'Chaperone' compounds offer new approach to Alzheimer's treatment

A wholly new approach to the treatment of Alzheimer's disease involving the so-called retromer protein complex has been devised by researchers. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer's.

Researchers have identified a new class of compounds -- pharmacologic chaperones -- that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer's. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels.

A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer's disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer's. 

Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer's Disease Research Center in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer's-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”

Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer's. The researchers are currently testing the clinical effects of R55 in the actual mouse model .
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
 

Journal Reference:

1. Vincent J Mecozzi, Diego E Berman, Sabrina Simoes, Chris Vetanovetz, Mehraj R Awal, Vivek M Patel, Remy T Schneider, Gregory A Petsko, Dagmar Ringe, Scott A Small. Pharmacological chaperones stabilize retromer to limit APP processing. Nature Chemical Biology, 2014; DOI: 10.1038/nchembio.1508 

Courtesy: ScienceDaily
 

 

Cancer stem cells linked to drug resistance

Most drugs used to treat lung, breast and pancreatic cancers also promote drug-resistance and ultimately spur tumor growth. Researchers have discovered a biomarker called CD61 on the surface of drug-resistant tumors that appears responsible for inducing tumor metastasis by enhancing the stem cell-like properties of cancer cells.

Some lung cancer cells become resistant to drugs. Researchers identified an existing drug that reverses stem cell-like properties of tumors, resensitizing them to drug.

Most drugs used to treat lung, breast and pancreatic cancers also promote drug-resistance and ultimately spur tumor growth. Researchers at the University of California, San Diego School of Medicine have discovered a molecule, or biomarker, called CD61 on the surface of drug-resistant tumors that appears responsible for inducing tumor metastasis by enhancing the stem cell-like properties of cancer cells.

The findings, published in the April 20, 2014 online issue of Nature Cell Biology, may point to new therapeutic opportunities for reversing drug resistance in a range of cancers, including those in the lung, pancreas and breast.
“There are a number of drugs that patients respond to during their initial cancer treatment, but relapse occurs when cancer cells become drug-resistant,” said David Cheresh, PhD, Distinguished Professor of Pathology and UC San Diego Moores Cancer Center associate director for Innovation and Industry Alliances. “We looked at the cells before and after they became resistant and asked, ‘What has changed in the cells?’”
Cheresh and colleagues investigated how tumor cells become resistant to drugs like erlotinib or lapatinib, known as receptor tyrosine kinase inhibitors and commonly used in standard cancer therapies. They found that as drug resistance occurs, tumor cells acquire stem cell-like properties that give them the capacity to survive throughout the body and essentially ignore the drugs.
Specifically, the scientists delineated the molecular pathway that facilitates both cancer stemness and drug resistance, and were able to identify existing drugs that exploit this pathway. These drugs not only reverse stem cell-like properties of tumors, but also appear to re-sensitize tumors to drugs that the cancer cells had developed resistance to.
“The good news is that we’ve uncovered a previously undefined pathway that the tumor cells use to transform into cancer stem cells and that enable tumors to become resistant to commonly used cancer drugs,” said Cheresh.
Based on these findings, Hatim Husain, MD, an assistant professor who treats lung and brain cancer patients at Moores Cancer Center, has designed a clinical trial to attack this pathway in patients whose tumors are drug-resistant. The trial will be open to patients with lung cancer who have experienced cancer progression and drug resistance to erlotinib. It is expected to begin in the next year.
“Resistance builds to targeted therapies against cancer, and we have furthered our understanding of the mechanisms by which that happens,” said Husain. “Based on these research findings we now better understand how to exploit the ‘Achilles heel’ of these drug-resistant tumors. Treatments will evolve into combinational therapies where one may keep the disease under control and delay resistance mechanisms from occurring for extended periods of time.”
Although the trial is expected to begin with patients who have already experienced drug resistance, Husain hopes to extend the study to reach patients in earlier stages to prevent initial resistance.
 

Journal Reference:

1. Laetitia Seguin, Shumei Kato, Aleksandra Franovic, M. Fernanda Camargo, Jacqueline Lesperance, Kathryn C. Elliott, Mayra Yebra, Ainhoa Mielgo, Andrew M. Lowy, Hatim Husain, Tina Cascone, Lixia Diao, Jing Wang, Ignacio I. Wistuba, John V. Heymach, Scott M. Lippman, Jay S. Desgrosellier, Sudarshan Anand, Sara M. Weis, David A. Cheresh. An integrin β3–KRAS–RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature Cell Biology, 2014; DOI: 10.1038/ncb2953 

Courtesy: ScienceDaily
 

First potentially habitable Earth-sized planet confirmed by Gemini and Keck observatories

The first Earth-sized exoplanet orbiting within the habitable zone of another star has been confirmed by observations with both the W. M. Keck Observatory and the Gemini Observatory. The initial discovery, made by NASA's Kepler Space Telescope, is one of a handful of smaller planets found by Kepler and verified using large ground-based telescopes. It also confirms that Earth-sized planets do exist in the habitable zone of other stars.

