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Liquid biopsy blood test could provide rapid, accurate method of detecting solid cancers, study finds

Liquid biopsy blood test could provide rapid, accurate method of detecting solid cancers, study finds | Amazing Science | Scoop.it

A blood sample could one day be enough to diagnose many types of solid cancers, or to monitor the amount of cancer in a patient’s body and responses to treatment. Previous versions of the approach, which relies on monitoring levels of tumor DNA circulating in the blood, have required cumbersome and time-consuming steps to customize it to each patient or have not been sufficiently sensitive.


Now, researchers at the Stanford University School of Medicine have devised a way to quickly bring the technique to the clinic. Their approach, which should be broadly applicable to many types of cancers, is highly sensitive and specific. With it they were able to accurately identify about 50 percent of people in the study with stage-1 lung cancer and all patients whose cancers were more advanced.


“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said Maximilian Diehn, MD, PhD, assistant professor of radiation oncology. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”


Even in the absence of treatment, cancer cells are continuously dividing and dying. As they die, they release DNA into the bloodstream, like tiny genetic messages in a bottle. Learning to read these messages — and to pick out the one in 1,000 or 10,000 that come from a cancer cell — can allow clinicians to quickly and noninvasively monitor the volume of tumor, a patient’s response to therapy and even how the tumor mutations evolve over time in the face of treatment or other selective pressures.


“The vast majority of circulating DNA is from normal, non-cancerous cells, even in patients with advanced cancer,” Bratman said. “We needed a comprehensive strategy for isolating the circulating DNA from blood and detecting the rare, cancer-associated mutations. To boost the sensitivity of the technique, we optimized methods for extracting, processing and analyzing the DNA.


The researchers’ technique, which they have dubbed CAPP-Seq, for Cancer Personalized Profiling by deep Sequencing, is sensitive enough to detect just one molecule of tumor DNA in a sea of 10,000 healthy DNA molecules in the blood. Although the researchers focused on patients with non-small-cell lung cancer (which includes most lung cancers, including adenocarcinomas, squamous cell carcinoma and large cell carcinoma), the approach should be widely applicable to many different solid tumors throughout the body. It’s also possible that it could one day be used not just to track the progress of a previously diagnosed patient, but also to screen healthy or at-risk populations for signs of trouble.


Tumor DNA differs from normal DNA by virtue of mutations in the nucleotide sequence. Some of the mutations are thought to be cancer drivers, responsible for initiating the uncontrolled cell growth that is the hallmark of the disease. Others accumulate randomly during repeated cell division. These secondary mutations can sometimes confer resistance to therapy; even a few tumor cells with these types of mutations can expand rapidly in the face of seemingly successful treatment.

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Researchers have genetically engineered trees that will be easier to break down to produce paper and biofuel

Researchers have genetically engineered trees that will be easier to break down to produce paper and biofuel | Amazing Science | Scoop.it
Researchers have genetically engineered trees that will be easier to break down to produce paper and biofuel, a breakthrough that will mean using fewer chemicals, less energy and creating fewer environmental pollutants.


"One of the largest impediments for the pulp and paper industry as well as the emerging biofuel industry is a polymer found in wood known as lignin," says Shawn Mansfield, a professor of Wood Science at the University of British Columbia.


Lignin makes up a substantial portion of the cell wall of most plants and is a processing impediment for pulp, paper and biofuel. Currently the lignin must be removed, a process that requires significant chemicals and energy and causes undesirable waste.


Researchers used genetic engineering to modify the lignin to make it easier to break down without adversely affecting the tree's strength.

"We're designing trees to be processed with less energy and fewer chemicals, and ultimately recovering more wood carbohydrate than is currently possible," says Mansfield.


Researchers had previously tried to tackle this problem by reducing the quantity of lignin in trees by suppressing genes, which often resulted in trees that are stunted in growth or were susceptible to wind, snow, pests and pathogens.


"It is truly a unique achievement to design trees for deconstruction while maintaining their growth potential and strength." The genetic modification strategy employed in this study could also be used on other plants like grasses to be used as a new kind of fuel to replace petroleum.


Genetic modification can be a contentious issue, but there are ways to ensure that the genes do not spread to the forest. These techniques include growing crops away from native stands so cross-pollination isn't possible; introducing genes to make both the male and female trees or plants sterile; and harvesting trees before they reach reproductive maturity.


In the future, genetically modified trees could be planted like an agricultural crop, not in our native forests. Poplar is a potential energy crop for the biofuel industry because the tree grows quickly and on marginal farmland. Lignin makes up 20 to 25 per cent of the tree.


"We're a petroleum reliant society," says Mansfield. "We rely on the same resource for everything from smartphones to gasoline. We need to diversify and take the pressure off of fossil fuels. Trees and plants have enormous potential to contribute carbon to our society."

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First comprehensive atlas of human gene activity released

First comprehensive atlas of human gene activity released | Amazing Science | Scoop.it

A large international consortium of researchers has produced the first comprehensive, detailed map of the way genes work across the major cells and tissues of the human body. The findings describe the complex networks that govern gene activity, and the new information could play a crucial role in identifying the genes involved with disease.


“Now, for the first time, we are able to pinpoint the regions of the genome that can be active in a disease and in normal activity, whether it’s in a brain cell, the skin, in blood stem cells or in hair follicles,” said Winston Hide, associate professor of bioinformatics and computational biology at Harvard School of Public Health (HSPH) and one of the core authors of the main paper in Nature.


“This is a major advance that will greatly increase our ability to understand the causes of disease across the body.”


The research is outlined in a series of papers published March 27, 2014, two in the journal Nature and 16 in other scholarly journals. The work is the result of years of concerted effort among 250 experts from more than 20 countries as part of FANTOM 5 (Functional Annotation of the Mammalian Genome). The FANTOM project, led by the Japanese institution RIKEN, is aimed at building a complete library of human genes.


Researchers studied human and mouse cells using a new technology called Cap Analysis of Gene Expression (CAGE), developed at RIKEN, to discover how 95% of all human genes are switched on and off. These “switches” — called “promoters” and “enhancers” — are the regions of DNA that manage gene activity. The researchers mapped the activity of 180,000 promoters and 44,000 enhancers across a wide range of human cell types and tissues and, in most cases, found they were linked with specific cell types.


“We now have the ability to narrow down the genes involved in particular diseases based on the tissue cell or organ in which they work,” said Hide. “This new atlas points us to the exact locations to look for the key genetic variants that might map to a disease.”

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Eli Levine's curator insight, March 28, 2014 11:27 PM
There it is. As it is in our genes, so too is it in our individual psyches and societies. Check it out!
Martin Daumiller's curator insight, March 29, 2014 4:27 PM

original article: http://www.nature.com/nature/journal/v507/n7493/full/nature13182.html

 

 

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Technology: With a unique program, the US government has managed to drive the cost of genome sequencing down to $1,000

Technology: With a unique program, the US government has managed to drive the cost of genome sequencing down to $1,000 | Amazing Science | Scoop.it

With a unique program, the US government has managed to drive the cost of genome sequencing down towards a much-anticipated target.


The quest to sequence the first human genome was a massive undertaking. Between 1990 and the publication of a working draft in 2001, more than 200 scientists joined forces in a $3-billion effort to read the roughly 3 billion bases of DNA that comprise our genetic material (International Human Genome Sequencing Consortium Nature 409860921; 2001).


