June 21, 2017 Liquid-like fusion of heterochromatin protein 1a droplets in the embryo of a fruit fly. Credit: Amy Strom/Berkeley Lab

The same mechanisms that quickly separate mixtures of oil and water are at play when controlling the organization in an unusual part of our DNA called heterochromatin, according to a new study by researchers at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab).

Researchers studying genome and cell biology provide evidence that heterochromatin organizes large parts of the genome into specific regions of the nucleus using liquid-liquid phase separation, a mechanism well known in physics but whose importance for biology has only recently been revealed.

They present their findings June 21 in the journal Nature, addressing a long-standing question about how DNA functions are organized in space and time, including how genes are regulated to be silenced or expressed.

"The importance of DNA sequences in health and disease has been clear for decades, but we only recently have come to realize that the organization of sections of DNA into different physical domains or compartments inside the nucleus is critical to promote distinct genome functions," said study corresponding author, Gary Karpen, senior scientist at Berkeley Lab's Biological Systems and Engineering Division.

The long stretches of DNA in heterochromatin contain sequences that, for the most part, need to be silenced for cells to work properly. Scientists once thought that compaction of the DNA was the primary mechanism for controlling which enzymes and molecules gain access to the sequences. It was reasoned that the more tightly wound the strands, the harder it would be to get to the genetic material inside.

That mechanism has been questioned in recent years by the discovery that some large protein complexes could get inside the heterochromatin domain, while smaller proteins can remain shut out.

In this new study of early Drosophila embryos, the researchers observed two non-mixing liquids in the cell nucleus: one that contained expressed genes, and one that contained silenced heterochromatin. They found that heterochromatic droplets fused together just like two drops of oil surrounded by water.

In lab experiments, researchers purified heterochromatin protein 1a (HP1a), a main component of heterochromatin, and saw that this single component was able to recreate what they saw in the nucleus by forming liquid droplets.

"We are excited about these findings because they explain a mystery that's existed in the field for a decade," said study lead author Amy Strom, a graduate student in Karpen's lab. "That is, if compaction controls access to silenced sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners."

The Berkeley Lab study, which used fruit fly and mouse cells, will be published alongside a companion paper in Nature led by UC San Francisco researchers, who showed that the human version of the HP1a protein has the same liquid droplet properties, suggesting that similar principles hold for human heterochromatin.

Interestingly, this type of liquid-liquid phase separation is very sensitive to changes in temperature, protein concentration, and pH levels.

"It's an elegant way for the cell to be able to manipulate gene expression of many sequences at once," said Strom.

Other cellular structures, including some involved in disease, are also organized by phase separation.

"Problems with phase separation have been linked to diseases such as dementia and certain neurodegenerative disorders," said Karpen.

He noted that as we age, biological molecules lose their liquid state and become more solid, accumulating damage along the way. Karpen pointed to diseases like Alzheimer's and Huntington's, in which proteins misfold and aggregate, becoming less liquid and more solid over time.

"If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease," Strom added.

The work is a big step forward for understanding how DNA functions, but could also help researchers improve their ability to manipulate genes.

"Gene therapy, or any treatment that relies on tight regulation of gene expression, could be improved by precisely targeting molecules to the right place in the nucleus," says Karpen. "It is very difficult to target genes located in heterochromatin, but this understanding of the properties linked to phase separation and liquid behaviors could help change that and open up a third of the genome that we couldn't get to before."

This includes targeting gene-editing technologies like CRISPR, which has recently opened up new doors for precise genome manipulation and gene therapy.

Explore further: Discovery of a novel chromosome segregation mechanism during cell division

More information: Amy R. Strom et al, Phase separation drives heterochromatin domain formation, Nature (2017). DOI: 10.1038/nature22989

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Researchers find new mechanism for genome regulation - Phys.Org

June 21, 2017 Credit: European Bioinformatics Institute EMBL-EBI

A picture may be worth a thousand words, but only if you understand what you are looking at. The life sciences rely increasingly on 2-D, 3-D and 4-D image data, but its staggering heterogeneity and size make it extremely difficult to collate into a central resource, link to other data types and share with the research community.

To address this challenge, scientists at the University of Dundee, the European Bioinformatics Institute (EMBL-EBI), the University of Bristol and the University of Cambridge have launched a prototype repository for imaging data: the Image Data Resource (IDR). This free resource, described in Nature Methods, is the first general biological image repository that stores and integrates data from multiple modalities and laboratories.

The IDR also reveals the potential impact of sharing and reusing imaging data for the life sciences.

