Scripps Research Institute Scientists Capture Picture of ‘MicroRNA’ In Action

Biologists at The Scripps Research Institute (TSRI) have described the atomic-level workings of “microRNA” molecules, which control the expression of genes in all animals and plants.

The findings add greatly to the understanding of a fundamental system of regulation in biology, and should accelerate the development of therapies that harness its power.

“We’ve obtained the clearest picture to date of how these crucial gene regulators work,” said TSRI Associate Professor Ian J. MacRae, who was senior investigator for the study reported in the October 31, 2014 issue of the journal Science.

The Gene Silencers

MicroRNAs, as their name suggests, are snippets of ribonucleic acid, only about 22 nucleotides long. Encoded by genes, they are meant to function as RNA molecules, and are never translated into proteins. In humans there are almost 2,000 distinct microRNAs, which collectively regulate somewhere between 30 and 80 percent of human genes.

MicroRNAs do their work by intercepting and effectively “silencing” the RNA transcripts of genes. These tiny gene-regulators operate in all multicellular organisms, including all plants and animals; even some viruses have them. Moreover, their normal workings appear to be disrupted in many human diseases. Yet their central importance in biology has become apparent only in the last decade or so, and the details of how they silence their targets have started to come into focus only in the last few years.

MicroRNAs operate not on their own, but in the company of large proteins called Argonautes, which microRNAs effectively guide to their RNA targets. In a study reported in Science in 2012, MacRae and his graduate student Nicole T. Schirle used X-ray crystallography techniques to determine, for the first time, the atomic structure of human Argonaute bound to a microRNA and its RNA target.

Seeing How the Process Works

In the new study, the researchers were able to determine the structure of human Argonaute-plus-microRNA in the act of binding to an RNA target. “We could see from these structural data the details of how the process works,” said MacRae.

The data show that Argonaute holds a microRNA molecule in a way that initially exposes only a few of its nucleotides—presumably to minimize interactions with RNAs that aren’t in its target set. These few exposed microRNA nucleotides will, however, stick to the complementary nucleotide sequences found on target RNAs. When such contact is made, Argonaute rearranges its structure to facilitate a tighter embrace of more closely matching targets.

“A key helix structure on Argonaute moves out of the way, allowing further base-pairing between the microRNA guide and its target,” said Schirle. “In general, Argonaute changes its conformation so as to expand the binding and stabilize the interaction with an appropriate target RNA.”

MicroRNAs bind to RNA targets that match its sequence only very partially, in short stretches, which is why a single microRNA may be able to intercept the transcripts of hundreds of different genes. When it binds such transcripts, the microRNA-Argonaute team summons other molecules that effectively block the transcripts from further meaningful activity. By contrast, related regulatory molecules called short interfering RNAs (siRNAs) match their RNA targets more completely, and induce Argonaute to silence those targets more directly, with a built-in enzyme that slices them in two.

The study hints at how Argonaute switches to this more direct mode of silencing. “Slicing requires a catalytic magnesium ion, which has to be held in a precise position over the target,” said Schirle. “What we see now is that this magnesium ion is positioned in the wrong place in the Argonaute structure when a microRNA is bound to its target, so that the target won’t be sliced. We propose that a more extensive pairing with the target RNA, as siRNAs make, would then swing the magnesium ion into the correct position to enable slicing.”

Untapped Medical Potential

The new wealth of structural detail on microRNA-Argonaute function will be of broad scientific interest, but should also make a big impact on medicine. The great therapeutic potential of drugs that mimic or inhibit microRNAs to control key processes in cells is at this point completely untapped.

“There is a whole new class of microRNA-targeting drugs that have been proposed and have started to be developed,” said MacRae, “and here we’ve provided information that should be very helpful in designing such drugs.”

The paper, “Structural basis for microRNA targeting,” was also co-authored by Jessica Sheu-Gruttadauria, a graduate student in the MacRae Laboratory. Funding for the research was provided by the National Institutes of Health (R01 GM104475).

