allaboutmedisci: March 2017

Thursday, March 30, 2017

Angina (Chest Pain)

Angina is chest pain or discomfort caused when your heart muscle doesn't get enough oxygen-rich blood. It may feel like pressure or squeezing in your chest. The discomfort also can occur in your shoulders, arms, neck, jaw, or back. Angina pain may even feel like indigestion.

But, angina is not a disease. It is a symptom of an underlying heart problem, usually coronary heart disease (CHD).There are many types of angina, including microvascular angina, Prinzmetal's angina, stable angina, unstable angina and variant angina. View an animation of angina.

This usually happens because one or more of the coronary arteries is narrowed or blocked, also called ischemia.

Angina can also be a symptom of coronary microvascular disease (MVD). This is heart disease that affects the heart’s smallest coronary arteries and is more likely to affect women than men. Coronary MVD also is called cardiac syndrome X and non-obstructive CHD. Learn more about angina in women.

Depending on the type of angina you have, there are many factors that can trigger angina pain. The symptoms also vary based on the type of angina you have.

Types of Angina - Knowing the types of angina and how they differ is important.

Understand Your Risk for Angina
If you’re at risk for heart disease or coronary MVD, you’re also at risk for angina. The major risk factors for heart disease and coronary MVD include:

Unhealthy cholesterol levels
High blood pressure
Smoking
Diabetes
Overweight or obesity
Metabolic syndrome
Inactivity
Unhealthy diet
Older age (The risk increases for men after 45 years of age and for women after 55 years of age.)
Family history of early heart disease

Diagnosis of Angina
All chest pain should be checked out by a healthcare provider. If you have chest pain, your doctor will want to find out whether it's angina and if it is, whether the angina is stable or unstable. If it's unstable, you may need emergency medical treatment to try to prevent a heart attack.

Your doctor will most likely perform a physical exam, ask about your symptoms, and ask about your risk factors for and your family history of heart disease and other cardiovascular conditions.

Talk to Your DoctorYour doctor will probably ask you a series of questions to rule out the most critical or life-threatening possibilities. Think ahead so you can provide as much information as possible. Here are some questions you might be asked:

How long have you had this condition?
On a scale of 1 (mild) to 10 (critical), what is your level of discomfort?
What behavior(s) provoke the pain? Physical activity? Eating?
What relieves the discomfort?

Treatment of Angina
All chest pain should be checked by a doctor. If your doctor thinks that you have unstable angina or that your angina is related to a serious heart condition, they may recommend the following tests and procedures:

EKG (Electrocardiogram)
Stress Testing
Blood Tests
Chest X-Rays
Coronary Angiography and Cardiac Catheterization
Computed Tomography Angiography

Treatment of angina includes:

Lifestyle changes
Medicines
Cardiac procedures
Cardiac Rehab

These treatments will help reduce pain and discomfort and how often the angina pain occurs. They will also prevent or lower your risk for heart attack and death by treating whatever underlying cardiovascular condition you may have.
Not all chest pain is a sign of heart disease.

Other conditions also can cause chest pain, such as:

Pulmonary embolism (a blockage in a lung artery)
Aortic dissection (tearing of a major artery)
A lung infection
Aortic stenosis (narrowing of the heart’s aortic valve)
Hypertrophic cardiomyopathy (heart muscle disease)
Pericarditis (inflammation in the tissues that surround the heart)
A panic attack

Microvascular Angina

This type of angina, or chest pain, may be a symptom of coronary microvascular disease (MVD). Coronary MVD is heart disease that affects the heart’s smallest coronary artery blood vessels.

Causes of microvascular angina: Spasms within the walls of these very small arterial blood vessels causes reduced blood flow to the heart muscle leading to a type of chest pain referred to as microvascular angina.

Symptoms of microvascular angina: Angina that occurs in coronary MVD may differ from the typical angina that occurs in heart disease in that the chest pain usually lasts longer than 10 minutes, and it can last longer than 30 minutes. If you have been diagnosed with MVD, follow the directions from your healthcare provider regarding how to treat your symptoms and when to seek emergency assistance.