The diagram compares the planets of the inner solar system to Kepler-186, a five-planet system about 500 light-years from Earth in the constellation Cygnus. The five planets of Kepler-186 orbit a star classified as a M1 dwarf, measuring half the size and mass of the sun. The Kepler-186 system is home to Kepler-186f, the first validated Earth-size planet orbiting a distant star in the habitable zone—a range of distances from a star where liquid water might pool on the surface of an orbiting planet. The discovery of Kepler-186f confirms that Earth-size planets exist in the habitable zone of other stars and signals a significant step closer to finding a world similar to Earth. Kepler-186f is less than ten percent larger than Earth in size, but its mass and composition are not known. Kepler-186f orbits its star once every 130-days and receives one-third the heat energy that Earth does from the sun, placing it near the outer edge of the habitable zone. The inner four companion planets all measure less than fifty percent the size of Earth. Kepler-186b, Kepler-186c, Kepler-186d, and Kepler-186e, orbit every three, seven, 13, and 22 days, respectively, making them very hot and inhospitable for life as we know it. The Kepler space telescope, which simultaneously and continuously measured the brightness of more than 150,000 stars, is NASA's first mission capable of detecting Earth-size planets around stars like our sun. Kepler does not directly image the planets it detects. The space telescope infers their existence by the amount of starlight blocked when the orbiting planet passes in front of a distant star from the vantage point of the observer. The artistic concept of Kepler-186f is the result of scientists and artists collaborating to help imagine the appearance of these distant

The first Earth-sized exoplanet orbiting within the habitable zone of another star has been confirmed by observations with both the W. M. Keck Observatory and the Gemini Observatory. The initial discovery, made by NASA's Kepler Space Telescope, is one of a handful of smaller planets found by Kepler and verified using large ground-based telescopes. It also confirms that Earth-sized planets do exist in the habitable zone of other stars.

"What makes this finding particularly compelling is that this Earth-sized planet, one of five orbiting this star, which is cooler than the Sun, resides in a temperate region where water could exist in liquid form," says Elisa Quintana of the SETI Institute and NASA Ames Research Center who led the paper published in the current issue of the journal Science. The region in which this planet orbits its star is called the habitable zone, as it is thought that life would most likely form on planets with liquid water.

Steve Howell, Kepler's Project Scientist and a co-author on the paper, adds that neither Kepler (nor any telescope) is currently able to directly spot an exoplanet of this size and proximity to its host star. "However, what we can do is eliminate essentially all other possibilities so that the validity of these planets is really the only viable option."

With such a small host star, the team employed a technique that eliminated the possibility that either a background star or a stellar companion could be mimicking what Kepler detected. To do this, the team obtained extremely high spatial resolution observations from the eight-meter Gemini North telescope on Mauna Kea in Hawai`i using a technique called speckle imaging, as well as adaptive optics (AO) observations from the ten-meter Keck II telescope, Gemini's neighbor on Mauna Kea. Together, these data allowed the team to rule out sources close enough to the star's line-of-sight to confound the Kepler evidence, and conclude that Kepler's detected signal has to be from a small planet transiting its host star.

"The Keck and Gemini data are two key pieces of this puzzle," says Quintana. "Without these complementary observations we wouldn't have been able to confirm this Earth-sized planet."

The Gemini "speckle" data directly imaged the system to within about 400 million miles (about 4 AU, approximately equal to the orbit of Jupiter in our solar system) of the host star and confirmed that there were no other stellar size objects orbiting within this radius from the star. Augmenting this, the Keck AO observations probed a larger region around the star but to fainter limits. According to Quintana,

"These Earth-sized planets are extremely hard to detect and confirm, and now that we've found one, we want to search for more. Gemini and Keck will no doubt play a large role in these endeavors."

The host star, Kepler-186, is an M1-type dwarf star relatively close to our solar system, at about 500 light years and is in the constellation of Cygnus. The star is very dim, being over half a million times fainter than the faintest stars we can see with the naked eye. Five small planets have been found orbiting this star, four of which are in very short-period orbits and are very hot. The planet designated Kepler-186f, however, is earth-sized and orbits within the star's habitable zone. The Kepler evidence for this planetary system comes from the detection of planetary transits. These transits can be thought of as tiny eclipses of the host star by a planet (or planets) as seen from Earth. When such planets block part of the star's light, its total brightness diminishes. Kepler detects that as a variation in the star's total light output and evidence for planets. So far more than 3,800 possible planets have been detected by this technique with Kepler.

The Gemini data utilized the Differential Speckle Survey Instrument (DSSI) on the Gemini North telescope. DSSI is a visiting instrument developed by a team led by Howell who adds, "DSSI on Gemini Rocks! With this combination, we can probe down into this star system to a distance of about 4 times that between Earth and the Sun. It's simply remarkable that we can look inside other solar systems." DSSI works on a principle that utilizes multiple short exposures of an object to capture and remove the noise introduced by atmospheric turbulence producing images with extreme detail.

Observations with the W.M. Keck Observatory used the Natural Guide Star Adaptive Optics system with the NIRC2 camera on the Keck II telescope. NIRC2 (the Near-Infrared Camera, second generation) works in combination with the Keck II adaptive optics system to obtain very sharp images at near-infrared wavelengths, achieving spatial resolutions comparable to or better than those achieved by the Hubble Space

Telescope at optical wavelengths. NIRC2 is probably best known for helping to provide definitive proof of a central massive black hole at the center of our galaxy. Astronomers also use NIRC2 to map surface features of solar system bodies, detect planets orbiting other stars, and study detailed morphology of distant galaxies.