It was a grand but sobering success. The project's advocates had said that it would reveal 'life's instruction book', but in fact it did not make it possible to interpret how the instructions encoded in DNA were transformed into biology. Understanding how DNA actually influences health and disease would require studying examples of the links between genes and biology in thousands, perhaps millions, more people. The dominant technology at the time was Sanger sequencing, an inherently slow, labour-intensive process that works by making copies of the DNA to be sequenced that include chemically modified and fluorescently tagged versions of the molecule's building blocks. One company, Applied Biosystems in Foster City, California, provided the vast majority of the sequencers to a limited number of customers — generally, large government-funded laboratories — and there was little incentive for it to reinvent its core technology.


A $7-million award from the NHGRI allowed the company to commercialize a technology called pyrosequencing, which was the first to begin chipping away at Applied Biosystems' monopoly. The funding commitments also ultimately helped to convince private investors to enter the market. Stephen Turner, founder and chief technology officer of Pacific Biosciences in Menlo Park, California, says that his company's 2005 NHGRI grant of $6.6 million helped to attract subsequent venture-capital funding.


The government program has invested $88 million in technologies based on nanopores and nanogaps. The form of this technology closest to the market involves reading bases as they are threaded through a pore (see Nature 456, 2325; 2008), a method that has long promised to save costs and time by reading DNA while it is processed. It would negate the need for expensive and slow reactions to make lots of copies of the molecule. But solving basic issues, including how to move the DNA through the pore slowly enough, has been a major challenge. The NHGRI has funded work to overcome these hurdles — including $9.3 million given to collaborators of the company now ushering the concept to market, UK-based Oxford Nanopore Technologies (Nature http://doi.org/rvm; 2014).


Sequencing still needs much improvement, especially in terms of quality. For all of Sanger sequencing's high cost, it remains the benchmark for accuracy. And sequencing costs are no longer dropping as quickly as they were a few years ago.


But researchers are optimistic that another technology will emerge to challenge Illumina. Most think, in fact, that the crucial questions for the field will shift away from technology. Now that sequencing is cheap enough to talk about scanning every patient's genome, or at least the protein-coding portion of it, it is still not clear how that information will translate into improved care (Nature http://doi.org/rvq; 2014). These more complex issues will require another great leap in genomic science — one that could make the trouncing of Moore's law seem easy


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Medical microrobots to deliver drugs on demand

Medical microrobots to deliver drugs on demand | Amazing Science | Scoop.it

Advances in micro- and nanoscale engineering in the medical field have led to the development of various robotic designs that one day will allow a new level of minimally invasive medicine. These micro- and nanorobots will be able to reach a targeted area, provide treatments and therapies for a desired duration, measure the effects and, at the conclusion of the treatment, be removed or degrade without causing adverse effects. Ideally, all these tasks would be automated but they could also be performed under the direct supervision and control of an external user.Several approaches have been explored for the wireless actuation of microrobots. Among these, magnetic fields have been the most widely employed strategy for propulsion because they do not require special environmental properties such as conductivity or transparency (for instance: "Artificial nano swimmers", with a video that shows the controlled motions of particles in a magnetic field).


This approach allows for the precise manipulation of magnetic objects toward specific locations, and magnetic fields are biocompatible even at relatively high field strengths (MRI).In a new work, a team of researchers from ETH Zurich and Harvard University (David Mooney's lab) demonstrate that additional intelligence – including sensing and actuation – can be instantiated in these microrobots by selecting appropriate materials and methods for the fabrication process.


"Our work combines the design and fabrication of near infrared light (NIR) responsive hydrogel capsules and biocompatible magnetic microgels with a magnetic manipulation system to perform targeted drug and cell delivery tasks, Dr." Mahmut Selman Sakar, a research scientist in Bradley Nelson's Institute of Robotics and Intelligent Systems at ETH Zurich, tells Nanowerk.Reporting their results in the November 4, 2013 online edition of Advanced Materials ("An Integrated Microrobotic Platform for On-Demand, Targeted Therapeutic Interventions"), first-authored by Sakar's co-researcher Stefano Fusco, the team fabricated an untethered, self-folding, soft microrobotic platform, in which different functionalities are integrated to achieve targeted, on-demand delivery of biological agents.

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Jose Mejia R's comment, March 30, 2014 4:40 PM
TRADUCCION:<br>Los avances en la ingeniería de micro-y nanoescala en el campo de la medicina han conducido al desarrollo de diversos diseños robóticos que un día permitirá un nuevo nivel de la medicina mínimamente invasiva. Estos micro-y nano-robots serán capaces de llegar a un área objetiva, proporcionar tratamientos y terapias para una duración deseada, medir los efectos y, a la conclusión del tratamiento, deberá ser eliminado o degradado sin causar efectos adversos. Lo ideal sería que todas estas tareas se pueden automatizar, pero también pueden ser realizados bajo la supervisión y el control directos de un usuario externo. Varios enfoques se han explorado para el accionamiento inalámbrico de microrobots. Entre éstos, los campos magnéticos han sido la estrategia más ampliamente empleada para la propulsión, ya que no requieren propiedades especiales del medio ambiente tales como la conductividad o la transparencia (por ejemplo: "nadadores nano artificial", con un vídeo que muestra los movimientos controlados de partículas en una magnética campo).<br> <br>Este enfoque permite la manipulación precisa de objetos magnéticos hacia lugares específicos, y los campos magnéticos son biocompatibles, incluso a intensidades de campo relativamente altas (MRI). En un nuevo trabajo, un equipo de investigadores de ETH Zurich y la Universidad de Harvard (el laboratorio de David Mooney) demuestran que con inteligencia adicional - incluyendo detección y actuación - se puede crear instancias de estos microrobots seleccionando materiales y procedimientos para el proceso de fabricación adecuadas.<br><br>"Nuestro trabajo combina el diseño y la fabricación de la luz en el infrarrojo cercano (NIR) cápsulas de hidrogel sensible y microgeles magnéticas biocompatibles con un sistema de manipulación magnética para realizar tareas de administración de drogas y de suministro de células específicas, nos diece el Dr. Mahmut Sakar Selman, un científico de investigación en el Instituto de Bradley Nelson de Robótica y Sistemas Inteligentes en la ETH Zurich. Sus resultados indicados el 04 de noviembre 2013 en la edición en línea de Materiales Avanzados ...
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Rice bioengineers invent light tube array to debug genetic circuits

Rice bioengineers invent light tube array to debug genetic circuits | Amazing Science | Scoop.it

Rice University bioengineers have created a toolkit that uses colored lights and engineered bacteria to bring both mathematical predictability and cut-and-paste simplicity to the world of genetic circuit design.


“Life is controlled by DNA-based circuits, and these are similar to the circuits found in electronic devices like smartphones and computers,” said Rice bioengineer Jeffrey Tabor, the lead researcher on the project.

“A major difference is that electrical engineers measure the signals flowing into and out of electronic circuits as voltage, whereas bioengineers measure genetic circuit signals as genes turning on and off.”


In a paper appearing online in the journal Nature Methods, Tabor and colleagues, including graduate student and lead author Evan Olson, describe a new, ultra high-precision method for creating and measuring gene expression signals in bacteria by combining light-sensing proteins from photosynthetic algae with a simple array of red and green LED lights and standard fluorescent reporter genes.