The pain or discomfort:

May be more severe and last longer than other types of angina pain
May occur with shortness of breath, sleep problems, fatigue, and lack of energy
Often is first noticed during routine daily activities and times of mental stress

Prinzmetal's or Prinzmetal Angina, Variant Angina and Angina Inversa

Prinzmetal's or Prinzmetal Angina, Variant

Angina and Angina Inversa

Unlike typical angina – which is often triggered by exertion or emotional stress - Prinzmetal’s angina almost always occurs when a person is at rest, usually between midnight and early morning. These attacks can be very painful.

Prinzmetal angina may also be referred to as:

Variant angina
Prinzmetal's variant angina
Angina inversa

Prinzmetal’s angina is rare, representing about two out of 100 cases of angina, and usually occurs in younger patients than those who have other kinds of angina.

Causes of Variant (Prinzmetal) Angina: The pain from variant angina is caused by a spasm in the coronary arteries (which supply blood to the heart muscle).

The coronary arteries can spasm as a result of:

Exposure to cold weather
Stress
Medicines that tighten or narrow blood vessels
Smoking
Cocaine use

Symptoms of Variant (Prinzmetal) Angina:

The pain or discomfort:

Usually occurs while resting and during the night or early morning hours
Are usually severe
Can be relieved by taking medication

Treatment of Variant Angina | Prinzmetal's Angina
Medicines can help control the spasms. Drugs such as calcium antagonists and nitrates are the mainstays of treatment.

The spasms tend to come in cycles – appearing for a time, then going away. After six to 12 months of treatment, doctors may gradually reduce the medication.

Prinzmetal's angina is a chronic condition that will need to be followed by your healthcare provider even though the prognosis is generally good.

Unstable Angina

Unstable angina or sometimes referred to as acute coronary syndrome causes unexpected chest pain, and usually occurs while resting. The most common cause is reduced blood flow to the heart muscle because the coronary arteries are narrowed by fatty buildups (atherosclerosis) which can rupture causing injury to the coronary blood vessel resulting in blood clotting which blocks the flow of blood to the heart muscle.

Unstable angina should be treated as an emergency. If you have new, worsening or persistent chest discomfort, you need to go to the ER. You could be having a heart attack which puts you at increased risk for severe cardiac arrhythmias or cardiac arrest, which could lead to sudden death. Learn about an unstable form of angina called Prinzmetal angina.

Causes of Unstable Angina: Blood clots that block an artery partially or totally are what causes unstable angina. Blood clots may form, partially dissolve, and later form again and angina can occur each time a clot blocks blood flow in an artery. Learn more about excessive blood clotting.
Symptoms of Unstable Angina - The pain or discomfort:

Often occurs while you may be resting, sleeping, or with little physical exertion
Comes as a surprise
May last longer than stable angina
Rest or medicine usually do not help relieve it
May get worse over time
Can lead to a heart attack

Treatment for Unstable AnginaFirst, your healthcare provider will need to find the blocked part or parts of the coronary arteries by performing a cardiac catheterization. In this procedure, a catheter is guided through an artery in the arm or leg and into the coronary arteries, then injected with a liquid dye through the catheter. High-speed X-ray movies record the course of the dye as it flows through the arteries, and doctors can identify blockages by tracing the flow. An evaluation of how well your heart is working also can be done during cardiac catheterization. View an illustration of a cardiac catheterization.

Next, based on the extent of the coronary artery blockage(s) your doctor will discuss with you the following treatment options:

Percutaneous coronary intervention (PCI) may be required to open a blocked coronary artery. Briefly, this procedure involves undergoing cardiac catheterization followed by using a catheter with a small inflatable balloon at the tip (View an illustration of a cardiac catheter). The balloon is inflated, squeezing open the fatty plaque deposit located on the inner lining of the coronary artery. Then the balloon is deflated and the catheter is withdrawn. This procedure is often followed by insertion of a stent to then keep the coronary artery vessel propped open to allow for improved blood flow to the heart muscle.
Coronary artery bypass graft surgery may be indicated depending on the extent of coronary artery blockages and medical history. In this procedure, a blood vessel is used to route blood around the blocked part of the artery, forming a kind of detour.

Before any of these procedures, a doctor must find the blocked part or parts of the coronary arteries. He or she will guide a catheter through an artery in the arm or leg and into the coronary arteries, then inject a liquid dye through the catheter. High-speed X-ray movies record the course of the dye as it flows through the arteries, and doctors can identify blockages by tracing the flow. An evaluation of how the heart works also can be done during cardiac catheterization.