20 Years After BRCA: What We’ve Learned About Genetics and Breast Cancer .

Twenty years ago, scientists announced the discovery of BRCA1, which arguably has become the best-known cancer susceptibility gene in the world. When inherited in a mutated form, the gene sharply increases a woman’s chances of developing breast orovarian cancer, often at an early age. The discovery has changed the way women with a family history of breast and ovarian cancer approach these diseases, helping them better understand their risk and the options for reducing it. It also presents them with complex choices about sharing genetic test results with family members who may also carry the mutated gene.

The hunt for BRCA1 began in earnest in 1990, after Mary-Claire King of the University of California at Berkeley discovered a genetic link to breast and ovarian cancer on chromosome 17. That set in motion a worldwide competition to scour chromosome 17 for the actual gene – dubbed BRCA1 for BReast CAncer 1. In August 1994, Mark Skolnick, PhD, of Myriad Genetics in Salt Lake City, announced his group had found BRCA1 and mapped its DNA sequence.

Huma Q. Rana, MD, medical director for Dana-Farber's Center for Cancer Genetics and Prevention.

While these discoveries led to the identification of BRCA1 – and, a year later, to a secondbreast cancer susceptibility gene, BRCA2 – their roots lay in research begun decades earlier by Dana-Farber’s Frederick P. Li, MD. With his colleague Joseph Fraumeni, MD, Li found that abnormalities in certain inherited genes explained why some families have a pattern of cancer across the generations.

Although only about 5-10 percent of women with breast cancer carry inherited mutations in BRCA1 or 2, those whodo have these harmful mutations face a substantially elevated chance of developing a second breast cancer or ovarian cancer. About 12 percent of women in the general population will develop breast cancer at some point during their lives, research shows. By contrast, 55-65 percent of women who inherit a harmful BRCA1 mutation and about 45 percent who inherit a harmful BRCA2 mutation will develop breast cancer by age 70.

The picture is similar for ovarian cancer. About 1-2 percent of women in the general population develop ovarian cancer. Compatively, 39 percent of women who inherit a BRCA1 mutation and 10-20 percent who inherit a BRCA2 mutation will develop ovarian cancer by age 70.

The discovery of BRCA1 and BRCA2 has removed some of the unknowns about breast and ovarian cancer risk and clarified the choices available to women and men who test positive for harmful mutations in these genes. Those choices include more frequent breast exams; enhanced and early breast imaging/screening; surgery to remove the breasts as well as the ovaries; and medications such as tamoxifen, which, according to several studies, can lower the risk of breast cancer in BRCA1 and 2 mutation carriers.

In the years since the discovery of BRCA1 and 2, research has identified the role these genes normally play in cells, and how mutations disrupt that role, potentially leading to cancer. Researchers led by Dana-Farber’s David Livingston, MD, for example, have shown BRCA1 and 2 to be “tumor-suppressor” genes that help repair damaged DNA within cells. When a mutation interferes with such repairs, the accumulation of DNA damage can send cells on a course to cancer.

Research into the basic workings of BRCA1 and 2 has led to some promising approaches to treating breast and ovarian cancers. Recent studies by investigators at the Susan F. Smith Center for Women’s Cancers at Dana-Farber have shown that chemotherapy agents with platinum, combined with drugs known as PARP inhibitors, are effective at treating BRCA1 and 2-related breast cancer.

Testing positive for BRCA1 or 2 mutations can raise concerns not only about one’s own health but also that of relatives who may also have inherited the mutations. Many cancer centers provide genetic counseling services to help people work through questions about how – or whether – to talk with loved ones about testing.

Rockets ‘destroy chemical weapons’

Micro rocket

The new rockets generate bubbles which powers them forward

A team has developed micro-rockets that can neutralise chemical and biological weapons.

Powered by seawater, the micrometre-sized rockets are capable of degrading agents like anthrax and sarin.

The rockets can “swim” in contaminated samples to decompose them, before eventually self-degrading.

Published in journal ACS Nano, the team says the technology could also decontaminate environmental waste.

“It needs no external stimuli, just expose it to seawater, it then generates a bubble and moves around. In the past, people needed external fuel but here we use seawater as the fuel,” explained Joseph Wang at the University of California, San Diego (UCSD), who was involved in developing the rockets.

