. Fecal shedding of the bacteria facilitates transmission to new hosts, especially by so-called “super shedders” that release high numbers of bacteria in their feces.NIAID scientists are studying how Salmonella bacteria establish and maintain a foothold in the GI tract of mammals. One of the first lines of defense in the GI tract is the physical barrier provided by a single layer of intestinal epithelial cells. These specialized cells absorb nutrients and are a critical barrier that prevent pathogens from spreading to deeper tissues. When bacteria invade these cells, the cells are ejected into the gut lumen — the hollow portion of the intestines. However, in previous studies, NIAID scientists had observed that some Salmonella replicate rapidly in the cytosol — the fluid portion — of intestinal epithelial cells. That prompted them to ask: does ejecting the infected cell amplify rather than eliminate the bacteria?To address this question, the scientists genetically engineered Salmonella bacteria that self-destruct when exposed to the cytosol of epithelial cells but grow normally in other environments, including the lumen of the intestine. Then they infected laboratory mice with the self-destructing Salmonella bacteria and found that replication in the cytosol of mouse intestinal epithelial cells is important for colonization of the GI tract and fuels fecal shedding. The scientists hypothesize that, by hijacking the epithelial cell response, Salmonella amplify their ability to invade neighboring cells and seed the intestine for fecal shedding.The researchers say this is an example of how the pressure exerted by the host immune response can drive the evolution of a pathogen, and vice versa. The new insights offer new avenues for developing novel interventions to reduce the burden of this important pathogen.Interphase Chromatin Undergoes a Local Sol-Gel Transition upon Cell Differentiationby Iraj Eshghi, Jonah A. Eaton, Alexandra Zidovska in Physical Review LettersThe organization of the human genome relies on physics of different states of matter — such as liquid and solid — a team of scientists has discovered. The findings, which reveal how the physical nature of the genome changes as cells transform to serve specific functions, point to new ways to potentially better understand disease and to create improved therapies for cancer and genetic disorders.The genome is the library of genetic information essential for life. Each cell contains the entire library, yet it uses only part of this information. Special types of cells, such as a white blood cell or a neuron, have only certain “books” open — those containing information relevant for their function. Researchers have long sought to determine how the genome manages these enormous libraries and allows access to the “books” that are needed, while storing away the ones not in use. The researchers revealed how this happens within a cell.Chromatin distribution before and after cell differentiation.“We found that the parts of the genome that are being used are liquid, while the unused parts form solid-like islands,” explains Alexandra Zidovska, an assistant professor in New York University’s Department of Physics and the senior author of the study. “These solid-like islands serve as library bookshelves storing the books with genes not currently in use, while the liquid genome part acts like an ‘open book,’ which is readily accessible and used for a cell’s life and function.”The genome’s genetic information is encoded in the DNA molecule. Proper reading and processing of this information is critical for human health and aging. In a human cell, the genome, which contains the genetic code, is housed in the cell nucleus. Barely 10 micrometers in size — or about 10 times smaller than the width of a strand of human hair — it stores about two meters of DNA.Storing this vast amount of genetic information in such a small space requires packing in such a way so that each piece of DNA, and thus of genetic code, is easily accessible when needed.What had been less understood is how this information was stored and what was the role of physics in it.To explore this phenomenon, the researchers, who also included Iraj Eshghi and Jonah Eaton, NYU doctoral candidates, compared cells before and after they become specialized. Specifically, the scientists mapped motions of the genome in nuclei of mouse stem cells — those that do not yet have a specialized function, but are poised to become any cell type, such as a neuron or a white blood cell — and then let these cells undergo a differentiation into neuronal cells before mapping the genomic motions again. In doing so, they generated the first-ever maps of a genome’s motions before and after cell differentiation.Here they found that stem cells keep their genome “open” — making it as accessible as an open book, with “genetic pages” being easily reachable.However, the mapping also showed that once a stem cell becomes a specialized cell, e.g. a neuron, this specialized cell keeps readily accessible only parts of the genome that are needed for its specific function. It puts away the unused parts of the genome on “bookshelves.” This leaves more space for information that is being actively read out and processed.