Angina Pectoris (Stable Angina)

You may have heard the term “angina pectoris” or “stable angina” in your doctor’s office, but what is it, and what could it mean for you? It’s important to understand the basics.

Angina pectoris is the medical term for chest pain or discomfort due to coronary heart disease. It occurs when the heart muscle doesn't get as much blood as it needs. This usually happens because one or more of the heart's arteries is narrowed or blocked, also called ischemia.
Angina usually causes uncomfortable pressure, fullness, squeezing or pain in the center of the chest. You may also feel the discomfort in your neck, jaw, shoulder, back or arm. (Many types of chest discomfort — like heartburn, lung infection or inflammation — aren‘t related to angina.) Angina in women can be different than in men.

When does angina pectoris occur?
Angina often occurs when the heart muscle itself needs more blood than it is getting, for example, during times of physical activity or strong emotions. Severely narrowed arteries may allow enough blood to reach the heart when the demand for oxygen is low, such as when you're sitting. But, with physical exertion—like walking up a hill or climbing stairs—the heart works harder and needs more oxygen.

Symptoms of Stable Angina - The pain or discomfort:

Occurs when the heart must work harder, usually during physical exertion
Doesn't come as a surprise, and episodes of pain tend to be alike
Usually lasts a short time (5 minutes or less)
Is relieved by rest or medicine
May feel like gas or indigestion
May feel like chest pain that spreads to the arms, back, or other areas

Possible triggers of stable angina include:

Emotional stress – learn stress management
Exposure to very hot or cold temperatures – learn how cold and hot weather affect the heart.
Heavy meals
Smoking – learn more about quitting smoking.

Treatment of Angina Pectoris
People with angina pectoris or sometimes referred to as stable angina have episodes of chest pain. The discomfort that are usually predictable and manageable. You might experience it while running or if you’re dealing with stress.
Normally this type of chest discomfort is relieved with rest, nitroglycerin or both. Nitroglycerin relaxes the coronary arteries and other blood vessels, reducing the amount of blood that returns to the heart and easing the heart's workload. By relaxing the coronary arteries, it increases the heart's blood supply.
If you experience chest discomfort, be sure and visit your doctor for a complete evaluation and, possibly, tests. If you have stable angina and start getting chest pain more easily and more often, see your doctor immediately as you may be experiencing early signs of unstable angina.

Wednesday, March 29, 2017

Improving memory with magnets

The ability to remember sounds, and manipulate them in our minds, is incredibly important to our daily lives -- without it we would not be able to understand a sentence, or do simple arithmetic. New research is shedding light on how sound memory works, and is even demonstrating a means to improve it

Researchers gave 17 individuals auditory memory tasks that required them to recognize a pattern of tones when it was reversed, while being recorded on MEG and EEG.

Scientists previously knew that a neural network of the brain called the dorsal stream was responsible for aspects of auditory memory. Inside the dorsal stream were rhythmic electrical pulses called theta waves, yet the role of these waves in auditory memory were until recently a complete mystery.

To learn precisely the relationship between theta waves and auditory memory, and to see how memory could be boosted, researchers at the Montreal Neurological Institute of McGill University gave seventeen individuals auditory memory tasks that required them to recognize a pattern of tones when it was reversed. Listeners performed this task while being recorded with a combination of magnetoencephalography (MEG) and electroencephalography (EEG). The MEG/EEG revealed the amplitude and frequency signatures of theta waves in the dorsal stream while the subjects worked on the memory tasks. It also revealed where the theta waves were coming from in the brain.

Using that data, researchers then applied transcranial magnetic stimulation (TMS) at the same theta frequency to the subjects while they performed the same tasks, to enhance the theta waves and measure the effect on the subjects' memory performance.

They found that when they applied TMS, subjects performed better at auditory memory tasks. This was only the case when the TMS matched the rhythm of natural theta waves in the brain. When the TMS was arrhythmic, there was no effect on performance, suggesting it is the manipulation of theta waves, not simply the application of TMS, which alters performance.

"For a long time the role of theta waves has been unclear," says Sylvain Baillet, one of the study's co-senior authors. "We now know much more about the nature of the mechanisms involved and their causal role in brain functions. For this study, we have built on our strengths at The Neuro, using MEG, EEG and TMS as complementary techniques."