"The observations from Keck and Gemini, combined with other data and numerical calculations, allowed us to be 99.98% confident that Kepler-186f is real," says Thomas Barclay, a Kepler scientist and also a co-author on the paper. "Kepler started this story, and Gemini and Keck helped close it," adds Barclay.

Journal Reference:

1. Elisa V. Quintana, Thomas Barclay, Sean N. Raymond, Jason F. Rowe, Emeline Bolmont, Douglas A. Caldwell, Steve B. Howell, Stephen R. Kane, Daniel Huber, Justin R. Crepp, Jack J. Lissauer, David R. Ciardi, Jeffrey L. Coughlin, Mark E. Everett, Christopher E. Henze, Elliott Horch, Howard Isaacson, Eric B. Ford, Fred C. Adams, Martin Still, Roger C. Hunter, Billy Quarles, Franck Selsis. An Earth-Sized Planet in the Habitable Zone of a Cool Star. Science, 2014 DOI: 10.1126/science.1249403 

Courtesy: ScienceDaily

Laboratory-grown vaginas implanted in patients

Scientists reported the first human recipients of laboratory-grown vaginal organs. They have described long-term success in four teenage girls who received vaginal organs that were engineered with their own cells.

The scaffold is configured into a vaginal shape.

Scientists reported today the first human recipients of laboratory-grown vaginal organs. A research team led by Anthony Atala, M.D., director of Wake Forest Baptist Medical Center's Institute for Regenerative Medicine, describes in the Lancet long-term success in four teenage girls who received vaginal organs that were engineered with their own cells.

"This pilot study is the first to demonstrate that vaginal organs can be constructed in the lab and used successfully in humans," said Atala. "This may represent a new option for patients who require vaginal reconstructive surgeries. In addition, this study is one more example of how regenerative medicine strategies can be applied to a variety of tissues and organs."
The girls in the study were born with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a rare genetic condition in which the vagina and uterus are underdeveloped or absent. The treatment could also potentially be applied to patients with vaginal cancer or injuries, according to the researchers.
The girls were between 13 and 18 years old at the time of the surgeries, which were performed between June 2005 and October 2008. Data from annual follow-up visits show that even up to eight years after the surgeries, the organs had normal function.
"Tissue biopsies, MRI scans and internal exams using magnification all showed that the engineered vaginas were similar in makeup and function to native tissue, said Atlantida-Raya Rivera, lead author and director of the HIMFG Tissue Engineering Laboratory at the Metropolitan Autonomous University in Mexico City, where the surgeries were performed.
In addition, the patients' responses to a Female Sexual Function Index questionnaire showed they had normal sexual function after the treatment, including desire and pain-free intercourse.
The organ structures were engineered using muscle and epithelial cells (the cells that line the body's cavities) from a small biopsy of each patient's external genitals. In a Good Manufacturing Practices facility, the cells were extracted from the tissues, expanded and then placed on a biodegradable material that was hand-sewn into a vagina-like shape. These scaffolds were tailor-made to fit each patient.
About five to six weeks after the biopsy, surgeons created a canal in the patient's pelvis and sutured the scaffold to reproductive structures. Previous laboratory and clinical research in Atala's lab has shown that once cell-seeded scaffolds are implanted in the body, nerves and blood vessels form and the cells expand and form tissue. At the same time the scaffolding material is being absorbed by the body, the cells lay down materials to form a permanent support structure -- gradually replacing the engineered scaffold with a new organ.
Followup testing on the lab-engineered vaginas showed the margin between native tissue and the engineered segments was indistinguishable and that the scaffold had developed into tri-layer vaginal tissue.
Current treatments for MRHK syndrome include dilation of existing tissue or reconstructive surgery to create new vaginal tissue. A variety of materials can be used to surgically construct a new vagina -- from skin grafts to tissue that lines the abdominal cavity. However, these substitutes often lack a normal muscle layer and some patients can develop a narrowing or contracting of the vagina.
The researchers say that with conventional treatments, the overall complication rate is as high as 75 percent in pediatric patients, with the need for vaginal dilation due to narrowing being the most common complication.
Before beginning the pilot clinical study, Atala's team evaluated lab-built vaginas in mice and rabbits beginning in the early 1990s. In these studies, scientists discovered the importance of using cells on the scaffolds. Atala's team used a similar approach to engineer replacement bladders that were implanted in nine children beginning in 1998, becoming the first in the world to implant laboratory-grown organs in humans. The team has also successfully implanted lab-engineered urine tubes (urethras) into young boys.
The team said the current study is limited because of its size, and that it will be important to gain further clinical experience with the technique and to compare it with established surgical procedures.
Co-researchers were James J. Yoo, M.D., Ph.D., and Shay Soker, Ph.D., Wake Forest Baptist, and Diego R. Esquiliano M.D., Reyna Fierro-Pastrana P.hD., Esther Lopez-Bayghen Ph.D., Pedro Valencia M.D., and Ricardo Ordorica-Flores, M.D.,Children's Hospital Mexico Federico Gomez Metropolitan Autonomous University, Mexico.