“These motions tell us exactly how accessible the genome is in a given place in the cell nucleus,” explains Zidovska. “Moreover, these motions reveal the physical state of different parts of the genome, with liquid parts corresponding to loosely packed DNA, and solid-like parts corresponding to tightly packed DNA gels. The genome packing in these different states of matter directly impacts the genome’s accessibility; the liquid parts are accessible, in contrast to the solid-like parts. The amazing thing is that this organization relies on physics of different states of matter, liquid and solid.”“Measuring motions of distinct parts of the genome allowed us to show these different physical properties of different parts of the genome, and thus understand the genome organization — the cell’s ‘library system,’ “ she adds.Rheological models of undifferentiated and differentiated chromatin.A proper cellular filing system is vital for human health, the researchers note.“Considering the vast number of cell types in the human body, if a book is missing or misplaced in this cellular library, it may lead to missing or unnecessary information, possibly leading to developmental and inherited disorders as well as afflictions such as cancer,” explains Zidovska. “Therefore, revealing how the genome is organized inside the cell nucleus is critical to our understanding of these conditions and diseases. Moreover, such knowledge may help us in designing future therapies and diagnostics of such disorders.”LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditionsby Selma A. Serra, Predrag Stojakovic, Ramon Amat, Fanny Rubio-Moscardo, Pablo Latorre, Gerhard Seisenbacher, David Canadell, René Böttcher, Michael Aregger, Jason Moffat, Eulàlia de Nadal, Miguel A. Valverde, Francesc Posas in Proceedings of the National Academy of SciencesCells have to constantly adapt to their surroundings in order to survive. A sudden increase in the environmental levels of an osmolyte, such as salt, causes cells to lose water and shrink. In a matter of seconds, they activate a mechanism that allows them to recover their initial water volume and avoid dying.Finding out which genes are involved in surviving osmotic stress was the subject of a study led by the laboratories of Dr. Posas and Dr. de Nadal at the Institute for Research in Biomedicine (IRB Barcelona) and Dr. Valverde at Pompeu Fabra University (UPF), in collaboration with a group led by Dr. Moffat from the University of Toronto (Canada). wide-genome genetic screening, the scientists discovered the central role of a gene known as LRRC8A in cellular ability to survive osmotic shock.This gene codes for a protein that forms channels in the membrane and that allow chloride ions to leave the cell. “Using a human epithelial cell model, as well as other human and mouse cell types, we have been able to demonstrate that this channel opens shortly after the cells are exposed to a high concentration of sodium chloride (NaCl),” explains Dr. De Nadal, who, together with Dr. Francesc Posas, heads the Cell Signalling laboratory at IRB Barcelona. The authors have also identified the molecular mechanism that causes this rapid opening. The chloride channel phosphorylates, which means a phosphate group is added to a specific amino acid in its sequence, thus activating the channel.“This has been a very complex project, and it has taken us years to see the light,” explains Dr. Miguel Ángel Valverde, head of UPF’s Laboratory of Molecular Physiology. “We have also shown how vital it is for this channel to become activated and remove chloride in order to start the volume recovery process and for cells to survive over time,” he adds.The use of a violet dye that stains only living cells has allowed the researchers to observe that cell death increases by approximately 50% when the activity of this chloride channel is blocked with a particular compound.LRRC8A activation is essential for cell fitness upon hypertonicity.In the ’90s, various landmark scientific papers on cell volume regulation described the process by which cells regulate their volume to survive. It was known that the proteins responsible for volume recovery under salt stress require low intracellular concentrations in order to become activated, but it was not known how this occurred under such adverse conditions. With this discovery, the authors have answered a question posed by researchers years ago: how does chloride exit the cell to start the whole process? In the words of Dr. Selma Serra (UPF): “Now we have the answer to that question. It is the LRRC8A channel that brings down the chloride levels in a cell. Until now we had a good understanding of the role played by this channel in cell adpatation to environments with very low salt concentrations. The big challenge was to find out how the same chloride channel could be crucial in the opposite mechanism. At the beginning of the project, it seemed to go against any kind of scientific logic that a channel used to shrink cells could also swell them.”Using electrophysiological and fluorescence microscopy techniques in living cells to ascertain intracellular chloride levels, the researchers have demonstrated the involvement of the LRRC8A chloride channel in responses to high-salt stimuli.Studying this process at the molecular level has posed a considerable challenge for the team involved in this project. Because it is very complicated to conduct in vivo studies of cells while they undergo osmotic shock and shrink. “Imagine you’re looking at a juicy grape, and