The most exciting aspect of the study is that the results are very specific and have a broad range of applications, according to Philippe Albouy, the study's first author.

"Now we know human behavior can be specifically boosted using stimulation that matched ongoing, self-generated brain oscillations," he says. "Even more exciting is that while this study investigated auditory memory, the same approach can be used for multiple cognitive processes such as vision, perception, and learning."

The successful demonstration that TMS can be used to improve brain performance also has clinical implications. One day this stimulation could compensate for the loss of memory caused by neurodegenerative diseases such as Alzheimer's.

"The results are very promising, and offer a pathway for future treatments," says Robert Zatorre, one of the study's co-senior authors. "We plan to do more research to see if we can make the performance boost last longer, and if it works for other kinds of stimuli and tasks. This will help researchers develop clinical applications."

This study was published in the journal Neuron on March 23, and was a result of collaboration between the Neuroimaging/Neuroinformatics and Cognition research groups of the MNI.

After blindness, the adult brain can learn to see again

More than 40 million people worldwide are blind, and many of them reach this condition after many years of slow and progressive retinal degeneration. The development of sophisticated prostheses or new light-responsive elements, aiming to replace the disrupted retinal function and to feed restored visual signals to the brain, has provided new hope. However, very little is known about whether the brain of blind people retains residual capacity to process restored or artificial visual inputs.

Fundus of the patient's eye implanted with Argus II Retinal 98 Prosthesis, taken soon after the surgery.

A new study publishing 25 October in the open-access journal PLOS Biology by Elisa Castaldi and Maria Concetta Morrone from the University of Pisa, Italy, and colleagues investigates the brain's capability to process visual information after many years of total blindness, by studying patients affected by Retinitis Pigmentosa, a hereditary illness of the retina that gradually leads to complete blindness.

The perceptual and brain responses of a group of patients were assessed before and after the implantation of a prosthetic implant that senses visual signals and transmits them to the brain by stimulating axons of retinal ganglion cells. Using functional magnetic resonance imaging, the researchers found that patients learned to recognize unusual visual stimuli, such as flashes of light, and that this ability correlated with increased brain activity. However, this change in brain activity, observed at both the thalamic and cortical level, took extensive training over a long period of time to become established: the more the patient practiced, the more their brain responded to visual stimuli, and the better they perceived the visual stimuli using the implant. In other words, the brain needs to learn to see again.

The results are important as they show that after the implantation of a prosthetic device the brain undergoes plastic changes to re-learn how to make use of the new artificial and probably aberrant visual signals. They demonstrate a residual plasticity of the sensory circuitry of the adult brain after many years of deprivation, which can be exploited in the development of new prosthetic implants.

Sunday, March 26, 2017

Spider silk demonstrates Spider man-like abilities

Spider silk offers new inspiration for developments in artificial muscle technology. The silk of the Ornithoctonus Huwena spider demonstrates impressive weight-lifting abilities with efficient, water-driven actuation.

Our muscles are amazing structures. With the trigger of a thought, muscle filaments slide past each other and bundles of contracting fibers pull on the bones moving our bodies. The triggered stretching behavior of muscle is inherently based in geometry, characterized by a decrease in length and increase in volume (or vice versa) in response to a change in the local environment, such as humidity or heat.

Variations of this dynamic geometry appear elsewhere in nature, exhibiting a variety of mechanisms and structures and inspiring development in artificial muscle technology. Spider silk, specifically Ornithoctonus Huwena spider silk, now offers the newest such inspiration thanks to research from a collaboration of scientists in China and the U.S., the results of which are published today in Applied Physics Letters, from AIP Publishing.

"Spider silk is a natural biological material with high sensitivity to water, which inspires us to study about the interaction between spider silk and water," said Hongwei Zhu, a professor in Tsinghua University's School of Material Science and Engineering in Beijing and part of the collaboration. "Ornithoctonus Huwena spider is a unique species as it can be bred artificially and it spins silk of nanoscale diameter."

Besides the shrink-stretch ability of muscles, the way in which the motion is triggered -- how the muscle is actuated -- is a key part of its functionality. These spider silk fibers, actuated by water droplets, showed impressive behavior in all the ways that matter to muscle performance (or to super heroes that may need them to swing from buildings).