Pooling resources

"Imaging will only be truly transformative for science if we make the data publicly available," explains Alvis Brazma, a lead author and Senior Scientist at EMBL-EBI. "Scientists should be able to query existing data to identify commonalities and patterns. But to make this possible we need a robust platform where researchers can upload their imaging data and easily access data from other experiments. The Image Data Resource is the first step towards creating a public image data repository for the life sciences."

There are many resources worldwide in which people publish imaging data, but none of these repositories is both generic and linked to other relevant bio-molecular data. This means that for all the effort that goes into them, it is difficult to reuse these datasets in new studies.

There are many reasons why sharing imaging data has been so difficult until now most notably the heterogeneity and complexity of the image data, but also a critical mass of storage, compute and curation expertise.

"Imaging data is large, yes, but the real challenge is that it is heterogeneous and multidimensional," says Jason Swedlow, senior author of the study and Professor of Quantitative Cell Biology at the University of Dundee. "Curating, storing and analysing imaging data require significant effort and computing power. The creation of the IDR prototype was only possible thanks to a strong collaboration between several scientific organisations."

Nice picture but what does it mean?

IDR contains a broad range of imaging data, including high-content screening, super-resolution microscopy, time-lapse and digital pathology imaging. But it's not just the diversity of data types that makes the resource unique; it is the additional information available that creates the added value.

"IDR doesn't just show you an image or a video of a cell. It also tells you what the image is about, where it was taken, by whom and what conclusions can be drawn from it," continues Brazma.

The new resource integrates imaging data with molecular and phenotype data. IDR includes information on experimental protocols: parameters, analyses and the effects scientists have observed in cells and features, for example. This makes it possible for users to analyse gene networks potentially revealing previously unknown interactions on a scale that would not be possible for individual studies. That requires a staggering amount of storage and compute power. The IDR collaboration was able to launch their project successfully thanks to the Embassy Cloud resource and support at EMBL-EBI.

The Image Data Repository

The prototype public image repository contains a broad range of data, including:

Demonstrating success

The Swedlow group at Dundee and the Carazo Salas group at the University of Bristol used IDR to illustrate how shared imaging data can push the boundaries of research. Using data deposited in the IDR, they identified genes from different studies that, when mutated or removed, caused cells to elongate and stretch out. They put together information from several different studies and built a gene network, which gives a clear view on how these genes affect cell shape an important property to consider in metastatic cancer.

"Expanding the public archives to include imaging is of huge interest to the biotech industry and drug development companies. It offers potential to identify new therapies and targets, and broadens the scope of research by allowing scientists around the world to access each other's imaging datasets," adds Swedlow.

"Bioimaging technologies are currently revolutionising life science. Sharing the rapidly increasing amount of image data is the key to enabling ground-breaking future research," says Jan Ellenberg, Head of EMBL's Cell Biology and Biophysics Unit and Coordinator of Euro-BioImaging, the pan-European infrastructure for imaging technologies. "For this reason image data archiving and sharing is a high priority for EMBL, and for Euro-BioImaging's future general data services, which can build on the IDR pilot example."

Next steps

So far, the collaborators have proven that IDR is both possible and useful. The next step is to secure the support and investment needed to transform the prototype into a production-ready imaging infrastructure.

IDR's software and technology is open source, so it can be accessed and built into other image data publication systems. This promotes and extends publication and re-analysis of scientific data.

Explore further: 'Big Data' resource raises possibility of research revolution

More information: Eleanor Williams et al. Image Data Resource: a bioimage data integration and publication platform, Nature Methods (2017). DOI: 10.1038/nmeth.4326

Journal reference: Nature Methods

Provided by: European Bioinformatics Institute EMBL-EBI

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Open imaging data for biology - Phys.org - Phys.Org

June 20, 2017 Scientists at the University of St Andrews have developed a new microscopy method that analyses interference patterns to create images of the forces living cells apply as they grow, divide and migrate: shown is the force pattern generated by a human embryonic kidney cell in contact with a probe that is read out by red light. Credit: University of St Andrews

Scientists at the University of St Andrews have developed an advanced new microscopy technique that could revolutionise our understanding of how immune and cancer cells find their way through the body.

Elastic Resonator Interference Stress Microscopy (ERISM) images the extremely weak mechanical forces that living cells apply when they move, divide, and probe their environment.

As described in Nature Cell Biology today (Monday 19 June 2017), ERISM resolves the tiny forces applied by feet-like structures on the surface of human immune cells.

These feet allow immune cells to find the fastest route to a site of infection in the body. Similar structures may be responsible for the invasion of cancer cells into healthy tissue and it is planned to use ERISM in the future to learn more about the mechanisms involved in cancer spreading.