suddenly it looks like a raisin, that makes things very complicated for us,” say the authors.Another high-impact factor is that, under these stress conditions, the mechanism for activating the chloride channel is very different to what has been described so far in the literature. The research’s lead co-author, Predrag Stojakovic, says, “It came as a big surprise to find out that the signalling pathways in response to stress, the MAP kinase, proteins we’ve been studying in the lab for months, are directly responsible for activating this channel.” MAP kinases are a group of signalling proteins that add phosphate groups to other proteins, thus activating or deactivating them. Using molecular techniques, the authors have looked throughout the channel’s protein to find the target sequence of these kinase proteins. “We have been able to identify the specific residue of the chloride channel that leads to activation under the control of the MAP kinase channel in response to stress,” says doctoral student Stojakovic.LRRC8A triggers WNK activation to promote RVI and cell survival under hypertonicity.“This new piece of research opens up new possibilities for studying cell adaptation and survival salt stress. Certain organs of the body, such as the kidneys, are often exposed to high salt concentration, which can threaten their survival. Knowing what molecules control survival under these conditions could be very useful for understanding certain pathologies that entail volume recovery in response to salts,” explains Dr. Posas.In addition, discovering the role of this channel in these cell regulation processes is highly relevant in many pathologies involving proteins regulated by LRRC8A. This may be significant in situations such as certain kinds of arterial hypertension or cerebral ischemia.Subgenomic flavivirus RNA (sfRNA) associated with Asian lineage Zika virus identified in three species of Ugandan bats (family Pteropodidae)by Anna C. Fagre, Juliette Lewis, Megan R. Miller, Eric C. Mossel, Julius J. Lutwama, Luke Nyakarahuka, Teddy Nakayiki, Robert Kityo, Betty Nalikka, Jonathan S. Towner, Brian R. Amman, Tara K. Sealy, Brian Foy, Tony Schountz, John Anderson, Rebekah C. Kading in Scientific ReportsA team of Colorado State University scientists, led by veterinary postdoctoral fellow Dr. Anna Fagre, has detected Zika virus RNA in free-ranging African bats. RNA, or ribonucleic acid, is a molecule that plays a central role in the function of genes.According to Fagre, the new research is a first-ever in science. It also marks the first time scientists have published a study on the detection of Zika virus RNA in any free-ranging bat.The findings have ecological implications and raise questions about how bats are exposed to Zika virus in nature.Fagre, a researcher at CSU’s Center for Vector-Borne Infectious Diseases, said while other studies have shown that bats are susceptible to Zika virus in controlled experimental settings, detection of nucleic acid in bats in the wild indicates that they are naturally infected or exposed through the bite of infected mosquitoes.“This provides more information about the ecology of flaviviruses and suggests that there is still a lot left to learn surrounding the host range of flaviviruses, like Zika virus,” she said. Flaviviruses include viruses such as West Nile and dengue and cause several diseases in humans.CSU Assistant Professor Rebekah Kading, senior author of the study, said she, Fagre and the research team aimed to learn more about potential reservoirs of Zika virus through the project.The team used 198 samples from bats gathered in the Zika Forest and surrounding areas in Uganda and confirmed Zika virus in four bats representing three species. Samples used in the study date back to 2009 from different parts of Uganda, years prior to the large outbreaks of Zika virus in 2015 to 2017 in North and South Americas.Subgenomic flavivirus RNA (sfRNA) associated with Asian lineage Zika virus identified in three species of Ugandan bats (family Pteropodidae)“We knew that flaviviruses were circulating in bats, and we had serological evidence for that,” said Kading. “We wondered: Were bats exposed to the virus or could they have some involvement in transmission of Zika virus?”The virus detected by the team in the bats was most closely related to the Asian lineage Zika virus, the strain that caused the epidemic in the Americas following outbreaks in Micronesia and French Polynesia. The first detection of the Asian lineage Zika virus in Africa was in late 2016 in Angola and Cape Verde.“Our positive samples, which are most closely related to the Asian lineage Zika virus, came from bats sampled from 2009 to 2013,” said Fagre. “This could mean that the Asian lineage strain of the virus has been present on the African continent longer than we originally thought, or it could mean that there was a fair amount of viral evolution and genomic changes that occurred in African lineage Zika virus that we were not previously aware of.”Fagre said the relatively low prevalence of Zika virus in the bat samples indicates that bats may be incidental hosts of Zika virus infection, rather than amplifying hosts or reservoir hosts.