"In this work, we reveal the 'shrink-stretch' behavior of the Ornithoctonus Huwena spider silk fibers actuated by water, and successfully apply it on weight lifting," said Zhu. "The whole process can cover a long distance with a fast speed and high efficiency, and further be rationalized through an analysis of the system's mechanical energy."

The research team looked at the actuation process in a few different scenarios, capturing the macro dynamics of the flexing fibers with high speed imaging. They actuated bare fibers on a flat surface (a microscope slide) and while dangling from a fixed point (held with tweezers) before adding a weight to the dangling configuration to test its lifting abilities.

Zhu and his group also investigated the micro structure of the proteins that make up the fibers, revealing the protein infrastructure that leads to its hydro-reflexive action.

Electron microscopy gave a clear picture of the smooth inner threads that make up the fibrous structure, and a laser-driven technique, called Raman spectroscopy, revealed the precise conformation of the protein folding structures making up each layer. Fundamentally, the specific molecular configurations, in this case having proteins that have a strong affinity for water and that rearrange in the presence of water, give rise to the spider silk's actuation.

"Alpha-helices and beta-sheets are two types of secondary protein folding structures in spider silk proteins," said Zhu. "Beta-sheets act as crosslinks between protein molecules, which are thought relevant to the tensile strength of spider silk. A-helices are polypeptide chains folded into a coiled structure, which are thought relevant to the extensibility and elasticity in spider silk protein."

Returning the fiber back to its relaxed state (as one-use muscles are far less useful) requires only removing the water, which offers conservation along with its simplicity. With some fine tuning, there is also potential for designing the precise behavior of the shrink-stretch cycle.

"In addition, as the falling water droplet can be collected and recycled, the lifting process is energy-saving and environmentally friendly," said Zhu. "This has provided the possibility that the spider silk can act as biomimetic muscle to fetch something with low energy cost. It can be further improved to complete staged shrink-stretch behavior by designing the silk fiber's thickness and controlling droplet's volume."

Understanding this remarkable material offers new insight for developing any of a number of drivable, flexible devices in the future.

"The interaction between matter and liquid may result in the structural changes of materials, which can be further applied to actuators, sensors and flexible devices," Zhu said.

Designer proteins fold DNA: Biophysicists construct complex hybrid structures using DNA and proteins

Scientists have developed a new method that can be used to construct custom hybrid structures using DNA and proteins. The method opens new opportunities for fundamental research in cell biology and for applications in biotechnology and medicine.

Desoxyribonucleic acid, better known by its abbreviation DNA, carries our genetic information. But to Prof. Hendrik Dietz and Florian Praetorius from TUM, DNA is also an excellent building material for nanostructures. Folding DNA to create three-dimensional shapes using a technique known as "DNA origami" is a long-established method in this context.

Florian Praetorius and Prof. Hendrik Dietz of the Technical University of Munich (TUM) have developed a new method that can be used to construct custom hybrid structures using DNA and proteins. The method opens new opportunities for fundamental research in cell biology and for applications in biotechnology and medicine.

But there are limits to this approach, explains Dietz. The "construction work" always takes place outside of biological systems and many components must be chemically synthesized. "Creating user-defined structures in sizes on the order of 10 to 100 nanometers inside a cell remains a great challenge," he adds. Their newly developed technique now allows the researchers to use proteins to fold double-stranded DNA into desired three-dimensional shapes. Here, both the DNA and the required proteins can be genetically encoded and produced inside cells.

Proteins act as staples

Designed "staple proteins" based on TAL effectors are the key to the method. TAL effectors are produced in nature by certain bacteria that infect plants and are able to bind to specific sequences in the plant DNA, thereby neutralizing the plant's defense mechanisms. "We've constructed variants of the TAL proteins which simultaneously recognize two custom target sequences at different sites in the DNA and then basically staple them together," says Dietz. "This was exactly the property we needed: proteins that can staple DNA together."

The second component of the system is a DNA double strand containing multiple binding sequences that can be recognized and linked by a set of different staple proteins. "In the simplest case a loop can be created by binding two points to one another," Praetorius explains. "When several of these binding sites exist in the DNA, it's possible to build more complex shapes." An essential aspect of the researcher's work was therefore determining a set of rules for arranging the staple proteins themselves and how to distribute the binding sequences on the DNA double strand in order to create the desired form.