The physical effect giving soap bubbles their rainbow-like appearance is a phenomenon called thin-film interference. It is based on interaction of light reflected on either side of a soap film. The different colours that white light consists of interact with different local thicknesses of the thin film and generate the familiar rainbow patterns. Effectively the colours are an image of the film thickness at each point on the surface of the soap bubble.

A similar effect can be used to determine the forces exerted by cells. Professor Malte Gather of the School of Physics and Astronomy at St Andrews explained: "Our microscope records very high colour resolution images of the light reflected by a thin and soft probe. From these images, we then create a highly accurate map of the thickness of the probe with a mind-blowing precision of one-billionth part of a metre.

"If cells apply forces to the probe, the probe thickness changes locally, thus providing information about the position and magnitude of the applied forces.

"Although researchers have recorded forces applied by cells before, our interference-based approach gives an unprecedented resolution and in addition provides an internal reference that makes our technique extremely robust and relatively easy to use."

This robustness means that measuring cell forces could soon become a tool in clinical diagnostics. For example, doctors may find that the ERISM method can complement existing techniques to assess the invasiveness of cancer. Work to scale up ERISM for use in the clinic is now underway.

Explore further: Researchers use optogenetics and mathematical modelling to identify a central molecule in cell mechanics

More information: Nils M. Kronenberg et al. Long-term imaging of cellular forces with high precision by elastic resonator interference stress microscopy, Nature Cell Biology (2017). DOI: 10.1038/ncb3561

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How the optics of soap bubbles may help us understand the ... - Phys.Org

ANN ARBOR, MI One of the oldest departments at the University of Michigan is about to get a new leader. The U-M Board of Regents today approved the appointment of Pierre A. Coulombe, Ph.D., to lead the Department of Cell and Developmental Biology in the Medical School.

Coulombe will become chair on August 1, and lead one of the nine basic science departments of Michigan Medicine, U-Ms academic medical center. The departments researchers study how structure governs function in cells and tissues throughout the body, and how complex arrays of signals are integrated to foster the proper development of tissues and organs. They also study stem cells, including embryonic stem cells, and train undergraduate, graduate and medical students in cell biology.

The department traces its roots back to 1854, soon after the founding of the Medical School, when it was known as the Department of Anatomy.

Coulombe comes to Michigan from Johns Hopkins University, where he chaired the Department of Biochemistry and Molecular Biology in the Bloomberg School of Public Health for nine years, and held the E.V. McCollum professorship as well as several joint appointments in the School of Medicine. At Hopkins, Coulombe was noted for at recruiting and nurturing junior faculty members to success, and developing robust training programs for graduate students and post-doctoral fellows. He was also instrumental in addressing the departments infrastructure needs.

To me, cell and developmental biology are critically important endeavors as one seeks to translate the wealth of knowledge acquired in biochemistry and molecular biology, along with the power of imaging techniques, into a better understanding of how organs and tissues form, and operate, under normal and disease conditions, he says. This knowledge is also important for developing novel therapies for human disease. U-M already is a formidable institution, and otherwise is making a substantial investment into biomedical research. Therefore, I am absolutely thrilled about the opportunity to lead Cell & Developmental Biology, and team up with my new colleagues in the department and at U-M, to fulfill this potential.

In addition to his appointment in Cell & Developmental Biology, Coulombe will have a joint appointment in the U-M Department of Dermatology. His research focuses on understanding how keratin proteins and the nanoscale filaments they form foster an optimal architecture and function in skin and related epithelia, and how disruption of these processes result in diseases ranging from inherited conditions to cancer.

A native of Montral, Qubec, Coulombe earned his undergraduate degree from the Universit du Qubec Montral and his Ph.D. in Pharmacology from Universit de Montral. He completed his postdoctoral fellowship in the Department of Molecular Genetics and Cell Biology & Howard Hughes Medical Institute at the University of Chicago before joining Johns Hopkins School of Medicine in 1992. He is the author of more than 140 peer-reviewed publications and one book, holds one patent, and has received multiple awards in recognition of his research and teaching endeavors.

For more about the U-M Department of Cell and Developmental Biology, visit https://medicine.umich.edu/dept/cell-developmental-biology.

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Pierre Coulombe, Ph.D. to lead UM Department of Cell & Developmental Biology - University of Michigan Health System News (press release)

The Center for Stem Cell and Regenerative Medicine will use a team-oriented, multidisciplinary approach, says Asrar Malik, head of pharmacology.

The College of Medicine launched a new center that focuses on understanding tissue regeneration and pioneering future developments in stem cell biology as a means to repair diseased organs and tissues.