Journal Reference:

1. Atlántida M Raya-Rivera, Diego Esquiliano, Reyna Fierro-Pastrana, Esther López-Bayghen, Pedro Valencia, Ricardo Ordorica-Flores, Shay Soker, James J Yoo, Anthony Atala. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. The Lancet, 2014; DOI: 10.1016/S0140-6736(14)60542-0

Courtesy: ScienceDaily

3-D printing cancer cells to mimic tumors

A 3-D model of a cancerous tumor using a 3-D printer has been successfully created by researchers. The model consists of a grid structure, 10 mm in width and length, made from gelatin, alginate and fibrin, which recreates the fibrous proteins that make up the extracellular matrix of a tumor. "With further understanding of these 3D models, we can use them to study the development, invasion, metastasis and treatment of cancer using specific cancer cells from patients. We can also use these models to test the efficacy and safety of new cancer treatment therapies and new cancer drugs," the lead author stated.

The model consists of a grid structure, 10 mm in width and length, made from gelatin, alginate and fibrin, which recreates the fibrous proteins that make up the extracellular matrix of a tumor.

A group of researchers in China and the US have successfully created a 3D model of a cancerous tumor using a 3D printer.

The model, which consists of a scaffold of fibrous proteins coated in cervical cancer cells, has provided a realistic 3D representation of a tumor's environment and could help in the discovery of new drugs and cast new light on how tumors develop, grow and spread throughout the body.
The results of the study have been published today, 11 April, in IOP Publishing's journal Biofabrication.
The model consists of a grid structure, 10 mm in width and length, made from gelatin, alginate and fibrin, which recreates the fibrous proteins that make up the extracellular matrix of a tumor.
The grid structure is coated in Hela cells -- a unique, 'immortal' cell line that was originally derived from a cervical cancer patient in 1951. Due to the cells' ability to divide indefinitely in laboratory conditions, the cell line has been used in some of the most significant scientific breakthrough studies of the past 50 years.
Although the most effective way of studying tumors is to do so in a clinical trial, ethical and safety limitations make it difficult for these types of studies to be carried out on a wide scale.
To overcome this, 2D models, consisting of a single layer of cells, have been created to mimic the physiological environment of tumors so that different types of drugs can be tested in a realistic way.
With the advent of 3D printing, it is now possible to provide a more realistic representation of the environment surrounding a tumor, which the researchers have demonstrated in this study by comparing results from their 3D model with results from a 2D model.
In addition to testing if the cells remained viable, or alive, after printing, the researchers also examined how the cells proliferated, how they expressed a specific set of proteins, and how resistant they were to anti-cancer drugs.
The proteins studied were part of the MMP protein family. These proteins are used by cancer cells to break through their surrounding matrix and help tumors to spread. Resistance to anti-cancer drugs, which was also studied, is a good indicator of tumor malignancy.
The results revealed that 90 per cent of the cancer cells remained viable after the printing process. The results also showed that the 3D model had more similar characteristics to a tumor compared to 2D models and in the 3D model the cancer cells showed a higher proliferation rate, higher protein expression and higher resistance to anti-cancer drugs.
The lead author of the research, Professor Wei Sun, from Tsinghua University, China, and Drexel University, USA, said: "We have provided a scalable and versatile 3D cancer model that shows a greater resemblance to natural cancer than 2D cultured cancer cells."
"With further understanding of these 3D models, we can use them to study the development, invasion, metastasis and treatment of cancer using specific cancer cells from patients. We can also use these models to test the efficacy and safety of new cancer treatment therapies and new cancer drugs."
 

Journal Reference:

1. Yu Zhao, Rui Yao, Liliang Ouyang, Hongxu Ding, Ting Zhang, Kaitai Zhang, Shujun Cheng, Wei Sun. Three-dimensional printing of Hela cells for cervical tumor modelin vitro. Biofabrication, 2014; 6 (3): 035001 DOI: 10.1088/1758-5082/6/3/035001 

Courtesy: ScienceDaily
 

Computer rendering: Graduate student brings extinct plants 'back to life'

Most fossilized plants are fragments indistinguishable from a stick, but a graduate student hopes a new technique will allow paleontologists to more precisely identify these fossils. A graduate student showed the power of this technique by turning a 375 million-year-old lycopod fossil into a life-like rendering.

Benca described this 400-million-year-old fossil lycopod, Leclercqia scolopendra, and created a life-like computer rendering. The stem of the lycopod is about 2.5 millimeters across.

Jeff Benca is an admitted über-geek when it comes to prehistoric plants, so it was no surprise that, when he submitted a paper describing a new species of long-extinct lycopod for publication, he ditched the standard line drawing and insisted on a detailed and beautifully rendered color reconstruction of the plant. This piece earned the cover of March's centennial issue of the American Journal of Botany.