New tools for fundamental research

What's more, the staple proteins serve as anchor points for additional proteins: A method referred to as genetic fusion can be used to attach any functional protein domain desired. The hybrid structures made of DNA and proteins then function as a three-dimensional framework which can put the other protein domains into a particular spatial position. All the building blocks for the DNA protein hybrid structures can be produced by the cell itself and then assemble themselves autonomously. The researchers were able to produce the hybrids in environments resembling cells starting from genetic information. "There is a fairly high probability that this will also work in actual cells," says Dietz.

The new method paves the way for controlling the spatial arrangement of molecules in living systems, which allows probing fundamental processes. For example, it's assumed that the spatial arrangement of the genome has a substantial influence on which genes can be read and how efficient the reading process is. The intentional creation of loops using TAL-DNA hybrid structures in genomic DNA may provide a tool for investigating such processes.

It would also be possible to geometrically position a series of proteins inside and outside the cell in custom ways in order to investigate the influence of spatial proximity for example on information processing in the cell. The spatial proximity of certain enzymes could also make processes in biotechnology more efficient. Lastly, it would also be conceivable to utilize protein-DNA hybrid structures for example to better stimulate the immune response of cells, which can depend on the precise geometrical arrangement of multiple antigens.

Computer program developed to diagnose and locate cancer from a blood sample

Researchers in the United States have developed a computer program that can simultaneously detect cancer and identify where in the body the cancer is located, from a patient's blood sample.

DNA from tumour cells is known to end up in the bloodstream in the earliest stages of cancer so offers a unique target for early detection of the disease.

Researchers in the United States have developed a computer program that can simultaneously detect cancer and identify where in the body the cancer is located, from a patient's blood sample. The program is described in research published this week in the open access journal Genome Biology.

Professor Jasmine Zhou, co-lead author from the University of California at Los Angeles, said: "Non-invasive diagnosis of cancer is important, as it allows the early diagnosis of cancer, and the earlier the cancer is caught, the higher chance a patient has of beating the disease. We have developed a computer-driven test that can detect cancer, and also identify the type of cancer, from a single blood sample. The technology is in its infancy and requires further validation, but the potential benefits to patients are huge."

The program works by looking for specific molecular patterns in cancer DNA that is free flowing in the patients' blood and comparing the patterns against a database of tumour epigenetics, from different cancer types, collated by the authors. DNA from tumour cells is known to end up in the bloodstream in the earliest stages of cancer so offers a unique target for early detection of the disease.

Professor Zhou explained: "We built a database of epigenetic markers, specifically methylation patterns, which are common across many types of cancer and also specific to cancers originating from specific tissue, such as the lung or liver. We also compiled the same 'molecular footprint' for non-cancerous samples so we had a baseline footprint to compare the cancer samples against. These markers can be used to deconvolute the DNA found freely in the blood into tumor DNA and non-tumor DNA."

In this study, the new computer program and two other methods (called Random Forest and Support Vector Machine) were tested with blood samples from 29 liver cancer patients, 12 lung cancer patients and 5 breast cancer patients. Tests were run 10 times on each sample to validate the results. The Random Forest and Support Vector Machine methods had an overall error rate (the chance that the test produces a false positive) of 0.646 and 0.604 respectively, while the new program obtained a lower error rate of 0.265.

Twenty-five out of the 29 liver cancer patients and 5 out of 12 lung cancer patients tested in this study had early stage cancers, which the program was able to detect in 80% of cases. Although the level of tumour DNA present in the blood is much lower during the early stages of these cancers, the program was still able to make a diagnosis demonstrating the potential of this method for the early detection of cancer, according to the researchers.

Professor Zhou added: "Owing to the limited number of blood samples, the results of this study are evaluated only on three cancer types (breast, liver and lung). In general, the higher the fraction of tumor DNAs in blood, the more accurate the program was at producing a diagnostic result. Therefore, tumors in well-circulated organs, such as the liver or lungs are easier to diagnose early using this approach, than in less-circulated organs such as the breast."

Cellular aging pinpointed

The body's ability to repair DNA damage declines with age, which causes gradual cell demise, overall bodily degeneration and greater susceptibility to cancer. Now, research reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The body's ability to repair DNA damage declines with age, which causes gradual cell demise, overall bodily degeneration and greater susceptibility to cancer.

