Day: 05/07/2015

Marijuana vs. Alcohol: The Effects Psychoactive Drugs Have On Physical And Mental Health

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Marijuana and alcohol are often pitted up against each other in an effort to determine which one is the healthier vice. Marijuana smokers are usually quick to cite smokers incur fewer deaths than drinkers, which is to say there are currently no reported deaths from simply smoking weed. The Huffington Post cited “a marijuana smoker would have to consume 20,000 to 40,000 times the amount of THC in a joint in order to be at risk of dying.”

Marijuana vs alcohol

This isn’t the case for alcohol. The World Health Organization (WHO) found 3.3 million deaths in 2012 were attributed to alcohol consumption. And recently, a comparative assessment published in Scientific Reports found alcohol to be 114 times more deadly than marijuana.

That marijuana doesn’t lead to as many deaths as alcohol does doesn’t mean it’s without any serious side effects. At the end of the day, both are considered to be psychoactive drugs that affect mental processes and cognition when taken or administered, WHO reported.

Here’s a closer look what goes on inside a marijuana smoker versus an alcohol drinker:

Marijuana

THC is the key ingredient in marijuana. It attaches to cannabinoid receptors throughout the body, some of which are more densely populated in certain parts of the brain: the cerebral cortex, hypothalamus, brain stem, hippocampus, cerebellum, and amygdala. The cerebral cortex plays a key role in memory, thinking, and consciousness — so it’s no surprise marijuana alters consciousness and impairs memory; the hypothalamus governs appetite, thus the munchies; and the amygdala plays a role in emotions, which is why some smokers experience anxiety, panic, and paranoia.

In 2012, an Australian study concluded long-term marijuana use reduces the brain’s white matter by 80 percent. White matter is responsible for passing information between different areas of gray matter within the nervous system. Long-term use, too, has been linked to an increased risk for psychosis and schizophrenia (in pre-disposed people). In schizophrenic patients themselves, smoking marijuana worsens symptoms, Forbes reported.

These negative side effects increase when smokers don’t know how much marijuana they’re taking — a more significant problem, it seems, when it comes to edibles. The New York Timesreported a 19-year-old Wyoming college student jumped off his hotel balcony after eating a cookie infused with 65 milligrams of THC. Following this incident a month later, a man “began talking like it was the end of the world” before retrieving a hand gun from the safe and using it to kill his wife.

“The whole industry was set up for people who smoked frequently,” Andrew Freedman, Colorado’s state’s director of marijuana coordination, told The Times. “It needs to learn how to educate new users in the market. We have to create a culture of responsibility around edibles, so people know what to expect to feel.”

That said, much of what people envision to be the effects of smoking marijuana aren’t entirely accurate. An article published in the New England Journal of Medicine suggested smoking marijuana lowers IQ in teens, yet separate research has shown this is only the case among “heavy” marijuana users; scores weren’t affected among “casual” users. In fact, a studypublished in the Journal of School Health found marijuana smokers tended to do better academically than their peers smoking cigarettes.

Forbes added as possible as it is for marijuana to lead to psychosis, one study found marijuana’s other active ingredients, 9-tetrahydrocannabinol (THC) and cannabidiol (CBD), may work as an anti-psychotic. The same is true for the brain stem: While marijuana affects heart rate and blood pressure, it also controls nausea and offers pain relief.

Alcohol

The Centers for Disease Control and Prevention reported a standard drink in the United States contains 1.2 tablespoons of pure alcohol. This amount is present in 12 ounces of beer; 8 ounces of malt liquor; 5-ounces of wine; and 1.5 ounces of 80-proof gin, rum, vodka, or whiskey. Drinking more than the standard amount becomes binge drinking, which the CDC found is the most common form of drinking.

Women who binge drink will drink four or more drinks during a single occasion compared to men who will drink five or more drinks.  Like marijuana, alcohol can make its way to the brain —it is a depressant after all. These sustained brain changes can alter a drinker’s personality.

Prior research has used brain imaging and psychological tests in order to measure the most vulnerable areas, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) reported; these are the cerebellum, limbic system, and cerebral cortex. Alcohol in the cerebellum leads to that loss of balance and stumble, while possibly also affecting memory and emotional response. Heavy alcohol consumption over time can shrink and disturb brain tissue, too.

The thing is, from there, alcohol finds its way to the heart, liver, and pancreas.