The opening of the Center for Stem Cell and Regenerative Medicinewas commemorated Monday with a symposium on stem cell and regenerative medicine.

The center will partner with colleges and departments across the University of Illinois System.

Researchers in the new center will investigate the molecular signals that drive stem cells to mature into different cell types, such as blood, heart and blood vessel cells. The center will also study the epigenetic regulation of stem cells; determine the best approaches to transplant engineered cells, tissues and organs; and look for ways to efficiently produce the regenerative cells needed for novel treatments.

The center will use a team-oriented, multidisciplinary approach that incorporates experts in biochemistry, biophysics, bioengineering and the clinical sciences to investigate stem cell biology and tissue regeneration, said Asrar Malik, the Schweppe Family Distinguished Professor and head of pharmacology, who is guiding the effort.

A search has begun to recruit a director and additional faculty members, he said.

The current program in stem cell biology and regenerative medicine includes seven faculty members, most within the department of pharmacology, who together have more than $10 million in research grants from the National Institutes of Health.

The intent in the next few years will be to carry out additional recruitments with other departments, to build from this interdisciplinary foundation and capitalize on our strengths, Malik said.

Three new faculty members in pharmacology have joined the center in the last two years. Owen Tamplin studies stem cells in zebrafish; Kostandin Pajcini investigates the role of stem cells in the development of leukemia; and Jae-Won Shin engineers stem cells and tissues with an eye toward transplantation.

As the only dedicated stem cell and regenerative medicine center in Chicago with a focus on basic biology and translational science, it will affirm UICs leadership role in these fields and help attract additional talent, Malik said.

Continue reading here:
Center to advance tissue regeneration, stem cell discoveries - UIC News

June 15, 2017

Researchers at the Stanford University School of Medicine have discovered an unexpected layer of the regulation of gene expression. The finding will likely disrupt scientists' understanding of how cells regulate their genes to develop, communicate and carry out specific tasks throughout the body.

The researchers found that cellular workhorses called ribosomes, which are responsible for transforming genes encoded in RNA into proteins, display a never-before-imagined variety in their composition that significantly affects their function. In particular, the protein components of a ribosome serve to tune the tiny machine so that it specializes in the translation of genes in related cellular pathways. One type of ribosome, for example, prefers to translate genes involved in cellular differentiation, while another specializes in genes that carry out essential metabolic duties.

The discovery is shocking because researchers have believed for decades that ribosomes functioned like tiny automatons, showing no preference as they translated any and all nearby RNA molecules into proteins. Now it appears that broad variation in protein production could be sparked not by changes in the expression levels of thousands of individual genes, but instead by small tweaks to ribosomal proteins.

'Broad implications'

"This discovery was completely unexpected," said Maria Barna, PhD, assistant professor of developmental biology and of genetics. "These findings will likely change the dogma for how the genetic code is translated. Until now, each of the 1 to10 million ribosomes within a cell has been thought to be identical and interchangeable. Now we're uncovering a new layer of control to gene expression that will have broad implications for basic science and human disease."

Barna is the senior author of the study, which will be published online June 15 in Molecular Cell. Postdoctoral scholars Zhen Shi, PhD, and Kotaro Fujii, PhD, share lead authorship. Barna is a New York Stem Cell Robertson Investigator and is also a member of Stanford's Bio-X and Child Health Research Institute.

The work builds upon a previous study from Barna's laboratory that was published June 1 in Cell. The lead author of that study was postdoctoral scholar Deniz Simsek, PhD. It showed that ribosomes also differ in the types of proteins they accumulate on their outer shells. It also identified more than 400 ribosome-associated proteins, called RAPs, and showed that they can affect ribosomal function.

Every biology student learns the basics of how the genetic code is used to govern cellular life. In broad strokes, the DNA in the nucleus carries the building instructions for about 20,000 genes. Genes are chosen for expression by proteins that land on the DNA and "transcribe" the DNA sequence into short pieces of mobile, or messenger, RNA that can leave the nucleus. Once in the cell's cytoplasm, the RNA binds to ribosomes to be translated into strings of amino acids known as proteins.

Every living cell has up to 10 million ribosomes floating in its cellular soup. These tiny engines are themselves complex structures that contain up to 80 individual core proteins and four RNA molecules. Each ribosome has two main subunits: one that binds to and "reads" the RNA molecule to be translated, and another that assembles the protein based on the RNA blueprint. As shown for the first time in the Cell study, ribosomes also collect associated proteins called RAPs that decorate their outer shell like Christmas tree ornaments.