Prof Wang said it could degrade both biological weapons and nerve agents like sarin, commonly used as weapons in the Middle East.

“Our rockets can protect against these, faster, cheaper and using less reagents,” he told BBC News.

The rocket is made from magnesium coated with titanium dioxide. A small eye-like opening exposes the magnesium which reacts with the seawater causing a “bubble propulsion” effect which powers it forward.

Anthrax bacteria
The micro-rockets can be used to neutralise dangerous biological weapons like anthrax

This propulsion then enables titanium dioxide to react and break down chemical and biological agents. Titanium dioxide is already known for its amazing ability to break down pollutants. It has previously been used for self-cleaning windows and engineers have even coated cotton with the chemical in an attempt to make clothes clean themselves.

The UCSD scientists say that titanium dioxide is also extremely useful for degrading chemical and biological warfare agents. It produces no toxic waste material and does not need chemicals which have toxic by-products.

One of the next challenges will be to scale up the project to enable the micro-motors to clear a large area of contaminants.

There are broader impacts of the technology too, said Prof Wang. His team are now working on a similar motor which could be used to help treat disease by targeting cancer cells, or it could release drugs inside the body.

The project was funded by the Defense Threat Reduction Agency, a US government organisation.

Measuring Your Sweat, A Health Monitor And Diagnostic Device Is The Future Of Wearable Technology

Scientists are creating a wearable gadget that stimulates and collects sweat via a patch the size of a band-aid, and then analyzes it using your smartphone. 

Sweat, the cooling system of your body, is made almost completely of water, with tiny amounts of other chemicals, including ammonia, urea, salts, and sugar. Remarkably, these chemicals along with the small molecules and peptides they contain can reveal what is going on inside your body. For this reason, scientists are trying to harness sweat through some form of wearable technology and turn it into a new way to measure and monitor your immediate health. “Sweat contains a trove of medical information and can provide it in almost real time,” wrote Dr. Jason Heikenfeld, associate professor of electronic and computing systems, University of Cincinnati, in an article for IEEE Spectrum.

Since, well, nearly forever doctors have been extracting fluids from our bodies in order to evaluate some aspect of our health. How many blood tests, urine tests, or saliva tests have you undergone in your life? For some time now, researchers have been exploring ideas and technologies that might continuously monitor a given biomarker and so open a window on the status of our overall health, in the manner, say, of a diabetic who daily tests her blood sugar levels. Because of its non-invasive (and therefore painless) possibilities, Heikenfeld and his co-researchers began to focus their efforts on using sweat as fuel.

Specifically, Heikenfeld envisions a wearable gadget that stimulates and collects sweat via a patch about the size of a band-aid, and then analyzes it using your smartphone. “Sweat is a vastly untapped biofluid for human performance monitoring,” said Heikenfeld’s collaborator, Dr. Joshua Hagen of the Air Force Research Laboratory, which funds the research.

What would this technology offer? According to Heikenfeld and Hagen, the new gadget would help us map the effects of our lifestyle choices on our immediate health while revealing, possibly, the unseen onset of cancer. The device could monitor heat stress in firefighters and fatigue in first responders. Taking a new prescription drug? Whether during a clinical study or after approval, the gadget could determine our response time and possible side effects in patients. With a complementary tool, paramedics might understand a patient’s condition in short order and then perform as necessary… or quickly diagnose a concussion in a backyard football player.

The value from the perspective of the Air Force is also clear. After investing millions in a fighter jet, a technology to monitor and improve the alertness and cognitive function of its pilot is the natural next step. In particular, the Air Force is hoping the device will be able to accurately measure cytokine biomarkers, as a determination of a pilot’s stress level, and to measure neuropeptide biomarkers, such as Orexin-A, to understand alertness levels and general brain states.

While there’s a good deal of work ahead, Heikenfeld’s lab is refining a patch that includes secure Bluetooth communication, data storage, and a small microcontroller to help conduct signals from the electronic sensors on the patch. In the meantime, a simple physical-exertion sensor patch, created for athletes and measuring only electrolyte imbalances causing dehydration, could appear on the market as early as 2015.