By varying the timing and intensity of the lights, the researchers were able to control exactly when and how much different genes were expressed.  “Light provides us a powerful new method for reliably measuring genetic circuit activity,” said Tabor, an assistant professor of bioengineering who also teaches in Rice’s Ph.D. program in systems, synthetic and physical biology.


“Our work was inspired by the methods that are used to study electronic circuits. Electrical engineers have tools likeoscilloscopes and function generators that allow them to measure how voltage signals flow through electrical circuits. Those measurements are essential for making multiple circuits work together properly, so that more complex devices can be built. We have used our light-based tools as a biological function generator and oscilloscope in order to similarly analyze genetic circuits.”


If a gene is not “expressed,” it is turned off, and its product is not produced. The bacteria used in Tabor’s study have about 4,000 genes, while humans have about 20,000. The processes of life are coordinated by different combinations and timings of genes turning on and off.

Each component of a genetic circuit acts on the input it receives — which may be one or more gene-expression products from other components — and produces its own gene-expression product as an output.


By linking the right genetic components together, synthetic biologists like Tabor and his students construct genetic circuits that program cells to carry out complex functions, such as counting, having memory, growing into tissues, or diagnosing the signatures of disease in the body.

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Five Times Stronger Than Steel: Spider Silk Finally Poised For Commercial Entry

Five Times Stronger Than Steel: Spider Silk Finally Poised For Commercial Entry | Amazing Science | Scoop.it

There is a scene in the film “Spider-Man 2” where Spider-Man prevents a train full of people from crashing by holding it back with about 10 sets of spider silk ropes each less than half an inch thick. It turns out the scene isn’t just fantasy.


“We calculated roughly how thick the fibers were, how many of them he had attached to the walls, how much the locomotive and people weighed, and how fast it appeared to be going,” says Randy Lewis, a professor of biology and biological engineering atUtah State University. “Spider-Man would have been able to stop that train,” says Lewis, a molecular biologist, materials scientist, and chemist who for 25 years has been striving to synthesize spider silk.


Despite being a protein, spider silk is by weight five times stronger than steel and three times tougher than Kevlar, a p-aramid fiber from DuPont. Strength is defined as the weight a material can bear, and toughness is the amount of kinetic energy it can absorb without breaking. The silk’s primary structure is its amino acid sequence, mainly consisting of repeated glycine and alanine blocks.


Potential applications include cables and bulletproof vests. Spider silk’s antimicrobial properties make it suitable for wound patches. Because the silk is not rejected by the human body, it can be used to manufacture artificial tendons or to coat implants. And its thermal conductivity is similar to that of copper but its mass density is one-seventh of copper’s, making it a potential heat management material.

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Sieg Holle's curator insight, March 17, 2014 1:31 AM

tech from nature

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'Barcoding' enables analysis of hundreds of tumor marker proteins at once from tiny tumor samples

'Barcoding' enables analysis of hundreds of tumor marker proteins at once from tiny tumor samples | Amazing Science | Scoop.it
A new technology developed at the Massachusetts General Hospital Center for Systems Biology allows simultaneous analysis of hundreds of cancer-related protein markers from miniscule patient samples gathered through minimally invasive methods.


Minimally invasive techniques – such as fine-needle aspiration or circulating tumor cell analysis – are increasingly employed to track treatment response over time in clinical trials, as such tests can be simple and cheap to perform. Fine needle aspirates are also much less invasive than core biopsies or surgical biopsies, since very small needles are used. The challenge has been to comprehensively analyze the very few cells that are obtained via this method. "What this study sought to achieve was to vastly expand the information that we can obtain from just a few cells," explains Cesar Castro, MD, of the MGH Cancer Centerand CSB, a co-author of the Science Translational Medicine paper. "Instead of trying to procure more tissue to study, we shrank the analysis process so that it could now be performed on a few cells.”  

Up until now, pathologists have been able to examine only a handful of protein markers at a time for tumor analyses. But with this new technology, researchers at CSB have demonstrated the ability to look at hundreds of markers simultaneously down to the single-cell level. "We are no longer limited by the scant cell quantities procured through minimally invasive procedures," says Castro. "Rather, the bottleneck will now be our own understanding of the various pathways involved in disease progression and drug target modulation."

The novel method centers on an approach known as DNA-barcoded antibody sensing, in which unique DNA sequences are attached to antibodies against known cancer marker proteins. The DNA 'barcodes' are linked the antibodies with a special type of glue that breaks apart when exposed to light. When mixed with a tumor sample, the antibodies seek out and bind to their targets; then a light pulse releases the unique DNA barcodes of bound antibodies that are subsequently tagged with fluorescently-labeled complementary barcodes.  The tagged barcodes can be detected and quantified via imaging, revealing which markers are present in the sample. 

After initially demonstrating and validating the technique's feasibility in cell lines and single cells, the team went on to test it on samples from patients with lung cancer.  The technology was able to reflect the great heterogeneity – differences in features such as cell-surface protein expression – of cells within a single tumor and to reveal significant differences in protein expression between tumors that appeared identical under the microscope.  Examination of cells taken at various time points from participants in a clinical trial of a targeted therapy drug revealed marker patterns that distinguished those who did and did not respond to treatment. 

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Egg 2.0: Startup Lab Is Using Plants to Make Next-Gen Super Eggs

Egg 2.0: Startup Lab Is Using Plants to Make Next-Gen Super Eggs | Amazing Science | Scoop.it

Startup Hampton Creek’s mission is to find plant proteins that can replace eggs in spreads, sauces, baked goods, and breakfast favorites. With the help of a few million in venture funding, and an investment from Bill Gates, the company’s scientists have spent the last year scouring the world’s flora with start-up scrappiness. So far, they’ve been surprisingly successful.  With the help of a few million in venture funding, and an investment from Bill Gates, Hampton Creek's scientists have spent the last year scouring the world's flora with start-up scrappiness.


One of Hampton Creek’s key innovations has simply been to look at the food industry from a slightly different perspective. The company’s scientists have approached the egg not as an indivisible unit but rather as a highly optimized tool capable of all sorts of different culinary tricks. “The reason why a chicken egg is great is because it has 22 different functionalities,” Tetrick explains. But different foods use different functionalities. In mayonnaise, the egg’s powers of emulsification and coagulation are key. In baked goods, the egg has other roles: aeration, browning, binding, and texture.


Instead of finding a single plant protein that can replicate all 22 of the egg’s functions, Hampton Creek’s scientists look for plants that can satisfy the criteria for just one of these edible applications. While Yellow Pea, for instance, proved to be the perfect fit for mayo, the company’s egg-less cookie dough is made possible by a particular grain of Sorghum

CEO Josh Tetrick sees a huge opportunity to sell his fake eggs for use in packaged baked goods where their taste (bland, in our experience) is less of a drawback, and their cost (48 percent cheaper than conventional eggs) is more of an asset. “The demand is so intense and the partnership we have with Li Ka-Shing’s group is so wildly phenomenal for us, we think it’s important for us to start by the end of this year,” says Tetrick, who will triple his staff as he spins up for the Asia expansion.

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Superbright fast X-rays image single layer of proteins, providing details of almost 25 percent of known proteins

Superbright fast X-rays image single layer of proteins, providing details of almost 25 percent of known proteins | Amazing Science | Scoop.it

In biology, a protein's shape is key to understanding how it causes disease or toxicity. Researchers who use X-rays to take snapshots of proteins need a billion copies of the same protein stacked and packed into a neat crystal. Now, scientists using exceptionally bright and fast X-rays can take a picture that rivals conventional methods with a sheet of proteins just one protein molecule thick.