'Hints of a more complex scenario'

"Until recently, ribosomes have been thought to take an important but backstage role in the cell, just taking in and blindly translating the genetic code," said Barna. "But in the past couple of years there have been some intriguing hints of a more complex scenario. Some human genetic diseases caused by mutations in ribosomal proteins affect only specific organs or tissues, for example. This has been very perplexing. We wanted to revisit the textbook notion that all ribosomes are the same."

In 2011, members of Barna's lab showed that one core ribosomal protein called RPL38/eL38 is necessary for the appropriate patterning of the mammalian body plan during development; mice with a mutation in this protein developed skeletal defects such as extra ribs, facial clefts and abnormally short, malformed tails.

Shi and Fujii used a quantitative proteomics technology called selected reaction monitoring to precisely calculate the quantities, or stoichiometry, of each of several ribosomal proteins isolated from ribosomes within mouse embryonic stem cells. Their calculations showed that not all the ribosomal proteins were always present in the same amount. In other words, the ribosomes differed from one another in their compositions.

"We realized for the first time that, in terms of the exact stoichiometry of these proteins, there are significant differences among individual ribosomes," said Barna. "But what does this mean when it comes to thinking about fundamental aspects of a cell, how it functions?"

To find out, the researchers tagged the different ribosomal proteins and used them to isolate RNA molecules in the act of being translated by the ribosome. The results were unlike what they could have ever imagined.

"We found that, if you compare two populations of ribosomes, they exhibit a preference for translating certain types of genes," said Shi. "One prefers to translate genes associated with cell metabolism; another is more likely to be translating genes that make proteins necessary for embryonic development. We found entire biological pathways represented by the translational preferences of specific ribosomes. It's like the ribosomes have some kind of ingrained knowledge as to what genes they prefer to translate into proteins."

The findings dovetail with those of the Cell paper. That paper "showed that there is more to ribosomes than the 80 core proteins," said Simsek. "We identified hundreds of RAPs as components of the cell cycle, energy metabolism, and cell signaling. We believe these RAPs may allow the ribosomes to participate more dynamically in these intricate cellular functions."

"Barna and her team have taken a big step toward understanding how ribosomes control protein synthesis by looking at unperturbed stem cells form mammals," said Jamie Cate, PhD, professor of molecular and cell biology and of chemistry at the University of California-Berkeley. "They found 'built-in' regulators of translation for a subset of important mRNAs and are sure to find more in other cells. It is an important advance in the field." Cate was not involved in the research.

Freeing cells from micromanaging gene expression

The fact that ribosomes can differ among their core protein components as well as among their associated proteins, the RAPs, and that these differences can significantly affect ribosomal function, highlights a way that a cell could transform its protein landscape by simply modifying ribosomes so that they prefer to translate one type of genesay, those involved in metabolismover others. This possibility would free the cell from having to micromanage the expression levels of hundreds or thousands of genes involved in individual pathways. In this scenario, many more messenger RNAs could be available than get translated into proteins, simply based on what the majority of ribosomes prefer, and this preference could be tuned by a change in expression of just a few ribosomal proteins.

Barna and her colleagues are now planning to test whether the prevalence of certain types of ribosomes shift during major cellular changes, such as when a cell enters the cell cycle after resting, or when a stem cell begins to differentiate into a more specialized type of cell. They'd also like to learn more about how the ribosomes are able to discriminate between classes of genes.

Although the findings of the two papers introduce a new concept of genetic regulation within the cell, they make a kind of sense, the researchers said.

"About 60 percent of a cell's energy is spent making and maintaining ribosomes," said Barna. "The idea that they play no role in the regulation of genetic expression is, in retrospect, a bit silly."

Explore further: In creation of cellular protein factories, less is sometimes more

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Again we're shocked to discover that the higher energy environment our solar system experiences, the greater the tightening and finite organizing we see at the cellular level. What will we find only to lose it as our system passes out of higher energy is astonishing. Looking thru this lens of higher energy in past cycles reforms myths into potential truths.

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Newly identified method of gene regulation challenges accepted ... - Phys.Org

GEN: Are 3D cell culture models as strongly focused as ever on drug safety testing, or are they finding new applications?

Dr. Aho: The focus of 3D cell culture models has definitely expanded beyond drug safety testing. It is becoming increasingly clear that these models mimic cells in vivo at a greater capacity than traditional cell culture.

In addition to drug toxicity, 3D models are progressively being developed and used in developmental biology research, disease modeling, and regenerative medicine. 3D models also provide an enhanced system for drug discovery. Because they better recapitulate disease in vitro, 3D models have the potential to accelerate the testing timeline for drug efficacy studies.