Alcohol’s short-term health risks range from car crashes, violence, alcohol poisoning, risky sexual behavior, and miscarriage or still birth. Each risk has a subset of additional risks; for example, violence includes homicide, suicide, sexual assault, and intimate partner violence.

Excessive alcohol (as many people know by now) can increase risk for chronic diseases and other serious physical and mental health problems, including high blood pressure, heart disease, liver disease, as well as cancer, dementia, depression and anxiety, plus a slew of social problems. The CDC reported excessive drinkers are less productive; experience more family problems; and unemployment. Of course, those who excessively drink also put themselves at risk for alcoholism.

There are, however, factors that make a difference, the NIAAA reported; how much and how often a person drinks is number one. A growing body of research suggests drinking alcohol moderately can improve a person’s health. Researchers from Brigham and Women’s Hospital in Boston found drinking seven drinks per week (one per day) was associated with lower risk of heart failure in men and a 16 percent lower risk in women compared to those who didn’t drink at all. One study published in Vaccine even found moderate alcohol improves the immune system’s response to vaccines.

Unlike marijuana, which hampers creativity, alcohol may lead to more “Aha!” moments. As drinkers grow less aware of what’s going on around them, unable to concentrate on tasks at hand (like operating a vehicle), a study from the university of Illinois found men with blood alcohol content just under the legal limit were more creative and insightful; a separate study showed advertising creatives allowed to drink as much as they wanted came up with better ideas than their peers who only drank water.

The bottom line: The way someone reacts to marijuana and alcohol will vary based on how much they use or imbibe, as well as any genetic predispositions (as is the case with marijuana increasing risk for schizophrenia). The general conversation surrounding these particular drugs has become more nuanced the more science and technology develops. As science forages ahead, we can expect to know more about the effects of recreational marijuana and alcohol use.

Physicians and the Right to Die: Anesthesiology News Report

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Marketing 101 for anesthesiologists, and saying ‘no’ to the ASA.

Administers of death: there’s a growing interest in the right to die, but how do physicians fit into it?

More and more anesthesiologists are saying no to the American Society of Anesthesiologists. Some don’t like the high costs, but there are also disagreements on issues and negative beliefs about the leadership.

Just like people who sell goods, anesthesiologists must determine the best ways to serve their “customers” to stay relevant.

Preoperative aspirin decreases postoperative acute kidney injury risk and mortality in patients with CKD undergoing cardiac surgery, found a study.

Opioids are widely prescribed for reproductive-age women, increasing their risk for having a child with birth defects, according to a report.

Post-Transplant LN Patients Can Have Viable Pregnancies

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Outcomes better in women with inactive systemic lupus erythematosus..

Having a renal transplant for lupus nephritis did not rule out successful pregnancies, but outcomes were better in those whose systemic lupus erythematosus (SLE) was inactive, according to an Italian case report.

The researchers, led by Gabriella Moroni, MD, of the Ospedale Maggiore IRCCS, in Milan, analyzed nine pregnancies in three of 38 women who had received kidney transplants at their center. Two patients had received a kidney from a living related donor and one had a received a transplant from a deceased donor.

From 2002 to 2013, five of these post-transplant pregnancies ended in miscarriage. All mothers were in their 30s by the time they conceived, and their initial pregnancies occurred at 4 years, more than 7 years, and almost 9 years after transplantation. In the last case, after two miscarriages, the woman had her first successful pregnancy more than 10 years’ post-transplant at age 38, the group wrote online in Lupus.

Miscarriages in transplanted patients are common, and preconception counseling is essential, the investigators noted.

“Women with stable and prolonged remission of SLE, normal renal function, normal blood pressure, and negative antiphospholipid antibodies (aPL) have good probabilities of positive fetal and maternal outcomes,” they explained.

However, they added that very few cases of post-transplant pregnancy in lupus nephritis (LN) patients have been reported in the literature.

In their study, patients were followed at least once a month and then followed twice weekly from 24 weeks’ gestation onward (including with serial placental Doppler imaging), hospitalized when necessary, and cared for by a multidisciplinary team of gynecologists and nephrologists.

All infants were delivered via cesarean, and the majority were of low birth rate, which may have been partly due to early surgical delivery, the authors explained. However, the infants were healthy and without serious complications, they added.