“Given that these results are from a single cross-sectional study, it would be risky and premature to draw any conclusions about the ecology and epidemiology of this pathogen, based on our study,” she said. “Studies like this only tell one part of the story.”The research team also created a unique assay for the study, focusing on a specific molecular component that flaviviruses possess called subgenomic flavivirus RNA, sfRNA. Most scientists that search for evidence of Zika virus infection in humans or animals use PCR, polymerase chain reaction, to identify bits of genomic RNA, the nucleic acid that results in the production of protein, said Fagre.Kading said her team will continue their research to try and learn more about how long these RNA fragments persist in tissues, which will allow them to approximate when these bats were infected with Zika virus.“There is always a concern about zoonotic viruses,” she said. “The potential for another outbreak is there and it could go quiet for a while. We know that in the Zika forest, where the virus was first found, the virus is in non-human primates. There are still some questions with that as well. I don’t think Zika virus has gone away forever.”An early-morning gene network controlled by phytochromes and cryptochromes regulates photomorphogenesis pathways in Arabidopsisby Martin Balcerowicz, Mahiar Mahjoub, Duy Nguyen, Hui Lan, Dorothee Stoeckle, Susana Conde, Katja E. Jaeger, Philip A. Wigge, Daphne Ezer in Molecular PlantTo describe something as slow and boring we say it’s “like watching grass grow,” but scientists studying the early morning activity of plants have found they make a rapid start to their day — within minutes of dawn.Just as sunrise stimulates the dawn chorus of birds, so too does sunrise stimulate a dawn burst of activity in plants.Early morning is an important time for plants. The arrival of light at the start of the day plays a vital role in coordinating growth processes in plants and is the major cue that keeps the inner clock of plants in rhythm with day-night cycles.This inner circadian clock helps plants prepare for the day such as when to make the best use of sunlight, the best time to open flowers for pollinators and release pollen and when to get ready to respond to drought conditions.There is a peak of gene activity within an hour of dawn; many of these genes code for transcription factors — proteins that regulate expression of a host of downstream genes — with roles related to light, stress and growth hormones, but the detail of how this peak is controlled is not understood.Researchers at the Sainsbury Laboratory Cambridge University (SLCU) and University of York set out to investigate this burst of activity so as to better understand what happens at the genetic level by sampling thale cress, Arabidopsis thaliana, every two minutes from dawn to measure gene activity.“We set out to characterise ‘dawn burst’ dynamics in more detail, focussing on the expression of transcription factor genes. We found three distinct gene expression waves within two hours after dawn. The first of these occurs just 16 minutes after dawn and lasts only 8 minutes.” said Dr Martin Balcerowicz, researcher at SLCU.“Many of these genes are known to be sensitive to light and temperature, but we wanted to find out specifically how the transcription of these genes is coordinated. Interfering in photoreceptor signalling, the circadian clock and chloroplast derived light signals did cause problems in some genes’ expression, but there was a large proportion of genes still unaffected. This indicated to us that some of the upstream pathways are redundant and that additional regulators are in play.”The team integrated their data with already published transcription factor-DNA binding data and identified a gene regulatory network at dawn, with two key regulators of light signalling — HY5 and BBX31 — at its core. These transcription factors are known to jointly control de-etiolation, which is the developmental switch a seedling undergoes when it emerges from the soil, experiencing light for the first time, and starts greening and unfolding its leaves. It appears that these genes also play a central role during the dark-to-light transition at dawn.“In fact, multiple BBX genes form part of the dawn burst alongside BBX31, HY5 and its homologue HYH,” says Dr Balcerowicz. “These genes include both positive and negative regulators of the light response. We found that they act downstream of phytochrome and cryptochrome photoreceptors to control a light-induced subset of dawn burst genes, with HY5 and BBX31 having largely antagonistic roles. This observation strengthens the idea that HY5 and BBX genes act in concert to fine-tune light responses in the context of the day-night cycle.”Dr Daphne Ezer, lecturer in Computational Biology at the University of York and senior author of the study, investigates gene-environment interactions through analysis of gene networks. “By studying gene networks we can interpret how plants integrate light and temperature signals in the early morning to entrain the circadian clock. Taken together, our results show that phytochrome and cryptochrome signalling is required for fine-tuning the dawn transcriptional response to light, but separate pathways can robustly activate much of the programme in their absence.”