Benca described this 400-million-year-old fossil lycopod, Leclercqia scolopendra, and created a life-like computer rendering. The stem of the lycopod is about 2.5 millimeters across.
"Typically, when you see pictures of early land plants, they're not that sexy: there is a green forking stick and that's about it. We don't have many thorough reconstructions," said Benca, a graduate student in the Department of Integrative Biology and Museum of Paleontology at UC Berkeley. "I wanted to give an impression of what they may have really looked like. There are great color reconstructions of dinosaurs, so why not a plant?"
Benca's realistic, full-color image could be a life portrait, except for the fact that it was drawn from a plant that lay flattened and compressed into rock for more than 375 million years.
Called Leclercqia scolopendra, or centipede clubmoss, the plant lived during the "age of fishes," the Devonian Period. At that time, lycopods -- the group Leclercqia belonged to -- were one of few plant lineages with leaves. Leclercqia shoots were about a quarter-inch in diameter and probably formed prickly, scrambling, ground-covering mats. The function of Leclercqia's hook-like leaf tips is unclear, Benca said, but they may have been used to clamber over larger plants. Today, lycopods are represented by a group of inconspicuous plants called club mosses, quillworts and spikemosses.
Both living and extinct lycopods have fascinated Benca since high school. When he came to UC Berkeley last year from the University of Washington, he brought a truckload of some 70 different species, now part of collections at the UC Botanical Garden.
Now working in the paleobotany lab of Cindy Looy, Berkeley assistant professor of integrative biology, Benca continues to establish a growing list of living lycopod species, several of which will eventually be incorporated into the UC and Jepson Herbaria collections.
Visualizing plant evolution
Benca and colleagues wrote their paper primarily to demonstrate a new technique that is helping paleobotanists interpret early land plant fossils with greater confidence. Since living clubmosses share many traits with early lycopods, the research team was able to test their methods using living relatives Benca was growing in greenhouses.
Early land plant fossils are not easy to come by, but they can be abundant in places where rocks from the Devonian Period form outcrops. But a large portion of these are just stem fragments with few diagnostic features to distinguish them, Benca said.
"The way we analyzed Leclercqia material makes it possible to gain more information from these fragments, increasing our sample size of discernible fossils," he said.
"Getting a better grip on just how diverse and variable Devonian plants were will be important to understanding the origins of key traits we see in so many plants today." Looy said. Benca's co-authors are Maureen H. Carlisle, Silas Bergen and Caroline A. E. Strömberg from the University of Washington and Burke Museum of Natural History and Culture, Seattle.

Journal Reference:

1. J. P. Benca, M. H. Carlisle, S. Bergen, C. A. E. Stromberg. Applying morphometrics to early land plant systematics: A new Leclercqia (Lycopsida) species from Washington State, USA. American Journal of Botany, 2014; 101 (3): 510 DOI: 10.3732/ajb.1300271 

Courtesy: ScienceDaily

Light-activated neurons from stem cells restore function to paralyzed muscles

A new way to artificially control muscles using light, with the potential to restore function to muscles paralyzed by conditions such as motor neuron disease and spinal cord injury, has been developed by scientists. The technique involves transplanting specially-designed motor neurons created from stem cells into injured nerve branches. These motor neurons are designed to react to pulses of blue light, allowing scientists to fine-tune muscle control by adjusting the intensity, duration and frequency of the light pulses.

A new way to artificially control muscles using light, with the potential to restore function to muscles paralyzed by conditions such as motor neuron disease and spinal cord injury, has been developed by scientists at UCL and King's College London.

The technique involves transplanting specially-designed motor neurons created from stem cells into injured nerve branches. These motor neurons are designed to react to pulses of blue light, allowing scientists to fine-tune muscle control by adjusting the intensity, duration and frequency of the light pulses. 

The technique involves transplanting specially-designed motor neurons created from stem cells into injured nerve branches. These motor neurons are designed to react to pulses of blue light, allowing scientists to fine-tune muscle control by adjusting the intensity, duration and frequency of the light pulses.

In the study, published this week in Science, the team demonstrated the method in mice in which the nerves that supply muscles in the hind legs were injured. They showed that the transplanted stem cell-derived motor neurons grew along the injured nerves to connect successfully with the paralyzed muscles, which could then be controlled by pulses of blue light.

"Following the new procedure, we saw previously paralyzed leg muscles start to function," says Professor Linda Greensmith of the MRC Centre for Neuromuscular Diseases at UCL's Institute of Neurology, who co-led the study. "This strategy has significant advantages over existing techniques that use electricity to stimulate nerves, which can be painful and often results in rapid muscle fatigue. Moreover, if the existing motor neurons are lost due to injury or disease, electrical stimulation of nerves is rendered useless as these too are lost."

Muscles are normally controlled by motor neurons, specialized nerve cells within the brain and spinal cord. These neurons relay signals from the brain to muscles to bring about motor functions such as walking, standing and even breathing. However, motor neurons can become damaged in motor neuron disease or following spinal cord injuries, causing permanent loss of muscle function resulting in paralysis

"This new technique represents a means to restore the function of specific muscles following paralysing neurological injuries or disease," explains Professor Greensmith. "Within the next five years or so, we hope to undertake the steps that are necessary to take this ground-breaking approach into human trials, potentially to develop treatments for patients with motor neuron disease, many of whom eventually lose the ability to breathe, as their diaphragm muscles gradually become paralyzed. We eventually hope to use our method to create a sort of optical pacemaker for the diaphragm to keep these patients breathing."

The light-responsive motor neurons that made the technique possible were created from stem cells by Dr Ivo Lieberam of the MRC Centre for Developmental Neurobiology, King's College London.
"We custom-tailored embryonic stem cells so that motor neurons derived from them can function as part of the muscle pacemaker device." says Dr Lieberam, who co-led the study. "First, we equipped the cells with a molecular light sensor. This enables us to control motor neurons with blue light flashes. We then built a survival gene into them, which helps the stem-cell motor neurons to stay alive when they are transplanted inside the injured nerve and allows them to grow to connect to muscle."
 