Immunosuppressive therapy consisted of steroids, calcineurin inhibitors, and mycophenolate mofetil (MMF), which had been replaced with azathioprine before conception. All patients had normal renal function and urinalysis (serum creatinine <1.5 mg/dL) and nonsignificant proteinuria (<500 mg/day). Some signs of immunological activity persisted after transplantation in two patients.

The authors stressed that before pregnancy, patients’ immunosuppressive regimens must be re-evaluated for possible teratogenic effects. They recommended switching from MMF to azathioprine. Also, ACE inhibitors must be discontinued before or at conception, they advised.

They reported that two pregnancies were uneventful. Pre-eclampsia occurred in a hypertensive patient in two pregnancies that ended in preterm delivery in one and newborns of small-for-gestational-age size in both. The authors ascribed these good results partly to the well-planned pregnancies and the specialized intensive care and imaging.

Significantly, although the risk of post-pregnancy graft loss in transplanted mothers is about around 6.9% within the first 5 years of giving birth, graft function continued to be normal in all patients. “To reduce such a risk it is wise to discourage pregnancy within the first year after transplantation,” they wrote. Urinalysis results also remained normal.

The authors noted that recent studies suggest that hydroxychloroquine improves obstetrical outcomes and should be part of immunosuppressive therapy throughout pregnancy.

“It is also important that patients start low-dose aspirin within the first trimester of pregnancy as primary prophylaxis for pre-eclampsia,” they cautioned.

Based on their experience and on published guidelines for renal transplanted patients, Moroni’s group concluded that “pregnancy in patients with kidney transplant due to LN should not be discouraged,” adding that “pre-conception counseling is mandatory.”

Venom As Medicine: How Spiders, Scorpions, Snakes, And Sea Creatures Can Heal

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Tarantula
Tarantulas harbor proteins and toxins that are used as painkillers. CC BY-NC-ND 2.0

Evolutionarily, humans are scared of creepy-crawlers and poisonous things. Our fight-or-flight kicks in whenever we’re confronted with something that has more than 4 legs, stares at us with 8 glistening eyes, or exhibits protruding fangs or a stinger. Either you kill that spider or you run away from it, as shudders contort your body and squeals escape your lips.

However, science shows that the venoms of the natural world can actually be harvested as potential medicinal treatments and cures. From using scorpion, bee, and snake venom for cancer treatments to employing venom immunotherapy to treat insect sting allergies, researchers have investigated the therapeutic effects of a wide variety of animal and insect poisons. And it turns out that when used the right way, the poisons that would typically kill us can actually save our lives, too.

“Ironically, the properties that make venom deadly are also what make it so valuable for medicine,” Jennifer Holland writes for National Geographic. “Many venom toxins target the same molecules that need to be controlled to treat disease. Venom works fast and is highly specific. Its active components — those peptides and proteins, working as toxins and enzymes – target particular molecules, fitting into them like keys into locks.”

Thousands of animals are venomous — from snakes, scorpions, spiders, and bees to lizards, octopuses, fish, and snails. Researchers still haven’t studied or unleashed all the medicinal properties of these thousands of different venoms, all of which are seething with various toxins, proteins, molecules, and enzymes that could potentially be used to treat diseases. But below are the current ways that scientists have used venoms in medicine.

SpiderTarantulas produce toxins that are used in painkiller drugs. 

Spiders

According to a 2012 study out of the University of Buffalo, a particular protein found in spider venom could work as a treatment for muscular dystrophy — an umbrella term for a number of diseases that cause loss of muscle mass and eventual inability to walk, move, or swallow. The study found that the protein helped stop muscle cells from deteriorating, and though it wasn’t a cure, it assisted in slowing down the progression of the disease.

Tarantulas, in particular, have been shown to harbor healing properties in their venom. One 2014 study out of Yale University described a new screening process known as “toxineering” that could sift through millions of spider toxins and find which ones were most compatible in painkiller drugs. They found that one toxin in the Peruvian green velvet tarantula could block chronic pain. Another recent study found that 7 different compounds in spider venom could potentially be used to help people with chronic pain too. Researchers analyzed 206 different spider species, and found that 40 percent of the venoms had compounds that blocked nerve activity linked to chronic pain.

centipedeThe creepy crawlers that hang out in niches and in your basement may provide scientists with certain therapeutic properties. 