Using a type of laser known as XFEL, the technique opens the door to learning the structural details of almost 25 percent of known proteins, many of which have been overlooked due to their inability to stack properly. The team of researchers led by the Department of Energy's Pacific Northwest and Lawrence Livermore National Laboratories report their results with this unique form of X-ray diffraction in the March issue of the International Union of Crystallography Journal.


"In this paper, we're proving it's possible to use an XFEL to study individual monolayers of protein," said PNNL microscopist James Evans. "Just being able to see any diffraction is brand new."


Evans co-led the team of two dozen scientists with LLNL physicist Matthias Frank. The bright, fast X-rays were produced at the Linac Coherent Light Source at SLAC National Accelerator Laboratory in Menlo Park, Calif., the newest of DOE's major X-ray light source facilities at the national laboratories. LCLS, currently the world's most powerful X-ray laser, is an X-ray free-electron laser. It produces beams millions of times brighter than earlier X-ray light sources.


Coming in at around 8 angstrom resolution (which can make out items a thousand times smaller than the width of a hair), the proteins appear slightly blurry but match the expected view based on previous research. Evans said this level of clarity would allow researchers, in some cases, to see how proteins change their shape as they interact with other proteins or molecules in their environment.


To get a clearer view of protein monolayers using XFEL, the team will need to improve the resolution to 1 to 3 angstroms, as well as take images of the proteins at different angles, efforts that are currently underway.


Researchers have been using X-ray crystallography for more than 60 years to determine the shape and form of proteins that form the widgets and gears of a living organism's cells. The conventional method requires, however, that proteins stack into a large crystal, similar to how oranges stack in a crate. The structure of more than 80,000 proteins have been determined this way, leading to breakthroughs in understanding of diseases, pathogens, and how organisms grow and develop.


But many proteins found in nature do not stack easily. Some jut from the fatty membranes that cover cells, detecting and interacting with other cells and objects, such as viruses or bacteria, in the surrounding area. These proteins are not used to having others of their kind stack on top. These so-called membrane proteins make up about 25 percent of all proteins but only 2 percent of proteins that researchers have determined structures for.


Evans, Frank and their team wanted to push this further. The team worked on a way to create one-sheet-thick crystals of two different proteins — a protein called streptavidin and a membrane protein called bacteriodopsin. The structures of both proteins are well-known to scientists, which gave the team something to compare their results to.


The team shined the super-bright X-rays for a brief moment — about 30 femtoseconds, a few million billionths of a second — on the protein crystals. They created so much data in the process that it took them more than a year to analyze all of it.


The resulting images look like the known structures, validating this method. Next, the researchers will try to capture proteins changing shape as they engage in a chemical reaction. For this, even shorter flashes of X-rays might be needed to see the action clearly.

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Why De-Extinction of Birds is a Challenge – The Passenger Pidgeon Case

Why De-Extinction of Birds is a Challenge – The Passenger Pidgeon Case | Amazing Science | Scoop.it

Birds are a huge challenge for de-extinction for two big reasons. The first is because less genomic research has been performed on birds than on mammals (but reptiles, amphibians, fish, invertebrates and plants are even less understood). We don’t know how precisely how the majority of gene pathways in birds work on the cellular levels and up.


Also, birds have no uterus. The reason that the absence of a uterus is a problem for cloning relates to how cloning is done. When you take the nucleus out of an egg cell you kill that cell, it is completely dead. Even after you put a new nucleus in it, the cell is still dead. You have to bring the cell back to life, just like when you shock someone’s heart into beating again. You run electricity through the newly cloned cell to get it to divide. The problem here is that you have to keep stimulating cell division for many generations, up to several hundred and even a few thousand cells before the embryo will develop on its own without assistance. Therefore you cannot take a single cloned cell and implant it into an ovary, oviduct, uterus or any reproductive organ and get it to grow – you have to grow it in the lab and then implant a partially developed embryo. This is okay in a uterus because the embryo implants and develops in a fixed place. In a bird, the embryo is in constant motion within the female’s body – literally tumbling down the oviduct as the oviduct coats the eggshell around the embryo. To implant a cloned embryo one would have to take out the developing embryo from within a developing hard shelled egg within the female’s body and replace it with the cloned embryo – and hope that the embryo integrates into the yolk of the egg and that all the puncturing doesn’t deform the egg or harm the female. So you can see it’s very very tricky.


Are there ways to introduce an extinct bird’s genetics into an embryo without cloning? You can introduce cells into the embryo, which will integrate and create a chimeric bird – a bird that has a patchwork of tissues made of cells of both the original embryo and the cells that were introduced. This can be done after the egg is laid, avoiding tampering with the mother’s internal organ systems. The problem for de-extinction is that adult stem cells (or induced Pluripotent Stem cells, iPCs) cannot contribute to the germ line, only Embryonic stem cells can contribute to the germ line. We can’t easily use embryonic stem cells to recreate the passenger pigeon genome. After as few as seven days in a lab culture, embryonic stem cells have undergone enough cell division to be adult stem cells, and lose the ability to become germ cells. A process to use embryonic stem cells would require introducing a mutation to a band-tailed pigeon embryonic stem cell in less than a matter of a few days, then put it into an embryo and hatch a chimera. This would then require hundreds to even thousands of generations of chimeric birds until we have a passenger pigeon. It would be far more efficient to introduce the thousands of mutations in cell lines, then create a bird. But by the time all the mutations were added, the cells would be adult stem cells. You could make as many chimeras as you want from these “de-extinct” stem cells, but they would never form a breeding line. This does not mean that stem cells cannot become germ cells under experimental conditions, what this means is that they do not naturally become germ cells when placed inside a developing bird embryo. It may be possible in the future to program iPSCs to become germ cells, but currently this is not possible.


Further reading: The Mammoth Cometh (NY Times)

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New live-cell printing technology improves on inkjet printing

New live-cell printing technology improves on inkjet printing | Amazing Science | Scoop.it

A new way to print living cells onto any surface and in almost any shape has been developed by researchers led by Houston Methodist Research Institute nanomedicine faculty member Lidong Qin. Unlike a similar inkjet printing process, almost all cells survive.


The new process, called Block-Cell-Printing (BloC-Printing), produces 2-D cell arrays in half an hour, prints the cells as close together as 5 microns (most animal cells are 10 to 30 microns wide), and allows the use of many different cell types.


“Cell printing is used in so many different ways now — for drug development and in studies of tissue regeneration, cell function, and cell-cell communication,” Qin said. “Such things can only be done when cells are alive and active. A survival rate of 50 to 80 percent is typical as cells exit the inkjet nozzles. “By comparison, we are seeing close to 100 percent of cells in BloC-Printing survive the printing process.”


BloC-Printing manipulates microfluidic physics to guide living cells into hook-like traps in the silicone mold. Cells flow down a column in the mold, past trapped cells to the next available slot, eventually creating a line of cells in a grid.


The position and spacing of the traps and the shape of the channel navigated by the cells is fully configurable during the mold’s creation. When the mold is lifted away, the living cells remain behind, adhering to the growth medium or other substrate, in prescribed formation.


The researchers also printed a grid of brain cells and gave the cells time to form synaptic and autaptic junctions. “The cell junctions we created may be useful for future neuron signal transduction and axon regeneration studies,” Qin said. “Such work could be helpful in understanding Alzheimer’s disease and other neurodegenerative diseases.”