Journal Reference:

1. J. B. Bryson, C. B. Machado, M. Crossley, D. Stevenson, V. Bros-Facer, J. Burrone, L. Greensmith, I. Lieberam. Optical Control of Muscle Function by Transplantation of Stem Cell-Derived Motor Neurons in Mice. Science, 2014; 344 (6179): 94 DOI: 10.1126/science.1248523

Courtesy: ScienceDaily
 

Blood test could detect solid cancers

A blood sample could one day be enough to diagnose many types of solid cancers, or to monitor the amount of cancer in a patient's body and responses to treatment. Now, researchers have devised a way to quickly bring the technique to the clinic. Their approach, which should be broadly applicable to many types of cancers, is highly sensitive and specific. With it they were able to accurately identify about 50 percent of people in the study with stage-1 lung cancer and all patients whose cancers were more advanced. 

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

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

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


The researchers describe their findings in a paper that will be published online April 6 in Nature Medicine. Diehn shares senior authorship with Ash Alizadeh, MD, PhD, assistant professor of medicine. Postdoctoral scholars Aaron Newman, PhD, and Scott Bratman, MD, PhD share lead authorship.


"We're trying to develop a general method to detect and measure disease burden," said Alizadeh, a hematologist and oncologist. "Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we're in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily."


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


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


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

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


"Cancer is a genetic disease," Alizadeh said. "But unlike Down syndrome, for example, which has a single dominant cause, for most cancers it's very difficult to identify any one particular genetic aberration or mutation that is found in every patient. Instead, each cancer tends to be genetically different from patient to patient, although sets of mutations can be shared among patients with a given cancer."


So the researchers took a population-based approach. National databases such as The Cancer Genome Atlas contain DNA sequences of tumors collected from thousands of patients -- and pinpoint places in which the cancer DNA differs from normal DNA. Although the significance of each individual change is not always clear, it's becoming possible to generate a mutational fingerprint for each cancer type that includes nucleotide changes, insertions or deletions of short pieces of genetic material and translocation events that shuffle or even flip DNA regions. Although no patient will have all the mutations, nearly all will have at least some.


The group began by using a bioinformatics approach to collect information from the atlas on 407 patients with non-small-cell lung cancer, looking for regions in the genome enriched for cancer-associated mutations.


"We looked for which genes are most commonly altered, and used computational approaches to identify what we call the genetic architecture of the cancer," Alizadeh said. "That allowed us to identify the part of the genome that would be best to identify and track the disease."


They identified 139 genes that are recurrently mutated in non-small-cell lung cancer and that represent about 0.004 percent of the human genome. Next, the team designed oligonucleotides, panels of short pieces of DNA, bracketing these regions. The oligonucleotides were then used to perform very deep sequencing (meaning each region was sequenced about 10,000 times) of the surrounding DNA.


"By sequencing only those regions of the genome that are highly enriched for cancer mutations, we're able to keep costs down and identify multiple mutations per patient," Diehn said.


In contrast, other methods of tracking circulating tumor DNA have relied on single, well-known mutations that nevertheless are unlikely to occur in every patient with a particular cancer. Tracking more than one mutation increases the sensitivity of the approach and allows researchers more flexibility in seeing how the cancer changes over time.


"There are currently no reliable biomarkers available for lung cancer patients, which is the most common cancer and No. 1 cause of cancer deaths," Diehn said. "We are very excited about our findings because a personalized, clinically useful biomarker could revolutionize how we detect and manage this devastating disease."


Next, the researchers used these oligonucleotides to selectively sequence tumor samples from patients with the disease and identify specific mutations in each patient's tumor. Starting with a predefined panel of oligonucleotides allowed the researchers to quickly home in on patient-specific mutations that could be used to monitor disease.


"A key advantage of our approach is that we can also track many different classes of mutations, and integrate information from all of them to get a much stronger signal," Newman said. "We've also developed statistical methods to suppress the background noise in a sample. This allows us to identify even very minute quantities of cancer DNA in a blood sample."


When the researchers applied the technique to patients with non-small-cell lung cancer, they found they could detect disease in all patients with stage-2 or higher disease, and in half of those with stage-1, the earliest stage of disease. Furthermore, the absolute levels of circulating tumor DNA were highly correlated with tumor volume estimated by conventional imaging techniques such as CT and PET scans. This suggests CAPP-Seq could be used to monitor tumors at a fraction of the cost of commonly used imaging studies.


CAPP-Seq may also be useful as a prognostic tool, the researchers found. The technique detected small levels of circulating tumor DNA in one patient thought to have been successfully treated for the disease; that patient experienced disease recurrence and ultimately died. Conversely, scans of a patient with early stage disease showed a mass thought to represent residual disease after treatment. However, CAPP-Seq detected no circulating tumor DNA, and the patient remained disease-free for the duration of the study.


Finally, CAPP-Seq was also able to identify the presence in one patient of a minor population of tumor cells with a mutation that confers resistance to a drug commonly used to treat non-small-cell lung cancer.


"If we can monitor the evolution of the tumor, and see the appearance of treatment-resistant subclones, we could potentially add or switch therapies to target these cells," Diehn said. "It's also possible we could use CAPP-Seq to identify subsets of early stage patients who could benefit most from additional treatment after surgery or radiation, such as chemotherapy or immunotherapy."

The researchers are now working to design clinical trials to see whether CAPP-Seq can improve patient outcomes and decrease costs. They're also aiming to extend the technique to other types of tumors.


Screening healthy but at-risk populations is another goal of the researchers. "It may be possible to develop assays that could simultaneously screen for multiple cancers," Diehn said. "This would include diseases such as breast, prostate, colorectal and lung cancer, for example."