Centipedes

It turns out that centipedes may be used as painkillers, too. In one study, researchers examined the effects of the Chinese redheaded centipede which injects its prey with venom that blocks a sodium channel protein and ultimately paralyzes its victims. They then tested mice with a peptide taken from the venom, and found that it was comparable to the effects of morphine — the mice were able to tolerate thermal, chemical, and acid pain tests.

ScorpionsScorpions may be some of the freakiest creepy-crawlers on this planet, but their venom has medicinal properties. 

Scorpions

Similarly to the centipede and spider peptides that are able to interact with sodium channels, researchers found in a 2010 study that scorpion venom too could have painkiller properties. But this isn’t all: researchers also found that scorpion venom could assist in fighting cancer.

Seattle researchers developed something called “tumor paint” out of scorpion venom, which was successful in identifying brain cancer and lighting it up for doctors to see. They re-engineered a specific protein from the Israeli deathstalker scorpion to make it bind to cancer cells, then tied it to a fluorescent molecule that acts as a sort of flashlight or glow to assist in surgeries or identifying cells within the body. “The scorpion toxin finds the cancer cells and drags the flashlight into them and makes them glow brilliantly,” Dr. Jim Olson, a brain cancer specialist at Seattle Children’s Hospital, said, according to ABC News.

SnakeSnake venom is already used by doctors in various drugs to treat heart problems and even disorders like Alzheimer’s and Parkinson’s. Wikimedia

Snakes

Scientists have been studying the medicinal properties of various snake venoms for decades. For example, certain Tunisian vipers have been shown to have anti-tumor properties. Others have antibacterial and painkiller features.

Hemotoxins in snake venom target the circulatory system, and typically attack the body’s clotting ability and muscles. But scientists have also found ways to use hemotoxins for medicine — such as treating heart attacks and blood disorders. Other drugs have been developed from neurotoxins in snake venom, which are used to treat Alzheimer’s and Parkinson’s, as well as stroke and brain injuries; more research will need to be done to better understand the medicinal properties of these toxins.

sea anemoneSea creatures like anemones that contain poison have also been shown to have medicinal properties.

Sea Creatures

Deep in the ocean, thousands and even millions of critters lurk way out of our sight. But many of them may harbor potential cures and treatments for diseases in their venom. One studyfound that sea anemones and core snails produce toxins that could treat autoimmune diseases like arthritis, multiple sclerosis, and lupus.

An alternative state of pluripotency: New stem cell may overcome hurdles for regenerative medicine

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Scientists at the Salk Institute have discovered a novel type of pluripotent stem cell—cells capable of developing into any type of tissue—whose identity is tied to their location in a developing embryo. This contrasts with stem cells traditionally used in scientific study, which are characterized by their time-related stage of development.

In the paper, published May 6, 2015 in Nature, the scientists report using these new to develop the first reliable method for integrating human stem cells into nonviable mouse embryos in a laboratory dish in such a way that the began to differentiate into early-stage tissues.

“The region-specific cells we found could provide tremendous advantages in the laboratory to study development, evolution and disease, and may offer avenues for generating novel therapies,” says Salk Professor Juan Carlos Izpisua Belmonte, senior author of the paper and holder of Salk’s Roger Guillemin Chair.

The researchers dubbed this new class of cells “region-selective pluripotent stem cells,” or rsPSCs for short. The rsPSCs were easier to grow in the laboratory than conventional human and offered advantages for large-scale production and gene editing (altering a cell’s DNA), both desirable features for cell replacement therapies.

To produce the cells, the Salk scientists developed a combination of chemical signals that directed human stem cells in a laboratory dish to become spatially oriented.

They then inserted the spatially oriented human stem cells (human rsPSCs) into specific regions of partially dissected mouse embryos and cultured them in a dish for 36 hours. Separately, they also inserted human stem cells cultured using conventional methods, so that they could compare existing techniques to their new technique.

While the human stem cells derived through conventional methods failed to integrate into the modified embryos, the human rsPSCs began to develop into early stage tissues. The cells in this region of an early embryo undergo dynamic changes to give rise to all cells, tissues and organs of the body. Indeed the human rsPSCs began the process of differentiating into the three major cell layers in early development, known as ectoderm, mesoderm and endoderm. The Salk researchers stopped the cells from differentiating further, but each germ layer was theoretically capable of giving rise to specific tissues and organs.
New stem cell may overcome hurdles for regenerative medicine

Collaborating with the labs of Salk Professors Joseph Ecker and Alan Saghatelian, the Izpisua Belmonte team performed extensive characterization of the new cells and found rsPSCs showed distinct molecular and metabolic characteristics as well as novel epigenetic signatures—that is, patterns of chemical modifications to DNA that control which genes are turned on or off without changing the DNA sequence.