“Characterising the peak we see in gene expression that results from the onset of light is useful in helping us to understand how plants respond to light and, in particular, for crops grown under artificial lighting, how this dawn burst impacts longer term on growth.”Bioinspired Biomaterial Composite for All‐Water‐Based High‐Performance Adhesivesby Marco Lo Presti, Giorgio Rizzo, Gianluca M. Farinola, Fiorenzo G. Omenetto in Advanced ScienceIf you have ever tried to chip a mussel off a seawall or a barnacle off the bottom of a boat, you will understand that we could learn a great deal from nature about how to make powerful adhesives. Engineers at Tufts University have taken note, and report a new type of glue inspired by those stubbornly adherent creatures.Starting with the fibrous silk protein harvested from silkworms, they were able to replicate key features of barnacle and mussel glue, including protein filaments, chemical crosslinking and iron bonding. The result is a powerful non-toxic glue that sets and works as well underwater as it does in dry conditions and is stronger than most synthetic glue products now on the market.“The composite we created works not only better underwater than most adhesives available today, it achieves that strength with much smaller quantities of material,” said Fiorenzo Omenetto, Frank C. Doble Professor of Engineering at Tufts School of Engineering, director of the Tufts Silklab where the material was created, and corresponding author of the study. “And because the material is made from extracted biological sources, and the chemistries are benign — drawn from nature and largely avoiding synthetic steps or the use of volatile solvents — it could have advantages in manufacturing as well.”The Silklab “glue crew” focused on several key elements to replicate in aquatic adhesives. Mussels secrete long sticky filaments called byssus. These secretions form polymers, which embed into surfaces, and chemically cross-link to strengthen the bond. The protein polymers are made up of long chains of amino acids including one, dihydroxyphenylalanine (DOPA), a catechol-bearing amino acid that can cross-link with the other chains. The mussels add another special ingredient — iron complexes — that reinforce the cohesive strength of the byssus.Schematic representation of the lap-shear test.Barnacles secrete a strong cement made of proteins that form into polymers which anchor onto surfaces. The proteins in barnacle cement polymers fold their amino acid chains into beta sheets — a zig-zag arrangement that presents flat surfaces and plenty of opportunities to form strong hydrogen bonds to the next protein in the polymer, or to the surface to which the polymer filament is attaching.Inspired by all of these molecular bonding tricks used by nature, Omenetto’s team set to work replicating them, and drawing on their expertise with the chemistry of silk fibroin protein extracted from the cocoon of silkworms. Silk fibroin shares many of the shape and bonding characteristics of the barnacle cement proteins, including the ability to assemble large beta sheet surfaces. The researchers added polydopamine — a random polymer of dopamine which presents cross-linking catechols along its length, much like the mussels use to cross-link their bonding filaments. Finally, the adhesion strength is significantly enhanced by curing the adhesive with iron chloride, which secures bonds across the catechols, just like they do in natural mussel adhesives.“The combination of silk fibroin, polydopamine and iron brings together the same hierarchy of bonding and cross-linking that makes these barnacle and mussel adhesives so strong,” said Marco Lo Presti, post-doctoral scholar in Omenetto’s lab and first author of the study. “We ended up with an adhesive that even looks like its natural counterpart under the microscope.”Getting the right blend of silk fibroin, polydopamine, and acidic conditions of curing with iron ions was critical to enabling the adhesive to set and work underwater, reaching strengths of 2.4 MPa (megapascals; about 350 pounds per square inch) when resisting shear forces. That’s better than most existing experimental and commercial adhesives, and only slightly lower than the strongest underwater adhesive at 2.8 MPa. Yet this adhesive has the added advantage of being non-toxic, composed of all-natural materials, and requires only 1–2 mgs per square inch to achieve that bond — that’s just a few drops.SEM images and relative film insets of different SF–PDA blends.“The combination of likely safety, conservative use of material, and superior strength suggests potential utility for many industrial and marine applications and could even be suitable for consumer-oriented such as model building and household use,” said Prof. Gianluca Farinola, a collaborator on the study from the University of Bari Aldo Moro, and an adjunct Professor of Biomedical Engineering at Tufts. “The fact that we have already used silk fibroin as a biocompatible material for medical use is leading us to explore those applications as well,” added Omenetto.MISC — @NatureGenet — @PLOSGenetics — @GENbioSubscribe to Paradigm!Medium. Twitter. Telegram. Telegram Chat. Reddit. LinkedIn.Main SourcesResearch articlesNature GeneticsGEN: Genetic Engineering & Biotechnology NewsNational Institutes of HealthNational Library of MedicinePLOS GeneticsScienceScience DirectScience DailyLongdomGT/ Cells reprogrammed to make synthetic polymers was originally published in Paradigm on Medium, where people are continuing the conversation by highlighting and responding to this story.

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