While it is too early to predict the market cost of BloC-Printing, Qin said the materials of a single BloC mold cost about $1 (US). After the mold has been fabricated and delivered, a researcher only needs a syringe, a carefully prepared suspension of living cells, a Petri dish, and a steady hand, Qin said. Inkjet cell printers can cost between $10,000 and $200,000.


“BloC-Printing can be combined with molecular printing for many types of drug screening, RNA interference, and molecule-cell interaction studies,” he said. “We believe the technology has big potential.” While the fidelity of BloC-Printing is high, Qin said inkjet printing remains faster, and BloC-Printing cannot yet print multi-layer structures as inkjetting can.

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Researchers use Google's exacycle cloud computing platform to simulate key drug receptor

Researchers use Google's exacycle cloud computing platform to simulate key drug receptor | Amazing Science | Scoop.it

Roughly 40 percent of all medications act on cells' G protein-coupled receptors. One of these receptors, beta 2 adrenergic receptor site (B2AR), naturally transforms between two base configurations; knowing the precise location of each of approximately 4,000 atoms is crucial for ensuring a snug fit between it and the drug.


Now, researchers at Stanford and Google have conducted an unprecedented, atom-scale simulation of the receptor site's transformation, a feat that could have significant impact on drug design. This is the first scientific project to be completed using Google Exacycle's cloud computing platform, which allows scientists to crunch big data on Google's servers during periods of low network demand.


The study was published in the January issue of Nature Chemistry.

As a type of GPCR, the B2AR is a molecule that sits within the membrane of most cells. Various molecules in the body interact with the receptor's exterior, like two hands shaking, to trigger an action inside the cell.


"GPCRs are the gateway between the outside of the cell and the inside," said co-author Vijay Pande, PhD, professor of chemistry and a senior author of the study. "They're so important for biology, and they're a natural, existing signaling pathway for drugs to tap into."


Lead authors of the study were former postdoctoral scholar Kai Kohlhoff, PhD, and current postdoctoral scholars Diwakar Shukla, PhD, and Morgan Lawrenz, PhD.


Roughly half of all known drugs—including pharmaceuticals and naturally occuring molecules, such as caffeine —target some GPCR, and many new medications are being designed with these receptor sites in mind. Brian Kobilka, professor of molecular and cellular physiology at Stanford, was awarded the 2012 Nobel Prize in Chemistry for his role in discovering and understanding GPCRs.


Traditionally, maps that detail each atom of GPCRs and other receptors are created through a technique called X-ray crystallography. The technique is industry standard, but it can only visualize a molecule in its resting state; receptors naturally change configurations, and their intermediate forms might also have medical potential.


When developing a drug, scientists will often run a computer program, known as a docking program, that predicts how well the atomic structure of a proposed drug will fit into the known receptor.


In the case of GPCRs, for example, the X-ray crystallography techniques have detailed their "on" and "off" configurations; many medications have been specifically designed to fit into these sites. Scientists expect, however, that other fruitful configurations exist. Many drugs engage with GPCR sites, even though computational models suggest that they don't fit either of the two defined reaction site configurations.

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Construction of a Full Vertebrate Embryo from Two Opposing Morphogen Gradients

Construction of a Full Vertebrate Embryo from Two Opposing Morphogen Gradients | Amazing Science | Scoop.it

Scientists at the University of Virginia School of Medicine have overcome one of the greatest challenges in biology and taken a major step toward being able to grow whole organs and tissues from stem cells. By manipulating the appropriate signaling, the UVA researchers have turned embryonic stem cells into a fish embryo, essentially controlling embryonic development.

The research will have dramatic impact on the future use of stem cells to better the human condition, providing a framework for future studies in the field of regenerative medicine aimed at constructing tissues and organs from populations of cultured pluripotent cells.


In accomplishing this, U.Va. scientists Bernard and Chris Thisse have overcome the most massive of biological barriers. "We have generated an animal by just instructing embryonic cells the right way," said Chris Thisse of the School of Medicine's Department of Cell Biology.


The importance of that is profound. "If we know how to instruct embryonic cells," she said, "we can pretty much do what we want." For example, scientists will be able one day to instruct stem cells to grow into organs needed for transplant.


The researchers were able to identify the signals sufficient for starting the cascade of molecular and cellular processes that lead to a fully developed fish embryo. With this study came an answer to the longstanding question of how few signals can initiate the processes of development: amazingly, only two.


The study has shed light on the important roles these two signals play for the formation of organs and full development of a zebrafish embryo. Moreover, the Thisses are now able to direct embryonic development and formation of tissues and organs by controlling signal locations and concentrations.


The embryo they generated was smaller than a normal embryo, because they instructed a small pool of embryonic stem cells, but "otherwise he has everything" in terms of appropriate development, said Bernard Thisse of the Department of Cell Biology.

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CRISPR-CAS9 Reverses Disease Symptoms in Living Animals for First Time

CRISPR-CAS9 Reverses Disease Symptoms in Living Animals for First Time | Amazing Science | Scoop.it

MIT scientists report the use of a CRISPR methodology to cure mice of a rare liver disorder caused by a single genetic mutation. They say their study (“Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype”), published in Nature Biotechnology, offers the first evidence that this gene-editing technique can reverse disease symptoms in living animals. CRISPR, which provides a way to snip out mutated DNA and replace it with the correct sequence, holds potential for treating many genetic disorders, according to the research team.


“What's exciting about this approach is that we can actually correct a defective gene in a living adult animal,” says Daniel Anderson, Ph.D., the Samuel A. Goldblith associate professor of chemical engineering at MIT, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the paper.


The recently developed CRISPR system relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have copied this cellular system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.


At the same time, the researchers also deliver a DNA template strand. When the cell repairs the damage produced by Cas9, it copies from the template, introducing new genetic material into the genome. Scientists envision that this kind of genome editing could one day help treat diseases such as hemophilia, and others that are caused by single mutations.


For this study, the researchers designed three guide RNA strands that target different DNA sequences near the mutation that causes type I tyrosinemia, in a gene that codes for an enzyme called FAH. Patients with this disease, which affects about 1 in 100,000 people, cannot break down the amino acid tyrosine, which accumulates and can lead to liver failure. Current treatments include a low-protein diet and a drug called NTCB, which disrupts tyrosine production.


In experiments with adult mice carrying the mutated form of the FAH enzyme, the researchers delivered RNA guide strands along with the gene for Cas9 and a 199-nucleotide DNA template that includes the correct sequence of the mutated FAH gene.

“Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ~1/250 liver cells,” wrote the investigators. “Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype.”


While the team used a high pressure injection to deliver the CRISPR components, Dr. Anderson envisions that better delivery approaches are possible. His lab is now working on methods that may be safer and more efficient, including targeted nanoparticles. 

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Holographic imaging for rapidly sorting stem cells and cancer cells

Holographic imaging for rapidly sorting stem cells and cancer cells | Amazing Science | Scoop.it

MIT scientists have developed a way to image cells (without fluorescent markers or other labels) as they flow through a tiny microfluidic channel for sorting. This is an important step toward cell-sorting systems that could help scientists separate stem cells at varying stages of development, or to distinguish healthy cells from cancerous cells, the scientists say.