“The region selective-state of these stem cells is entirely novel for laboratory-cultured stem cells and offers important insight into how human stem cells might be differentiated into derivatives that give rise to a wide range of tissues and organs,” says Jun Wu, a postdoctoral researcher in Izpisua Belmonte’s lab and first author of the new paper. “Not only do we need to consider the timing, but also the spatial characteristics of the stem cells. Understanding both aspects of a stem cell’s identity could be crucial to generate functional and mature cell types for regenerative medicine.”

Fresh evidence for how water reached Earth found in asteroid debris

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Water delivery via asteroids or comets is likely taking place in many other planetary systems, just as it happened on Earth, new research strongly suggests.

Published by the Royal Astronomical Society and led by the University of Warwick, the research finds evidence for numerous planetary bodies, including asteroids and comets, containing large amounts of water.

Fresh evidence for how water reached Earth found in asteroid debris

The research findings add further support to the possibility water can be delivered to Earth-like planets via such bodies to create a suitable environment for the formation of life.

Commenting on the findings lead researcher Dr Roberto Raddi, of the University of Warwick’s Astronomy and Astrophysics Group, said:”Our research has found that, rather than being unique, water-rich asteroids similar to those found in our Solar System appear to be frequent. Accordingly, many of planets may have contained a volume of water, comparable to that contained in the Earth.

“It is believed that the Earth was initially dry, but our research strongly supports the view that the oceans we have today were created as a result of impacts by water-rich comets or asteroids”.

In observations obtained at the William Herschel Telescope in the Canary Islands, the University of Warwick astronomers detected a large quantity of hydrogen and oxygen in the atmosphere of a white dwarf (known as SDSS J1242+5226). The quantities found provide the evidence that a water-rich exo- was disrupted and eventually delivered the water it contained onto the star.

The asteroid, the researchers discovered, was comparable in size to Ceres – at 900km across, the largest asteroid in the Solar System. “The amount of water found SDSS J1242+5226 is equivalent to 30-35% of the oceans on Earth”, explained Dr Raddi.

The impact of water-rich asteroids or comets onto a planet or white dwarf results in the mixing of hydrogen and oxygen into the atmosphere. Both elements were detected in large amounts in SDSS J1242+5226.

Research co-author Professor Boris Gänsicke, also of University of Warwick, explained:

“Oxygen, which is a relatively heavy element, will sink deep down over time, and hence a while after the disruption event is over, it will no longer be visible.

“In contrast, hydrogen is the lightest element; it will always remain floating near the surface of the white dwarf where it can easily be detected. There are many that hold large amounts of hydrogen in their atmospheres, and this new study suggests that this is evidence that water-rich asteroids or comets are common around other stars than the Sun”.

Read more at: http://phys.org/news/2015-05-fresh-evidence-earth-asteroid-debris.html#jCp

Russian physicists launch campaign to rebuild teslas wardenclyffe tower and power the world

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“Tesla was right and we are ready to prove it!” So say the two Russian physicists who have just launched an Indiegogo campaign to rebuild Nikola Tesla’s Wardenclyffe Tower in Fall, 2014. Tesla believed that the tower could transmit power wirelessly but this was never definitively proven in his lifetime.

If he was right, and after extensive study the team are convinced he was, the project could provide an efficient, worldwide energy transmission system that would distribute all the clean energy we can use. That Tesla was a genius is undisputed even by his detractors, but more than 70 years after his death, he remains a polarizing figure.

Leonid Plekhanov and Sergey Plekhanov have spent the last five years studying and modeling Tesla’s notes and patents for the tower and they are certain the project is viable with the use of modern materials and technology. As their Indiegogo page notes: “Nikola Tesla had left us a very detailed description of the design of his Magnifying Transmitter System and the physical principles of its operation. We are a group of modern-day physicists, trained in many areas related to the operation of his Worldwide Energy System.