DNA repair is essential for cell vitality, cell survival and cancer prevention, yet cells' ability to patch up damaged DNA declines with age for reasons not fully understood.

Now, research led by scientists at Harvard Medical School reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The findings, published March 24 in Science, offer a critical insight into how and why the body's ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. NAD, identified a century ago, is already known for its role as a controller of cell-damaging oxidation.

Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure.

The scientists caution that the effects of many therapeutic substances are often profoundly different in mice and humans owing to critical differences in biology. However, if affirmed in further animal studies and in humans, the findings can help pave the way to therapies that prevent DNA damage associated with aging and with cancer treatments that involve radiation exposure and some types of chemotherapy, which along with killing tumors can cause considerable DNA damage in healthy cells. Human trials with NMN are expected to begin within six months, the researchers said.

"Our results unveil a key mechanism in cellular degeneration and aging but beyond that they point to a therapeutic avenue to halt and reverse age-related and radiation-induced DNA damage," said senior author David Sinclair, professor in the Department of Genetics at HMS and professor at the University of New South Wales School of Medicine in Sydney, Australia.

A previous study led by Sinclair showed that NMN reversed muscle aging in mice.

A plot with many characters

The investigators started by looking at a cast of proteins and molecules suspected to play a part in the cellular aging process. Some of them were well-known characters, others more enigmatic figures.

The researchers already knew that NAD, which declines steadily with age, boosts the activity of the SIRT1 protein, which delays aging and extends life in yeast, flies and mice. Both SIRT1 and PARP1, a protein known to control DNA repair, consume NAD in their work.

Another protein DBC1, one of the most abundant proteins in humans and found across life forms from bacteria to plants and animals, was a far murkier presence. Because DBC1 was previously shown to inhibit vitality-boosting SIRT1, the researchers suspected DBC1 may also somehow interact with PARP1, given the similar roles PARP1 and SIRT1 play.

"We thought if there is a connection between SIRT1 and DBC1, on one hand, and between SIRT1 and PARP1 on the other, then maybe PARP1 and DBC1 were also engaged in some sort of intracellular game," said Jun Li, first author on the study and a research fellow in the Department of Genetics at HMS.

They were.

To get a better sense of the chemical relationship among the three proteins, the scientists measured the molecular markers of protein-to-protein interaction inside human kidney cells. DBC1 and PARP1 bound powerfully to each other. However, when NAD levels increased, that bond was disrupted. The more NAD present inside cells, the fewer molecular bonds PARP1 and DBC1 could form. When researchers inhibited NAD, the number of PARP1-DBC1 bonds went up. In other words, when NAD is plentiful, it prevents DBC1 from binding to PARP1 and meddling with its ability to mend damaged DNA.

What this suggests, the researchers said, is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and PARP1. The result: DNA breaks go unrepaired and, as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death and loss of organ function.

Averting mischief

Next, to understand how exactly NAD prevents DBC1 from binding to PARP1, the team homed in on a region of DBC1 known as NHD, a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team's experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair.

And, Sinclair added, since NHD is so common across species, the finding suggests that by binding to it, NAD may play a similar role averting harmful protein interactions across many species to control DNA repair and other cell survival processes.

To determine how the proteins interacted beyond the lab dish and in living organisms, the researchers treated young and old mice with the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can easily slip across it. Once inside the cell, NMN binds to another NMN molecule to form NAD.

As expected, old mice had lower levels of NAD in their livers, lower levels of PARP1 and a greater number of PARP1 with DBC1 stuck to their backs.

However, after receiving NMN with their drinking water for a week, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage.

In a final step, scientists exposed mice to DNA-damaging radiation. Cells of animals pre-treated with NMN showed lower levels of DNA damage. Such mice also didn't exhibit the typical radiation-induced aberrations in blood counts, such as altered white cell counts and changes in lymphocyte and hemoglobin levels. The protective effect was seen even in mice treated with NMN after radiation exposure.

Taken together, the results shed light on the mechanism behind cellular demise induced by DNA damage. They also suggest that restoring NAD levels by NMN treatment should be explored further as a possible therapy to avert the unwanted side effects of environmental radiation, as well as radiation exposure from cancer treatments.