Other cell-sorting methods require adding a fluorescent molecule that highlights the cells of interest, but those tags can damage the cells and make them unsuitable for therapeutic uses. The new method is based on a 2007 microscopy development that allowed the scientists to detail the interior of a living cell in three dimensions, without adding any fluorescent markers or other labels. This technique also revealed key properties, such as the cells’ density.


“Many stem cell applications require sorting of cells at different stages of differentiation. This can be done with fluorescent staining, but once you stain the cells they cannot be used,” says Yongjin Sung, a former postdoc in MIT’sLaser Biomedical Research Center and lead author of a paper describing the technique in the inaugural issue of the journal PRApplied.


“With our approach, you can utilize a vast amount of information about the 3-D distribution of the cells’ mass to sort them.” Instead of using fluorescent tags, the MIT method analyzes the cells’ index of refraction — a measurement of how much the speed of light is reduced as it passes through a material. Every material has a distinctive index of refraction, and this property can be used, along with cells’ volume, to calculate their mass and density.


Different parts of a cell, including individual organelles, have different indices of refraction, so the information generated by this approach can also be used to identify some of these internal cell structures, such as the nucleus and nucleolus, a structure located within the nucleus.


In the original 2007 version of this technology, known as tomographic phase microscopy, researchers led by the late MIT professor Michael Feld created 3-D images by combining a series of 2-D images taken as laser beams passed through cells from hundreds of different angles. This is the same concept behind CT scanning, which combines X-ray images taken from many different angles to create a 3-D rendering.


A key feature of the new MIT system is the use of a focused laser beam that can illuminate cells from many different angles, allowing the researchers to analyze the scattered light from the cells as they flow across the beam. Using a technique known as off-axis digital holography, the researchers can instantaneously record both the amplitude and phase of scattered light at each location of the cells. “As the cell flows across, we can effectively illuminate the entire sample from all angles without having to rotate a light source or the cell,” says former MIT graduate student Niyom Lue, a coauthor of the new paper.


The current system can image about 10 cells per second, but the researchers hope to speed it up to thousands of cells per second, which would make it useful for applications such as sorting stem cells. The researchers also hope to use the system to learn more about how cancer cells grow and respond to different drug treatments.

“This label-free method can look at different states of the cell, whether they are healthy or whether they maybe have cancer or viral or bacterial infections,” says Peter So, an MIT professor of mechanical engineering and biological engineering who is senior author of the new paper. “We can use this technique to look at the pathological state of the cell, or cells under treatment of some drug, and follow the population over a period of time.”


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Two-dimensional crystalline structure assembled from outer shells of a virus

Two-dimensional crystalline structure assembled from outer shells of a virus | Amazing Science | Scoop.it

From steel beams to plastic Lego bricks, building blocks come in many materials and all sizes. Today, science has opened the way to manufacturing at the nanoscale with biological materials. Potential applications range from medicine to optoelectronic devices.


In a paper published in Soft Matter, September 2013, scientists announced their discovery of a two-dimensional crystalline structure assembled from the outer shells of a virus. A virus consists of a protein shell protecting an interior consisting of either DNA or RNA.


"We are excited about the potential of virus-like particles as building blocks for creating new nanostructures," said the paper's lead author, Masafumi Fukuto, a physicist in the Condensed Matter Physics and Materials Science Department at Brookhaven National Laboratory. "For the particular virus that we studied, we discovered two new forms of 2D crystals that are distinct from previously observed hexagonal and square crystals."


The team used as their model system the turnip yellow mosaic virus (TYMV), which infects cruciferous vegetables like cabbages, cauliflower and broccoli. TYMV's protein shell resembles a soccer ball, which is characterized by a set of many axes with rotational symmetry, including two-fold axes between a pair of hexagons, three-fold axes through the center of hexagons, and five-fold axes through pentagons. This is known as icosahedral symmetry: all 20 hexagons are identical and all 12 pentagons are identical.


Fukuto described their work as new because it focuses on the structural diversity in the 2D arrays that arise from the constituent particle's high symmetry and regular shape. "Viruses have been used in previous studies of self-assembly, but in nearly all of those studies, the virus particles were treated as spheres and the ordered 2D arrays observed were hexagonal lattices," he said. "Second, this work is unique for demonstrating a rational approach to 2D crystallization that is based on controlling the interactions of virus particles, which occur at the surface of an aqueous solution where the 2D arrays are formed."

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Siberian scientists announce they now have a high chance to clone the woolly mammoth

Siberian scientists announce they now have a high chance to clone the woolly mammoth | Amazing Science | Scoop.it
Discovery of blood in creature frozen for 43,000 years is seen as major breakthrough by international team.


Viktoria Egorova, chief of the Research and Clinical Diagnostic Laboratory of the Medical Clinic of North-Eastern Federal University, said: 'We have dissected the soft tissues of the mammoth - and I must say that we didn't expect such results. The carcass that is more than 43,000 years old has preserved better than a body of a human buried for six months. 


'The tissue cut clearly shows blood vessels with strong walls. Inside the vessels there is haemolysed  blood, where for the first time we have found erythrocytes. Muscle and adipose tissues are well preserved. 

'We have also obtained very well visualised migrating cells of the lymphoid tissue, which is another great discovery. 


'The upper part of the carcass has been eaten by animals, yet the lower part with the legs and, astonishingly, the trunk are very well preserved. 


'We also have the mammoth's liver - very well preserved, too, and looks like with some solid fragments inside it. We haven't managed to study them yet, but the first suggestion is that possibly these are kidney stones. 


'Another discovery was intestines with remains of the vegetation the mammoth ate before its death, and a multi-chambered stomach what we've been working with today, collecting tissue samples. There is a lot more material that will have to go through laboratory research'. 

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Scientists learn how to ‘herd’ cells – a new approach to tissue engineering

Scientists learn how to ‘herd’ cells – a new approach to tissue engineering | Amazing Science | Scoop.it

Researchers at UC Berkeley found that an electrical current can be used to orchestrate the flow of a group of cells, an achievement that could establish the basis for more controlled forms of tissue engineering and for potential applications such as “smart bandages” that use electrical stimulation to help heal wounds.


In the experiments, described in a study published this week in the journal Nature Materials, the researchers used single layers of epithelial cells, the type of cells that bind together to form robust sheathes in skin, kidneys, cornea and other organs. They found that by applying an electric current of about five volts per centimeter, they could encourage cells to migrate along the direct current electric field.


They were able to make the cells swarm left or right, to diverge or converge and to make collective U-turns. They also created elaborate shapes, such as a triceratops and the UC Berkeley Cal bear mascot, to explore how the population and configuration of cell sheets affect migration.


This is the first data showing that direct current fields can be used to deliberately guide migration of a sheet of epithelial cells,” said study lead author Daniel Cohen, who did this work as a student in the UC Berkeley-UC San Francisco Joint Graduate Program in Bioengineering. “There are many natural systems whose properties and behaviors arise from interactions across large numbers of individual parts – sand dunes, flocks of birds, schools of fish, and even the cells in our tissues. Just as a few sheepdogs exert enormous control over the herding behavior of sheep, we might be able to similarly herd biological cells for tissue engineering.”


Galvanotaxis – the use of electricity to direct cell movement – had been previously demonstrated for individual cells, but how it influences the collective motion of cells was still unclear.


“The ability to govern the movement of a mass of cells has great utility as a scientific tool in tissue engineering,” said study senior author Michel Maharbiz, UC Berkeley associate professor of electrical engineering and computer sciences. “Instead of manipulating one cell at a time, we could develop a few simple design rules that would provide a global cue to control a collection of cells.”