We’ve conducted a thorough scientific expertise of his works and came to the conclusion that Tesla was on the right track.” The principle behind the current design is that we already have an unlimited source for all the energy we could need – the sun. A 100,000 square kilometer solar array in a nice, sunny desert somewhere could provide for all our global power needs. The problem lies in distributing that power, as current systems leak so much energy. Tesla’s proposed network of towers were designed to make use of the Earth’s own inherent conductivity, transmitting energy through the ground and the ionosphere with very little wastage.

A detailed description of how a tower works can be found here. While Tesla’s original tower on Long Island weighed in at 60 tons, the prototype the Plekhanovs plan to build will only weigh two tons due to advances in materials.

Its Tesla coil will be about 20 meters long. The team are hoping to raise $800,000 to build their prototype via the Indiegogo campaign, which finishes up on July 25, 2014. They successfully raised $40,000 via crowdfunding last year for research and design work on the power source. A project timeline and budget are provided, and in the spirit of Tesla’s magnanimity, they pledge to make their results freely available online once the tower has been put into operation.

Patient Turned Researcher Helps Advance Understanding of Brain Tumors

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Interested in seeing images of his brain, Steven Keating, currently a graduate student at the MIT Media Lab, volunteered for a research study while attending school in Canada in 2007. When researchers returned his brain scans, they delivered some startling news.

“The researchers told me I had an abnormality near the smell center in my brain, but that lots of people have abnormalities and I shouldn’t be alarmed,” says Steven. However, as a precaution, researchers advised Steven to get his brain re-scanned in a few years.

Brain tumor patient turned researcher

 

 

 

 

 

 

 

 

 

Steven’s next set of brain scans, performed in 2010, showed no changes. But in July 2014, he started smelling a strange vinegar scent for about 30 seconds each day. He immediately had his brain scanned and learned that the strange smell was associated with small seizures due to the presence of a brain tumor called a glioma. Steven’s glioma had grown to the size of a baseball.

Steven met with E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at Brigham and Women’s Hospital (BWH), who performed image-guided brain surgery on Steven last summer in BWH’s Advanced Multimodality Image Guided Operating (AMIGO) suite.

Since his surgery, Steven has gone through rounds of proton radiation and chemotherapy. He began another round of chemotherapy at Dana-Farber Cancer Institute in February 2015. Steven says he is extremely grateful for his care team, including Chiocca; Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber/Brigham and Women’s Cancer Center; Keith Ligon, MD, PhD, a neuropathologist at Dana-Farber/Brigham and Women’s; and Helen Alice Shih, MD, associate medical director of the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital.

Ever curious, Steven asked to have his surgery videotaped and his genome sequenced, and this information was used to print 3-D models of his brain and tumor. He also has been working with Chiocca and others on 3-D printing research and has given various talks and presentations about his work and his patient experience. Most recently, Steven was invited to the White House for discussions on the importance of allowing patients to have access to their health data.

Chiocca said it has been wonderful working with Steven, both as a patient and researcher. While it’s pretty rare that patients ask for their surgery to be filmed, he said it is valuable for them to participate in the research side of their care when possible.

“It is very easy for a patient to become depressed by their disease,” says Chiocca. “But Steven’s approach of being actively involved to raise consciousness and funding for more research for this type of tumor is remarkable. I’m just so proud to have been involved in his care.”

Study finds protein ‘cement’ that stabilizes the crossroad of chromosomes

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Cell division is the basis of life and requires that each daughter cell receive the proper complement of chromosomes. In most organisms, this process is mediated at the familiar constricted intersection of X-shaped chromosomes. This area, called the centromere, is where special proteins gather and attach to pull daughter cells apart during cell division. The structure and biology of the centromere is of considerable scientific interest because problems with it can lead to abnormalities in the chromosomes of daughter cells, which are the basis of such disorders as Down syndrome.
Penn team finds protein 'cement' that stabilizes the crossroad of chromosomes

A new study by researchers at the Perelman School of Medicine at the University of Pennsylvania published in Science this week describes how the centromere is stabilized during replication. DNA in the nucleus is packaged into protein/DNA complexes called nucleosomes. As it turns out, the centromere is distinguished not only by its DNA sequence but also by a special type of nucleosome, which includes a protein called CENP-A.