6 Foods You Think Are Vegetarian But Aren’t

Woman buying bananas at the supermarket
These foods — from bananas to orange juice — are commonly mistaken as vegetarian, but actually contain bizarre animal parts that can make a vegetarian cringe. Photo courtesy of Shutterstock

The Food and Drug Administration’s Food Allergen Labeling and Consumer Protection Act of 2004 ruling requires food manufacturers to label common food allergens, leading some companies to be more transparent about the source of their ingredients. However, the FDA does not require food companies to clearly indicate all ingredient sources on the label. This has presented concerns for vegetarians and vegans who have to deal with the ambiguity of ingredients like “natural flavors,” which could be derived from either an animal or plant source.

Most common foods considered to be vegetarian actually contain remnants of non-veg food. Vegetarians and non-vegetarians alike still have to deal with shades of gray when it comes to thinking green. Below are the most common foods considered to be vegetarian but, surprisingly, aren’t receiving a green thumb of approval.

1. Altoids

The go-to fresh breath mint may be friendly for your breath but not for your vegetarian needs. Altoids contain gelatin — a thickening agent used to give gummies and yogurt a jelly-like consistency, but it’s derived from collagen obtained from various animal by-products. Gelatin is used as a stabilizing agent in Altoids. However, in 2011, the mint company altered the ingredients of their Wintergreen mints, adding blue food coloring. Altoid mints labeled “sugar-free smalls” do not contain gelatin. They are a vegetarian friendly option.

2. Bananas

It may seem “bananas” that this potassium-rich food is not vegetarian, but it turns out a spray-on coating designed to lengthen its shelf life may contain animal parts. Chitosan, a bacteria-fighting compound derived from shrimp and crab shells, is used to prevent bananas from ripening, softening and rotting into mush, according to Science Daily. This presents bad news for vegetarians, vegans and those with a shellfish allergy.

Although the banana itself is fine, it’s the spray used to extend its shelf life that makes it non-veg. Gina Keatley, a New York-based dietician at Keatley Medical Nutrition Therapy, told Medical Daily in an email: “The coating is made of shellfish and works amazingly well; however, this makes the product no longer vegan.” She suggests vegetarians and vegans go organic to avoid the spray.

3. Beer

Not all beer is created equal when it comes to being vegetarian friendly. Guinness beer is known to use fish bladder as a fining agent, meaning it removes unwanted leftovers from the brewing process, and could possibly end up in your pint. However, the beer company does not list it as an ingredient on the label.

According to Keatley, fish bladder is used to filter the yeast in some brands, with the thicker British brands being more prone to using tropical fish bladders to filter. She suggests sticking to the big American brands like Budweiser and Coors, which are both vegetarian and vegan friendly.

4. Chips

The nutrition labels on chips sometimes do not distinguish between animal and plant-based enzymes. FritoLay explains on their website enzymes from pork are used to develop the cheese in some of their cheese seasonings. Their BBQ-flavored baked chips contain chicken fat. However, there are FritoLay chips that are free of pork enzymes for vegetarians and vegans to consume.

5. Orange Juice

Orange juice is marketed as “heart healthy,” meaning manufacturers add omega-3s from anchovies, tilapia, and sardines — unless they are synthetic. “[A]lso the vitamin D added is derived from lanolin, which comes from sheep wool, but this differs from brand to brand,” Keatley said. She suggests opting for fresh squeezed orange juice to avoid the non-veg ingredients.

6. Supplements And Vitamins

Vegetarians and vegans looking to get the daily recommended amount of vitamins and minerals should opt for supplements and vitamins that are not in gel caps. Dr. Jennie Ann Freiman, a New York obstetrician-gynecologist told Medical Daily: “[G]el caps are not vegetarian because the capsule is made of gelatin, which is usually beef (can be fish etc. but less likely).” She believes not many people realize this when they shop for supplements and vitamins.

Keep these six vegetarian foods that are actually non-veg in your back pocket when you go food shopping.

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