"This approach could, theoretically, work for any tumor," Alizadeh said. "We expect it to be broadly applicable across cancers."

Journal Reference:

1. Aaron M Newman, Scott V Bratman, Jacqueline To, Jacob F Wynne, Neville C W Eclov, Leslie A Modlin, Chih Long Liu, Joel W Neal, Heather A Wakelee, Robert E Merritt, Joseph B Shrager, Billy W Loo, Ash A Alizadeh, Maximilian Diehn. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature Medicine, 2014; DOI: 10.1038/nm.3519

Courtesy: ScienceDaily

Key cells in touch sensation identified: Skin cells use new molecule to send touch information to the brain

Biologists have solved an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures. Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision -- rod and cone cells and light-sensitive receptors -- have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch.

In a study published in the April 6 online edition of the journal Nature, a team of Columbia University Medical Center researchers led by Ellen Lumpkin, PhD, associate professor of somatosensory biology, solve an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures.

 

Merkel cell.

Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision -- rod and cone cells and light-sensitive receptors -- have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch.

This study is the first to use optogenetics -- a new method that uses light as a signaling system to turn neurons on and off on demand -- on skin cells to determine how they function and communicate.

The team showed that skin cells called Merkel cells can sense touch and that they work virtually hand in glove with the skin's neurons to create what we perceive as fine details and textures.

"These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us," Dr. Lumpkin said.

The findings not only describe a key advance in our understanding of touch sensation, but may stimulate research into loss of sensitive-touch perception.

Several conditions -- including diabetes and some cancer chemotherapy treatments, as well as normal aging -- are known to reduce sensitive touch. Merkel cells begin to disappear in one's early 20s, at the same time that tactile acuity starts to decline. "No one has tested whether the loss of Merkel cells causes loss of function with aging -- it could be a coincidence -- but it's a question we're interested in pursuing," Dr. Lumpkin said.

In the future, these findings could inform the design of new "smart" prosthetics that restore touch sensation to limb amputees, as well as introduce new targets for treating skin diseases such as chronic itch.

The study was published in conjunction with a second study by the team done in collaboration with the Scripps Research Institute. The companion study identifies a touch-activated molecule in skin cells, a gene called Piezo2, whose discovery has the potential to significantly advance the field of touch perception.

"The new findings should open up the field of skin biology and reveal how sensations are initiated," Dr. Lumpkin said. Other types of skin cells may also play a role in sensations of touch, as well as less pleasurable skin sensations, such as itch. The same optogenetics techniques that Dr. Lumpkin's team applied to Merkel cells can now be applied to other skin cells to answer these questions.

"It's an exciting time in our field because there are still big questions to answer, and the tools of modern neuroscience give us a way to tackle them," she said.

Movie of Merkel cell responding to touch: http://youtu.be/tU1jeOpjsTE

The research was supported by NIH (R01AR051219, R21AR062307, R01DE022358, T32HL087745, F32NS080544, P30AR044535, P30CA013696, and P30CA125123), a Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science (24-7585), and the McNair Foundation.

The other authors of the paper are: Srdjan Maksimovic (Columbia), Masashi Nakatani (Columbia and Keio University, Japan), Yoshichika Baba (Columbia), Aislyn Nelson (Columbia and Baylor College of Medicine), Kara Marshall (Columbia), Scott Wellnitz (Baylor), Pervez Firozi (Baylor), Seung-Hyun Woo (Scripps Research Institute), Sanjeev Ranade (Scripps), and Ardem Patapoutian (Scripps). 


Journal Reference:

1. Srdjan Maksimovic, Masashi Nakatani, Yoshichika Baba, Aislyn M. Nelson, Kara L. Marshall, et al. Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature, 2014 DOI: 10.1038/nature13250 

Courtesy: ScienceDaily

Marriage linked to lower heart risks in study of more than 3.5 million adults

People who are married have lower rates of several cardiovascular diseases compared with those who are single, divorced or widowed, according to research. The relationship between marriage and lower odds of vascular diseases is especially pronounced before age 50. For people aged 50 and younger, marriage is associated with 12 percent lower odds of any vascular disease. This number drops to 7 percent for people ages 51 to 60 and only 4 percent for those 61 and older.

People who are married have lower rates of several cardiovascular diseases compared with those who are single, divorced or widowed, according to research to be presented at the American College of Cardiology's 63rd Annual Scientific Session. The relationship between marriage and lower odds of vascular diseases is especially pronounced before age 50.

"These findings certainly shouldn't drive people to get married, but it's important to know that decisions regarding who one is with, why, and why not may have important implications for vascular health," said Carlos L. Alviar M.D., cardiology fellow, New York University Langone Medical Center, and the lead investigator of the study.

Alviar said that while earlier, smaller studies reported similar findings, the size of this study, as well as the ability to consider four different vascular diseases -- peripheral artery disease, cerebrovascular disease, abdominal aortic aneurysm and coronary artery disease -- and to discriminate between various types of marital status makes this research different from anything that's previously been done.

"We are able to take a better look at a spectrum of relationships," Alviar said.