The work was borne from a project, led by Maharbiz, to develop electronic nanomaterials for medical use that was funded by the National Science Foundation’s Emerging Frontiers in Research and Innovation program. The researchers collaborated with W. James Nelson, professor of molecular and cellular physiology at Stanford University and one of the world’s top experts in cell-to-cell adhesion. Cohen is now a postdoctoral research fellow in Nelson’s lab. 

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Silk-Based Implants Could Offer A Better Way to Heal Broken Bones

Silk-Based Implants Could Offer A Better Way to Heal Broken Bones | Amazing Science | Scoop.it

When a person suffers a broken bone, treatment calls for the surgeon to insert screws and plates to help bond the broken sections and enable the fracture to heal. These “fixation devices” are usually made of metal alloys.

But metal devices may have disadvantages: Because they are stiff and unyielding, they can cause stress to underlying bone. They also pose an increased risk of infection and poor wound healing. In some cases, the metal implants must be removed following fracture healing, necessitating a second surgery. Resorbable fixation devices, made of synthetic polymers, avoid some of these problems but may pose a risk of inflammatory reactions and are difficult to implant.


Now, using pure silk protein derived from silkworm cocoons, a team of investigators from Tufts University School of Engineering and Beth Israel Deaconess Medical Center (BIDMC) has developed surgical plates and screws that may not only offer improved bone remodeling following injury, but importantly, can also be absorbed by the body over time, eliminating the need for surgical removal of the devices.


The findings, demonstrated in vitro and in a rodent model, are described in the March 4 issue of Nature Communications. “Unlike metal, the composition of silk protein may be similar to bone composition,” says co-senior author Samuel Lin, MD, of the Division of Plastic and Reconstructive Surgery at BIDMC and Associate Professor of Surgery at Harvard Medical School. “Silk materials are extremely robust. They maintain structural stability under very high temperatures and withstand other extreme conditions, and they can be readily sterilized.”

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Encompass HealthCare's curator insight, July 28, 2014 7:44 PM

At Encompass HealthCare and Wound Medicine, we treat a lot of patients with hardware-related infections following hip replacements, knee replacements, anklebone fusions, and more. There are several reasons that patients sometimes develop these infections.


One reason patients can develop hardware-related infections is due to an infection that develops during the time of the surgery. Even under the most sterile conditions, bacteria that normally sit on the skin can spread into the freshly made incision, causing an infection that tunnels its way down and attaches itself to the very hardware that has been put in place. If this occurs, the patient needs treatment. Usually, I.V. antibiotics are given to try to clear the infection. This works some of the time, however, on occasion, the hardware must be removed, the patient must then be treated with another course of I.V. antibiotics, and then new hardware can be re-inserted by the patient's surgeon.


A second reason patients can develop hardware-related infections is due to an infection that develops sometime after the hardware has been in place. The patient may incur an infection from a completely unrelated incident and the bacteria can attach itself to the hardware. Again, medical protocol most often is a course of I.V. antibiotics, with the possibility of needing to remove the hardware if unsuccessful. Once the body is completely clear of infection, new hardware may be reinserted.


Due to foreign nature of hardware in the human body, a team at Tufts University has tried to find a more body-friendly substance that reduces the risk of infection, while impacting the bones in a less stressful manner.  Scientific gains have been reported by this group, experimenting with silkworm-cocoon derived proteins that may achieve these goals. Consequently, their research suggests that surgical plates and screws made from this material may be better in the long-run for these populations of patients. 


In the meantime, should you suffer an infection, seek help right away. Hardware related infections can be serious.


EncompassHealthcare and Wound Medicine is an outpatient facility featuring advanced wound care, IV antibiotic therapies, hyperbaric oxygen treatment, stem cell and artificial skin grafts, nutritional assessment, wound debridement, wound vacs, venous ablation and other treatment modalities for serious, non-healing wounds and infections. Dr. Bruce Ruben, TheWoundDoc, is the Founder and Medical Director of Encompass HealthCare, located in West Bloomfield, Michigan.

www.encompasshealthcare.com

248-624-9800




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Comparing Genome Editing Technologies (ZNF, TALEN and CRISPR-CAS)

Comparing Genome Editing Technologies (ZNF, TALEN and CRISPR-CAS) | Amazing Science | Scoop.it
ZFN, TALEN, and CRISPR/Cas systems help scientists dissect
the vast amount of information accumulated through
the Genomic Revolution.


The Genomic Revolution has promised to advance medicine and biotechnology by providing scientists with enormous amounts of data that can be converted into useful information.


Over 10 years ago, the Human Genome Project produced the first draft of the more than 3 billion base pairs of DNA that make up the genetic code in each of our cells.


More recent efforts like the 1000 Genomes and HapMap Projects have since focused on identifying the differences within these billions of base pairs of DNA between individuals, while genome-wide association studies have pinpointed specific sequences that determine health and disease. The ENCODE Project and other studies have annotated chromatin states, regulatory elements, transcription factor binding sites, and other epigenetic states throughout the genome.


Dozens of other species have since undergone similar analyses, with the number of sequenced genomes continuously growing. Collectively, these efforts have generated an incredibly rich source of data that promises to aid our understanding of the function and evolution of any genome. However, until recently, scientists have been lacking the tools necessary to interrogate the structure and function of these elements.


While conventional genetic engineering methods could be used to add extra genes to cells, they cannot be easily used to modify the sequences or control the expression of genes that already exist within these genomes. These types of tools are necessary to determine not only the function of genes, but also the role of genetic variants and regulatory elements. They can also be used to overcome longstanding challenges in the field of gene therapy. Without these technologies, it has been difficult—and in some cases impossible—for scientists to capitalize on the Genomic Revolution.

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Scientists use DNA strands to build decomposable nanostructures

Scientists use DNA strands to build decomposable nanostructures | Amazing Science | Scoop.it

A team of researchers in Canada has found a way around the problem of large nanostructures that are used to combat tumors, remaining in the body after they are no longer needed. In their paper published in the journal Nature Nanotechnology, the team describes a technique they developed where they used DNA strands to tie together small nanostructures creating larger nanostructures, that over time—after a tumor had been reduced—broke down and left the body.

Over the past several years, researchers have discovered that nanostructures, built from nanoparticles can be used to deliver drugs directly to a tumor, killing it. This is preferential to chemotherapy because it harms only tumor cells, rather than healthy cells throughout the body. The down side is that the nanostructures are made of materials that are considered toxic if they build up in the body and worse, are a little too big for the body to break down and get rid of. Thus, the nanostructures remain after they are no longer needed. To get around this problem, the researchers took a very unique approach, they used DNA strands to tie small nanostructures together, creating a large enough structure to transport tumor killing drugs. But because they are tied together with DNA, they become untied as the body breaks down the DNA strands. Once loosed, the nanostructures revert back to groups of smaller structures which the body can process and get rid of.


The concept was tested in mice, and results thus far indicate that the process worked as planned—the team was able to actually see the nanostructures as they appeared in the mouse urine, proving that the mice's systems were able to remove the smaller sized nanostructures from the tumor site and pass them through to the renal system.


The researchers report that their technique at this time shows promise, but of course, more work will have to be done to prove that the technique is safe, and that the nanostructures can hold together long enough to do their job. They believe their work will lead to new types of cancer killing agents, but they won't be ready for use in humans for at least five to ten years.