Senior author Ben E. Black PhD, associate professor of Biochemistry and Biophysics, and his Penn team described the structure of CENP-A almost five years ago. The question the investigators asked now was, how does the cell ensure that CENP-A-containing nucleosomes remain at, and thus continue to mark, the centromere during the massive changes a cell undergoes when it divides?

Simply put, it involves an accessory protein called CENP-C. “Overall, my lab is interested in better understanding the molecular basis of inheritance and the role of the centromere, as a ‘control locus,’ for maintaining heredity,” says Black.

His team applied a battery of biophysical techniques to study the structure and stability of CENP-A-containing nucleosomes in a test tube. Their data indicate that CENP-A-bearing nucleosomes have an unexpectedly flexible structure, adopting a relaxed conformation in the absence of CENP-C, and a more compact shape in its presence. This CENP-C-induced shape shift correlates with changes in how DNA wraps around the centromere’s nucleosomes, making the structure similar to that found in living cells.

Their findings also address the question of the stability of CENP-A molecules at centromeres. Under normal conditions CENP-A binds centromeres and effectively never lets go. Indeed, when the authors tracked where proteins “reside” in live cells, they found that, unlike traditional nucleosomes that package the DNA throughout the rest of the chromosome, CENP-A-containing nucleosomes apparently never dissociate after newly generated CENP-A protein is first delivered to the centromere during a short time window following . “The CENP-A is basically cemented at the centromere of origin,” Black explains. But in cells lacking CENP-C, CENP-A dissociates readily, suggesting that CENP-C binding to CENP-A is what imparts that stability.

Investigators have known for the past 20 years that part of chromosome inheritance is controlled by epigenetics, implicating the protein spools around which DNA is wound as the driving force, rather than what is encoded in the DNA sequence itself. Those spools are built of histone proteins, and chemical changes to these spool proteins can either loosen or tighten their interaction with DNA. This, in turn, alters a gene’s expression up or down. In the case of the centromere, it marks the site where spindle fibers attach independently of the underlying DNA sequence.

Earlier, Black and other chromosome researchers established that CENP-A is the key epigenetic protein at the centromere and replaces the regular histone protein H3. CENP-A attracts other proteins, and in cell division builds a massive structure called the kinetochore, for pulling duplicated chromosomes apart during cell division.

Black notes that these data suggest a model of epigenetic biology distinct from the traditional view of nucleosomes as static scaffolds on which key functional molecules assemble. Instead, the team’s data suggest that histone variants and post-translational modifications, which change the biological properties of nucleosomes through changes in shape (by adding or removing enzyme docking sites) make nucleosomes active participants in cell division and gene expression.

“This is conceptually very similar to thinking about how enzymes can be regulated—their activity can be turned on and off,” he explains. “In this case, we’re not talking about how enzymes affect a chemical reaction; we’re talking about how the nucleosome and this entire part of the chromosome is stabilized. If stability is lost, then the chromosome and all the genes carried on it would not be delivered faithfully to each cell upon division. This is the sort of genetic catastrophe that is a hallmark of cancer cells. Or if it happens in the sperm or egg cell lines, it leads to spontaneous abortions or children with disorders such as Down syndrome.”

This mode of nucleosome regulation and stabilization may well be common to other epigenetic processes, Black adds. Indeed, he says the results suggest that other histone variants and histone post-translational modifications may serve a similar function as the example at the centromere with CENP-A and CENP-C, for instance in the regulation of gene expression.

“I don’t know how widely this occurs,” he says, “but I’d be very surprised if this was the only place in nature that had evolved to take advantage of the fact that the shape of nucleosomes can be regulated by protein-binding events.”

Black says CENP-A-mediated stability could explain how oocytes retain the epigenetic information that preserves the fidelity of chromosome inheritance over so many years of fertility, and he is preparing to test that hypothesis now.

Team develops custom artificial membranes to study the molecular basis of disease

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Decorating the outside of cells like tiny antenna, a diverse community of sugar molecules acts like a telecommunications system, sending and receiving information, recognizing and responding to foreign molecules and neighboring cells.
Penn researchers develop custom artificial membranes with programmable surfaces

“The sugar part of our biomembranes are as crucial to our health as our DNA, and yet we know almost nothing about it,” said Virgil Percec, a professor of chemistry in the University of Pennsylvania School of Arts and Sciences.

Part of the reason cell membrane sugars, called glycans, are so poorly understood is that scientists were unable to accurately model them until last year, when Percec’s lab devised a way of programming artificial membranes with a precise number and spatial arrangement of sugars.