Researchers prospectively analyzed records from a database of more than 3.5 million people nationwide who were evaluated for cardiovascular diseases. Patients' demographic information and cardiovascular risk factors were obtained, and researchers estimated the odds of disease by marital status after analyzing the presence of vascular disease in different blood vessel locations such as the coronary arteries, leg arteries, carotids and the abdominal aorta. Traditional cardiovascular risk factors such as hypertension, diabetes, smoking and obesity were similar to the overall U.S. population, according to authors. Participants' ages ranged from 21 to 102 years old, with the average age of 64, and 63 percent were female. Overall, 69.1 percent (2.4 million) were married, 13 percent (477,577) were widowed, 8.3 percent (292,670) were single; 9 percent (319,321) were divorced.

After adjusting for age, sex, race and other cardiovascular risk factors, researchers found marital status was independently associated with cardiovascular disease. These findings were consistent for both men and women across the four conditions.

In particular, married people were 5 percent less likely to have any vascular disease compared with singles. They also had 8 percent, 9 percent and 19 percent lower odds of abdominal aortic aneurysm, cerebrovascular disease and peripheral arterial disease, respectively. The odds of coronary disease were lower in married subjects compared with those who were widowed and divorced, but this was not statistically significant when compared to single subjects, which were used as the reference group for comparison.

On the other hand, being divorced or widowed was associated with a greater likelihood of vascular disease compared with being single or married. After multivariable adjustment, widowers had 3 percent higher odds of any vascular disease and 7 percent higher odds of coronary artery disease. Divorce was linked with a higher likelihood of any vascular disease, abdominal aortic aneurysm, coronary artery disease and cerebrovascular disease.

"The association between marriage and a lower likelihood of vascular disease is stronger among younger subjects, which we didn't anticipate," Alviar said.

For people aged 50 and younger, marriage is associated with 12 percent lower odds of any vascular disease. This number drops to 7 percent for people ages 51 to 60 and only 4 percent for those 61 and older.

"Of course, it's true that not all marriages are created equal, but we would expect the size of this study population to account for variations in good and bad marriages," Alviar said.

The database researchers used consists primarily of people who participated in the self-referred Life Line Screening program at more than 20,000 screening sites covering all 50 states and broad geographical and socioeconomic representation between 2003 and 2008. Potential limitations of the study are that the sample was drawn from people who sought and paid $100 for a vascular screening service and therefore may not be representative of the population. Additionally, the study included a relatively small proportion of racial/ethnic minorities.

Future research is needed to better understand what aspects of marriage might be associated with improved vascular health; for example, better access to health insurance and health care, socioeconomic status and the potential benefits of having companionship. Alviar said a long-term follow-up study would help identify dynamic changes in disease patterns as subjects move from one status to another such as moving from being married to divorced or widowed; or single to married, especially at later stages in life, and allow researchers to see if and how soon after these changes occur vascular disease appears.

Story Source:
The above story is based on materials provided by American College of Cardiology. Note: Materials may be edited for content and length.
 

Courtesy: ScienceDaily

 

Crows understand water displacement at the level of a small child: Show causal understanding of a 5- to 7-year-old child

New Caledonian crows may understand how to displace water to receive a reward, with the causal understanding level of a 5- to 7-year-old child. Understanding causal relationships between actions is a key feature of human cognition. However, the extent to which non-human animals are capable of understanding causal relationships is not well understood. Scientists used the Aesop's fable riddle -- in which subjects drop stones into water to raise the water level and obtain an out-of reach-reward -- to assess New Caledonian crows' causal understanding of water displacement.

New Caledonian crows may understand how to displace water to receive a reward, with the causal understanding level of a 5-7 year-old child, according to results published March 26, 2014, in the open access journal PLOS ONE by Sarah Jelbert from University of Auckland and colleagues.

Understanding causal relationships between actions is a key feature of human cognition. However, the extent to which non-human animals are capable of understanding causal relationships is not well understood. Scientists used the Aesop's fable riddle -- in which subjects drop stones into water to raise the water level and obtain an out-of reach-reward -- to assess New Caledonian crows' causal understanding of water displacement. These crows are known for their intelligence and innovation, as they are the only non-primate species able to make tools, such as prodding sticks and hooks. Six wild crows were tested after a brief training period for six experiments, during which the authors noted rapid learning (although not all the crows completed every experiment). The authors note that these tasks did not test insightful problem solving, but were directed at the birds' understanding of volume displacement.
Crows completed 4 of 6 water displacement tasks, including preferentially dropping stones into a water-filled tube instead of a sand-filled tube, dropping sinking objects rather than floating objects, using solid objects rather than hollow objects, and dropping objects into a tube with a high water level rather than a low one. However, they failed two more challenging tasks, one that required understanding of the width of the tube, and one that required understanding of counterintuitive cues for a U-shaped displacement task. According to the authors, results indicate crows may possess a sophisticated -- but incomplete -- understanding of the causal properties of volume displacement, rivalling that of 5-7 year old children.
Sarah Jelbert added, "These results are striking as they highlight both the strengths and limits of the crows' understanding. In particular, the crows all failed a task which violated normal causal rules, but they could pass the other tasks, which suggests they were using some level of causal understanding when they were successful."

Journal Reference:

1. Sarah A. Jelbert, Alex H. Taylor, Lucy G. Cheke, Nicola S. Clayton, Russell D. Gray. Using the Aesop's Fable Paradigm to Investigate Causal Understanding of Water Displacement by New Caledonian Crows. PLoS ONE, 2014; 9 (3): e92895 DOI: 10.1371/journal.pone.0092895 

Courtesy: ScienceDaily