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MicroRNA-Target Binding Structures Mimic MicroRNA Duplex Structures in Humans

MicroRNA-Target Binding Structures Mimic MicroRNA Duplex Structures in Humans | Amazing Science | Scoop.it

MicroRNAs (miRNAs) have emerged as key gene regulators in diverse biological pathways. These small non-coding RNAs bind to target sequences in mRNAs, typically resulting in repressed gene expression. Traditionally, researchers match a microRNA guide strand to mRNA sequences using sequence comparisons to predict its potential target genes. However, many of the predictions can be false positives due to limitations in sequence comparison alone. In a recently published study, scientists consider the association of two related RNA structures that share a common guide strand: the microRNA duplex and the microRNA-target binding structure. They have analyzed thousands of such structure pairs and found many of them share high structural similarity. From this investigation, they conclude that when predicting microRNA target genes, considering just the microRNA guide strand matches to gene sequences may not be sufficient – The microRNA duplex structure formed by the guide strand and its companion passenger strand must also be considered. They have also developed software to translate RNA binding structure into encoded representations, and we have also created novel automatic comparison methods utilizing such encoded representations to determine RNA structure similarity. The presented software and methods can be utilized in the other RNA secondary structure comparisons as well.

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Truncated guide RNAs drastically improve specificity of CRISPR-Cas nucleases

Truncated guide RNAs drastically improve specificity of CRISPR-Cas nucleases | Amazing Science | Scoop.it
A simple adjustment to a powerful gene-editing tool may be able to improve its specificity. Investigators have found that adjusting the length of the the guide RNA component of the synthetic enzymes called CRISPR-Cas RNA-guided nucleases can substantially reduce the occurrence of off-target DNA mutations.


Clustered, regularly interspaced, short palindromic repeat (CRISPR) RNA-guided nucleases (RGNs) are highly efficient genome editing tools123. CRISPR-associated 9 (Cas9) RGNs are directed to genomic loci by guide RNAs (gRNAs) containing 20 nucleotides that are complementary to a target DNA sequence. However, RGNs can induce mutations at sites that differ by as many as five nucleotides from the intended target456. A research team recently reports that truncated gRNAs, with shorter regions of target complementarity <20 nucleotides in length, can decrease undesired mutagenesis at some off-target sites by 5,000-fold or more without sacrificing on-target genome editing efficiencies. In addition, use of truncated gRNAs can further reduce off-target effects induced by pairs of Cas9 variants that nick DNA (paired nickases). These results delineate a simple, effective strategy to improve the specificities of Cas9 nucleases or paired nickases.


"Simply by shortening the length of the gRNA targeting region, we saw reductions in the frequencies of unwanted mutations at all of the previously known off-target sites we examined," says J. Keith Joung, MD, PhD, associate chief for Research in the MGH Department of Pathology and senior author of the report. "Some sites showed decreases in mutation frequency of 5,000-fold or more, compared with full length gRNAs, and importantly these truncated gRNAs -- which we call tru-gRNAs -- are just as efficient as full-length gRNAs at reaching their intended target DNA segments."


CRISPR-Cas RGNs combine a gene-cutting enzyme called Cas9 with a short RNA segment and are used to induce breaks in a complementary DNA segment in order to introduce genetic changes. Last year Joung's team reported finding that, in human cells, CRISPR-Cas RGNs could also cause mutations in DNA sequences with differences of up to five nucleotides from the target, which could seriously limit the proteins' clinical usefulness. The team followed up those findings by investigating a hypothesis that could seem counterintuitive, that shortening the gRNA segment might reduce off-target mutations.


"Some of our experiments from last year suggested that one could mismatch a few nucleotides at one end of the gRNA complementarity region without affecting the targeting activity," Joung explains. "That led us to wonder whether removing these nucleotides could make the system more sensitive to mismatches in the remaining sequence."


Based on a natural system a species of bacteria uses against other pathogens, the CRISPR-Cas RGNs most widely used by researchers includes a 20-nucleotide targeting region within the gRNA. To test their theory, the MGH team constructed RGNs with progressively shorter gRNAs and found that, while gRNAs with targeting segments of 17 or 18 nucleotides were as or more efficient than full-length gRNAs in reaching their targets, those with 15- or 16-nucleotide targeting segments had reduced or no targeting activity. Subsequent experiments found that 17-nucleotide truncated RGNs efficiently induced the desired mutations in human cells with greatly reduced or undetectable off-target effects, even at sites with only one or two mismatches.


"While we don't fully understand the mechanism by which tru-gRNAs reduce off-target effects, our hypothesis is that the original system might have more energy than it needs, enabling it to cleave even imperfectly matched sites," says Joung, who is an associate professor of Pathology at Harvard Medical School. "By shortening the gRNA, we may reduce the energy to a level just sufficient for on-target activity, making the nuclease less able to cleave off-target sites. But more work is needed to define exactly why tru-gRNAs have reduced off-target effects."


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First monkeys with customized mutations born, promising better models for human genetic diseases

First monkeys with customized mutations born, promising better models for human genetic diseases | Amazing Science | Scoop.it

Twin cynomolgus monkeys born in China are the first with mutations in specific target genes. This is an important milestone for targeted gene-editing technology, which in turn promises better models for human diseases.


The ultimate potential of precision gene-editing techniques is beginning to be realized. Today, researchers in China report the first monkeys engineered with targeted mutations1, an achievement that could be a stepping stone to making more realistic research models of human diseases.


Xingxu Huang, a geneticist at the Model Animal Research Center of Nanjing University in China, and his colleagues successfully engineered twin cynomolgus monkeys (Macaca fascicularis) with two targeted mutations using the CRISPR/Cas9 system — a technology that has taken the field of genetic engineering by storm in the past year. Researchers have leveraged the technique to disrupt genes in mice and rats23, but until now none had succeeded in primates.

Transgenic mice have long dominated as models for human diseases, in part because scientists have honed a gene-editing method for the animals that uses homologous recombination — rare, spontaneous DNA-swapping events — to introduce mutations. The strategy works because mice reproduce quickly and in large numbers, but the low rates of homologous recombination make such a method unfeasible in creatures such as monkeys, which reproduce slowly.


"We need some non-human primate models," says Hideyuki Okano, a stem-cell biologist at Keio University in Tokyo. Human neuropsychiatric disorders can be particularly difficult to replicate in the simple nervous systems of mice, he says.


Stem-cell researcher Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, calls the result an interesting demonstration, but says that it offers little scientific insight. "The next step is to see if we can learn anything from it," says Jaenisch, who pioneered the use of transgenic mice in the 1970s.


The combined mutations in Ppar-γ and Rag1 do not represent a particular disease syndrome, says Huang, although each gene is associated with human disorders.The group has yet to fully analyze the monkeys' condition, and must run further tests to assess whether the mutations occurred in all of the animals' cells."Our first aim was to get it done, to get it to work," Huang says. But the finding suggests that researchers could one day model other human conditions involving multiple mutations.


The race is already on to create more CRISPR-modified monkeys, and with greater reliability. Zhang and his colleagues are working to optimize the technology for primate cells, in order to boost mutation efficiency. Okano's team is analyzing unpublished results from monkey models of autism and immune dysfunction, recently created with older gene-editing technologies; they, too, are now trying their luck with CRISPR. And Huang's group is expecting results from eight other pending pregnancies. "There are a lot more things to do," says Huang.

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