Now, as a proof-of-concept for their , the team has tested its interactions with galectin-8, a cell signaling protein that, when mutated, may contribute to rheumatoid arthritis. Gal-8 is one of a large family of growth-regulatory proteins the team is testing their model against. By modifying a single building block in Gal-8’s structure, exactly as nature does in a portion of the population, the researchers dramatically impaired its ability to communicate with the artificial membrane, suggesting a possible molecular basis for the disease.

Percec’s new study demonstrates how researchers can use this membrane model to examine the interactions of cell surfaces with other , with far ranging applications in medicine, biochemistry and biophysics.

“There are lots of membrane sugar-protein interactions that are important for disease,” Percec said. “Now, we have the critical tool we need to develop these disease models.”

Other team members from Penn include postdoctoral chemistry researchers Shaodong Zhang and Ralph-Oliver Moussodia. They collaborated with Temple University’s Michael Klein, as well as Sabine Vértesy and Sabine André and Hans-Joachim Gabius of Ludwig-Maximillians University in Munich.

The study was published in the Proceedings of the National Academy of Sciences.

Cell membranes are composed of two layers of fatty molecules known as phospholipids, each of which has a water-loving head and a water-repellant tail. The simplest form of a membrane, called a liposome or vesicle, will self-assemble when its phospholipid building blocks are placed in water. But vesicles are difficult to produce in the lab and don’t remain stable for long. For decades, these challenges hindered scientific efforts to create artificial membranes for research.

But in 2010 Percec and his lab discovered they could produce stable, self-assembling vesicles by replacing phospholipids with a class of molecules called amphiphilic Janus dendrimers, which have water-loving and water-hating branches, instead of heads and tails. Not only are dendrimer-based vesicles much easier to produce, their size, number of functional ends-groups and the number of concentric layers they contain can be precisely tuned.

“This was a big advance. It provided us the tool we were looking for while saving a huge amount of work,” Percec said. “The next step was to ask ‘can we add surface sugars to it?'”

Early efforts to mimic membrane surfaces in the lab were crude and simplistic, with no control over the number or distribution of sugars. That posed a major limitation to researchers, who need an accurate representation of these surfaces to study how other cells, proteins or viruses, will interact with them.

Building off their dendrimer-based vesicles, Percec’s lab constructed a library of amphiphilic glycodendrimer molecules: dendrimers with chemically bonded glycan sugars. By diluting these glycodendrimers to a series of different concentrations in an organic solvent and injecting them in water, the team found they could program vesicles, called glycodendrimersomes, with different surface sugar topologies. Details of this work were published in 2013 in the Journal of the American Chemical Society.

“As our molecules self-assemble, the vesicles formed have a precise number and of the sugars, something never possible before,” Percec said.

One of the most important roles membrane sugars play is receiving messages from signaling proteins and communicating those messages to the cell. Many diseases are thought to be the result of communication errors that arise when a signaling protein incurs a mutation or the membrane’s glycan structure is altered. To demonstrate the utility of their new model, the researchers studied how mutant varieties of Gal-8 interacted with a custom artificial membrane containing Gal-8’s specific binding sugars. By modifying a single amino acid in the protein’s structure, as occurs naturally in human populations, they could significantly impair Gal-8’s ability to bind to the membrane.

“By testing this model with a sugar binding protein of human origin, we show that single mutation of an amino acid from a giant can induce a dramatic change in its interactions with the cell,” Percec said. “This demonstrates just how efficient and sensitive a model this is for biological membranes.”

In the future, the team will continue to develop and refine their glycodendrimersomes models, building membranes of increasing complexity and studying how membrane functions are affected. Besides Gal-8, there are many other biologically interesting signaling proteins, which researchers can now study using a robust and customizable membrane model.

Percec’s glycodendrimersome research is housed at Penn’s interdisciplinary Laboratory for Research on the Structure of Matter and in his own laboratory. Through the LRSM, Percec is collaborating with researchers in bioengineering, computational biology, biology, biophysics and biomedicine who are interested in using his programmable membranes for a variety of purposes, from visualizing the interactions between viruses and cells to developing biological capsules for vaccine and drug delivery.

“A biomembrane with a programmable surface topology is a tool to answer almost any question in cell biology,” Percec said.