Dr. Banks: Another major application area of 3D cell culture models is in oncology. Spheroids in both media and Matrigel can be used as surrogate models of tumor proliferation and tumor invasion. Automated brightfield or fluorescence microscopy is typically used for spheroid or invadipodia area measurements. In addition to spheroids, collagen-based scaffolds that encourage cell aggregation into tumoroids have been used for immunotherapy applications such as natural killer cell cytotoxicity assays. Finally, magnetic particles have been used to bioprint cells for cell migration and invasion experiments.

Dr. Eglen: We would argue that 3D cell culture models have been used for many years in basic research and disease modeling, notably in cancer researchthis was, after all, one of the original applications of Corning Matrigel, a naturally occurring extracellular matrix for us in 3D cell culture. That said, it is true that 3D cell culture models are increasingly being used in preclinical lead optimization, particularly in evaluating potential compound toxicity and metabolic liability.

Furthermore, disease research areas are expanding to include neurology, stem cell research, cell therapy, and (potentially) tissue engineering. Perhaps the most exciting work is the development of 3D technologies for the optimal production of patient-specific cells, either for compound testing or possibly cell therapy.

Interestingly, spheroids derived from stem cells grown in 3D models show improved stemness, that is, characteristics that may lead to increased efficacy in regenerative medicine. Researchers have seen that spheroids display enhanced anti-inflammatory, tissue regenerative, and reparative responses, as well as better post-transplant survival of mesenchymal stem cells.

Autologous tissue for transplantation may also come from organoids produced via 3D cell culture. For example, renal organoids derived from pluripotent stem cells have been successfully transplanted under the renal capsules of adult mice. Clearly, research in this area is advancing rapidly, probably due to a convergence of several multidisciplinary fields, ranging from bioengineering, materials science, phenotypic screening, and cell biology.

Dr. Trezise: Drug safety continues to be a significant application area for 3D models. This application area has become only more interesting as more data has become available indicating that 3D models offer translational benefits. In addition, there is a growing trend to develop 3D models that can advance developmental biology, target validation, and drug efficacy studies. This trend is particularly evident in the field of oncology, where researchers are combining patient-specific tumor cells and 3D cell culture methods to create tumor organoids. These mini-tumors are being used to determine sensitivity to combinations of different chemical, biological, and cellular therapeutics in the context of personalized medicine.

Dr. Klette: 3D cell culture models are widely used for drug safety testing, such as studying hepatic injury from compound screens, and for examining drug metabolism using 3D hepatocyte models. In personalized medicine, however, patient-derived primary 3D models are being used for cancer screening in biotherapeutics. Here, 3D models provide enhanced physiological relevance to determine drug efficacy and potential impacts on carcinogenesis, metastasis, and tumor reoccurrence. If we look outside drug discovery and biologics, we notice that areas such as regenerative medicine and cell therapies can take advantage of 3D models as a predictor of disease and (when scaled to therapeutic levels) as a disease treatment.

Dr. Guye: 3D cell models are applied throughout the biomedical and life sciences. 3D technologies that are compatible with high-throughput screening are used not only for screening purposes, but also for target and hit validation, lead optimization, and investigational toxicology.

Basically, given their ability to extend cell lifetimes and incorporate multiple cell types, 3D models are increasingly finding their way into basic research, where they are helping to recapitulate disease progression and assess the impact of certain genes and pathways on disease progression/preventionactivities that help scientists define adverse outcome pathways. Importantly, we expect human 3D cell culture models to significantly reduce the percentage of drugs that progress to clinical trials and fail due to lack of efficacy.

Dr. Kugelmeier: The focus on drug safety testing is still valid, and sophisticated organoid models might contribute to even more accurate drug safety testing because of increased physiological fidelity of these models. But there are also significant new research areas. Combining organoid technology with stem cell biology could lead to therapeutic applications. Also, cancer researchespecially cancer research that focuses on cancer stem cellsneeds 3D models. Of these models, cell spheroids are among the most important. Sophisticated cell-spheroid platforms not only allow research but also provide drug-testing possibilities using patient cells for personalized medicine. Finally, these platforms may enable therapeutic applications with stem cell spheroids in regenerative medicine.

Mrs. Hussain: The focus for 3D cell culture methods is still the drug safety testing that occurs before in vivo testing. Recently, there has been a renewed interest in phenotypic drug screening to discover new drug targets. With this shift, there is growing emphasis on bridging the gap between phenotypic screens and 3D methods. Phenotypic screens, in vitro, were traditionally carried out using 2D methods that do not take into account the complexity of the in vivo environment. 3D methods are now sought to build biologically relevant models that are more predictive of phenotypic response to new drug targets.