In December 2016, a collaborative project between the Sinclair Lab and Liberty Biosecurity became a national winner in NASA's iTech competition for their concept of using NAD-boosting molecules as a potential treatment in cosmic radiation exposure during space missions.

Co-authors on the research included Michael Bonkowski, Basil Hubbard, Alvin Ling, Luis Rajman, Sebastian Moniot, Clemens Steegborn, Dapeng Zhang, L. Aravind, Bo Qin, Zhenkun Lou, and Vera Gorbunova.

The work was funded by the Glenn Foundation for Medical Research, the American Federation for Aging Research, Edward Schulak, grants from the National Institute on Aging and the National Institutes of Health, by the National Library of Medicine/NIH intramural program, the National Cancer Institute, and by Deutsche Forschungsgemeinschaft.

This research project was dedicated to David Sinclair's mother, Diana Sinclair, who bravely survived cancer for two decades

A closer look at living nerve synapses

The brain hosts an extraordinarily complex network of interconnected nerve cells that are constantly exchanging electrical and chemical signals at speeds difficult to comprehend. Now, scientists at Washington University School of Medicine in St. Louis report they have been able to achieve -- with a custom-built microscope -- the closest view yet of living nerve synapses. Nerve synapses are the junctions between neurons that govern how these cells communicate. The researchers have been able to achieve even closer looks than shown, however this image shows multiple working nerve synapses.

Understanding the detailed workings of a synapse -- the junction between neurons that govern how these cells communicate with each other -- is vital for modeling brain networks and understanding how diseases as diverse as depression, Alzheimer's or schizophrenia may affect brain function, according to the researchers.

The study is published March 23 in the journal Neuron.

Studying active rat neurons, even those growing in a dish, is a challenge because they are so small. Further, they move, making it difficult to keep them in focus at high magnifications under a light microscope.

"Synapses are little nanoscale machines that transmit information," said senior author Vitaly A. Klyachko, PhD, an associate professor of cell biology and physiology at the School of Medicine. "They're very difficult to study because their scale is below what conventional light microscopes can resolve. So what is happening in the active zone of a synapse looks like a blur.

"To remedy this, our custom-built microscope has a very sensitive camera and is extremely stable at body temperatures, but most of the novelty comes from the analysis of the images," he added. "Our approach gives us the ability to resolve events in the synapse with high precision."

Until now, close-up views of the active zone have been provided by electron microscopes. While offering resolutions of mere tens of nanometers -- about 1,000 times thinner than a human hair and smaller -- electron microscopes can't view living cells. To withstand bombardment by electrons, samples must be fixed in an epoxy resin or flash frozen, cut into extremely thin slices and coated in a layer of metal atoms.

"Most of what we know about the active zone is from indirect studies, including beautiful electron microscopy images," said Klyachko, also an associate professor of biomedical engineering at the School of Engineering & Applied Science. "But these are static pictures. We wanted to develop a way to see the synapse function."

A synapse consists of a tiny gap between two nerves, with one nerve serving as the transmitter and the other as the receiver. When sending signals, the transmitting side of the synapse releases little packages of neurotransmitters, which traverse the gap and bind to receptors on the receiving side, completing the information relay. On the transmitting side of the synapse the neurotransmitters at the active zone are packaged into synaptic vesicles.

"One of the most fundamental questions is: Are there many places at the active zone where a vesicle can release its neurotransmitters into the gap, or is there only one?" Klyachko said. "A lot of indirect measurements suggested there might be only one, or maybe two to three, at most."

In other words, if the active zone could be compared to a shower head, the question would be whether it functions more as a single jet or as a rain shower.

Klyachko and first author Dario Maschi, PhD, a postdoctoral researcher, showed that the active zone is more of a rain shower. But it's not a random shower; there are about 10 locations dotted across the active zone that are reused too often to be left to chance. They also found there is a limit to how quickly these sites can be reused -- about 100 milliseconds must pass before an individual site can be used again. And at higher rates of vesicle release, the site usage tends to move from the center to the periphery of the active zone.

"Neurons often fire at 50 to 100 times per second, so it makes sense to have multiple sites," Klyachko said. "If one site has just been used, the active zone can still be transmitting signals through its other sites.

"We're studying the most basic machinery of the brain," he added. "Our data suggest these machines are extremely fine-tuned -- even subtle modulations may lead to disease. But before we can study disease, we need to understand how healthy synapses work."

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