Dr. Bulpin: Applications continue to expand for 3D models, including the development of specific disease models and complex tissue models that can be used for basic research as well as drug discovery. Another promising area for 3D models is personalized medicine. Several types of cells can be used in these models including immortalized cells, genetically engineered cells, induced pluripotent stem cellderived cells, primary human cells, and patient-derived cells (including patient-derived xenografts). Another potential research avenue is engineering 3D tissues for organ transplants.

Dr. Joore: Over the last year, we observed a growing interest in 3D tissue models that could be used in studies of disease processes, whether the studies emphasized screening or efficacy analysis. These are, I think, two sides of the same coin. Once researchers realize they need better predictive models for safety testing, they start to see that improved models would also have potential for discovery and development. Molecule-to-molecule screens have generated lots of very specific inhibitors, but not so many therapies. Researchers are now starting to appreciate the richness of 3D model data, especially in combination with the throughput of our organ-on-a-chip platforms.

Ms. Floyd: Cancer researchers and developmental biologists have certainly benefitted from 3D cell culture models, which are more physiologically relevant than are 2D systems to the study of cellular differentiation. Further, 3D in vitro systems are well positioned to obtain approvals from authorities such as the Organization for Economic Co-operation and Development Organization (OECD). The OECD and other bodies are considering alternatives to whole-animal testing, including alternatives that can accomplish skin-sensitization studies for the safety assessment of chemicals.

Prof. Przyborski: What has changed more recently is the ease of access to innovative technologies on the market that enable researchers to more readily practice 3D cell culture routinely. 3D cell culture has had impact in multiple areas in basic research, drug screening, and safety assessment. Researchers are now looking to 3D technologies to create more sophisticated models that are representative of real human tissues. Investment in more advanced in vitro assays at an early stage will improve predictions of drug action and inform the decision-making process as to whether to further invest in a particular drug candidate.

Dr. Kennedy: 3D cell cultures continue to be extensively explored for drug safety screening; however, there is a growing interest in expanding the use of more complex 3D models into areas such as disease modeling and precision medicine. For example, preclinical hepatic research is now looking to exploit the benefits of spheroid cultures by building 3D co-culture models that consist of multiple primary liver cell types to create new models of hepatic and biliary disease. Likewise, stem cellderived organoids are opening the possibility of tailoring therapeutic regimens to patients genetic makeups and to identify the best treatment options.

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Watch This 3D Cell Culture Space - Genetic Engineering & Biotechnology News (press release)

Fixing glitches in the assembly of RNA may hold the key to treating ALS and frontal lobe dementia, according to a Harvard Medical School(HMS) study published this week in Cell Reports.

Researchers found that a genetic mutation often linked to those diseases creates a toxic protein that disrupts the editing, or splicing, of RNA, the molecular messengers that turn genes into functional proteins.

What we are finding is that disruptions in RNA splicing appear to be a common thread linking these motor neuron disorders, said senior study author Robin Reed, professor of cell biology at HMS.Much more research is needed, but if we could correct splicing errors with so-called splicing modulator compounds, we could prevent disruptions which may have efficacy for the treatment of ALS and FTD.

In the HMS study, toxic peptides produced by mutation of gene C9ORF72dislocated part of the spliceosome, the molecular machine responsible for RNA assembly, driving it to the cytoplasm of the cell instead of the nucleus, where it should be located. Exactly how these peptides cause toxicity was previously unclear but studies have shown that they significantly increase splicing failures.

Since splicing is upstream of so many critical cellular functions, Reed said, a better understanding of this mechanism could illuminate new approaches to help patients with these diseases, which currently have no effective treatments.

The C9ORF72 mutation accounts for around 25 percent of cases of frontotemporal dementia and 30-40 percent of inherited forms of amyotrophic lateral sclerosis. Roughly one in five patients with ALS also develops FTD.

The mutation causes the abnormal duplication of a segment of DNA that is processed by cells into messenger RNA. These extraneous copies of RNA messengers code for proteins, two of which GR and PR have been found to be toxic in human, yeast, and fruit fly cells.

Reed and her colleagues found that these toxic peptides associate with a component of the spliceosome known as U2 snRNP.

It was striking how these peptides are so specific to U2 snRNP. No other cellular processes appeared to be affected, whereas splicing was completely blocked, Reed said. When these peptides are expressed at high levels, they are completely toxic to the cell, but if they are produced at a low enough level, they can inhibit the splicing of genes that are U2-dependent, which may have some role in the development of disease.

Co-authors on the study include Shanye Yin, Rodrigo Lopez-Gonzalez, Ryan C. Kunz, Jaya Gangopadhyay, Carl Borufka, Steven P. Gygi and Fen-Biao Gao.

This work was supported by the National Institutes of Health (grants GM043375, NS057553 and NS079725), an ALS Therapy Alliance Grant and the ALS Association.

Continued here:
RNA errors linked to ALS and dementia - Harvard Gazette

Why mosquito-borne dengue virus causes more severe disease in some individuals, including hemorrhagic fever with or without shock, remains controversial and researchers are focusing on the factors related to the interaction between the virus and the host immune system, including the role of mast cells.

An in-depth review of the latest research showing how mast cells can be both protective and can contribute to the most severe forms of dengue is presented in the article Role of Mast Cells in Dengue Virus Pathogenesis, published in DNA and Cell Biology, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the DNA and Cell Biology website through July 3, 2017.

Coauthors Berlin Londono-Renteria, Kansas State University, Manhattan, KS, Julio Marinez-Angarita, Instituto Nacional de Salud, Bogota, Colombia, and Andrea Troupin and Tonya Colpitts, University of South Carolina School of Medicine, Columbia, SC, study how mast cells recognize and interact with dengue virus and how mosquito saliva may affect the degranulation response of mast cells and the local immune responses during dengue virus infection in human skin. The researchers provide insights on what occurs during the early stages of dengue transmission and the mechanisms involved in mast cell activation and degranulation, which can increase the permeability of the human vasculature, causing it to become leaky.

Mast cells are best known for their roles in allergies (such as pollen or food) and, for rare people, sensitivity to the saliva injected by mosquitos during bites. In this BIT, Colpitts and co-authors demonstrate the contributions of these cells to the pathogenesis of dengue, a severe disease, says Carol Shoshkes Reiss, PhD, Editor-in-Chief of DNA and Cell Biology and Professor, Departments of Biology and Neural Science, and Global Public Health at New York University, NY. Understanding this may lead us to new approaches to the treatment of dengue fever and dengue shock syndrome. The latter secondary infection can be life-threatening.

Related:

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Dengue: Do mast cells contribute to more severe disease? - Outbreak News Today

June 14, 2017

Female babies are born with a full set of egg precursors in their ovaries, yet the molecular mechanism by which these cells proliferate during embryonic development was unclear. Now, using a mouse model created at A*STAR, an international team of researchers has pinpointed the regulatory factors needed for this rapid cell division to occur in the developing female gonad.

"We have paved the way to study different cell cycle regulatory pathways that may go awry during development," says study author Philipp Kaldis, a senior principal investigator at the A*STAR Institute of Molecular and Cell Biology. Future research in this area, he notes, could lead to new treatments for cancer and infertility.

The embryonic cells that give rise to eggs are known as primordial germ cells, or PGCs. In micewhich have a similar but faster gestation than humansPGCs are identifiable at around the 7th day of development. By day 8, these cells temporarily stop dividing as they migrate inside the embryo. Then, around day 9.5, the cells enter a three-day period of frenetic growth in which they duplicate every 12 hours and the total number of PGCs increases around 50-fold.

Kaldis suspected that a protein called MASTL might be involved in this 72-hour bonanza of cell division since he and others had previously shown that MASTL is essential for the cell cycle to move forward in other cell types and other species.

He thus genetically engineered a mouse in which he could selectively delete the gene encoding MASTL from PGCs. Kaldis then sent the mice to Kiu Liu and Sanjiv Risal at the University of Gothenberg in Sweden, and collectively they showed that the PGCs in these mice could not complete the anaphase step in the cell cycle, in which the duplicated sets of chromosomes are meant to separate inside the dividing cell.

As a result, the PGCs were defective and died instead of multiplying. However, Kaldis and his team showed that proper cell division could be restored in the MASTL-deficient mice if they simultaneously wiped out another cell cycle regulator called PP2A.

The researchers concluded that MASTL normally functions to suppress the activity of PP2A to enable anaphase to proceed properly. And since defects in these germ cells often lead to tumors or infertility, it's possible, Kaldis notes, that MASTL and PP2A are implicated in these health problems as well. "We hope this work will stimulate new research in PGCs," he says.

Explore further: A protein that ensures correct chromosome segregation during cell division can lead to cancer if mutated

More information: Sanjiv Risal et al. MASTL is essential for anaphase entry of proliferating primordial germ cells and establishment of female germ cells in mice, Cell Discovery (2017). DOI: 10.1038/celldisc.2016.52

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Excerpt from:
Regulatory protein ensures that egg precursor cells boost their numbers during embryonic development - Phys.Org