Beyond genes: Are centrioles carriers of biological information?

EPFL scientists discover that certain cell structures, the centrioles, could act as information carriers throughout cell generations. The discovery raises the possibility that transmission of biological information could involve more than just genes.

Electron micrograph of a centriole.

Centrioles are barrel-shaped structures inside cells, made up of multiple proteins. They are currently the focus of much research, since mutations in the proteins that make them up can cause a broad range of diseases, including developmental abnormalities, respiratory conditions, male sterility and cancer. Publishing in the Nature journal Cell Research, EPFL scientists show that the original centrioles of a fertilized egg, which only come from the father, persist across tens of cell divisions in the developing embryo. The surprising finding raises the possibility that centrioles may actually be carriers of information, with profound implications for biology and disease treatment.
Perhaps best known for their role in cell division, centrioles ensure that chromosomes are properly passed on to the new daughter cells. However, they are also found in cilia, the long eyelash-like structures that allow many cells in the body to signal to their neighbors and other cells to exhibit motility, e.g. in cells that line the respiratory tracts. During reproduction, both parents equally contribute genetic material, while the female egg donates most of the cell organelles, such as mitochondria. However, the centrioles of the newly fertilized embryo come exclusively from the male's sperm, bringing with them any malfunctions to the first embryo cells.
Passing information across generations
The lab of Pierre Gönczy at EPFL's Swiss Institute for Experimental Cancer Research has found that centrioles can carry such information beyond the first cells to many of a developing embryo to several cell generations. The study focused on the worm C. elegans, which is commonly used as a model organism for embryonic development and human genetic diseases. As in other species, including humans, centrioles in C. elegans are only contributed by sperm cells. Gönczy's team wanted to know how far do these "original" centrioles last across the cell divisions that turn a fertilized egg into a fully formed embryo.
In order to track the fate of the centrioles, the scientists used genetically modified versions of C. elegans, in which they could tag three different centriole proteins with a fluorescent signal. Tagged male worms were mated to untagged females, so that the scientists could specifically track centriole components that were contributed from the father during the course of embryogenesis.
Gönczy's team imaged the fluorescent signals at different cell divisions of the developing embryos, and discovered that paternally contributed centriole proteins can actually persist up to ten cell generations. The data show for the first time that centrioles are remarkably persistent in the developing embryo.
Even more intriguing are the implications the study has for biology at large, as it raises the possibility that centrioles, persisting across several cell cycles, could effectively be a non-genetic information carrier. If this were confirmed, it could represent a paradigm shift in the way we think and understand the biology of an organelle that has been present across eukaryotic evolution.
Nonetheless, this does not detract from the value this study holds for medicine. Considering the number of diseases associated with centrioles, this could open the way for innovative treatment approaches. In particular, the study demonstrates how malfunctioning centrioles can pass directly from the father and well into the life of the embryo. This can have serious implications for the way we understand centriole diseases.
"Centrioles have always been seen as something that just jumpstarts the development of the embryo," says Pierre Gönczy. "Here we show that centrioles could be the means of a unidirectional inheritance of information, with considerable impact in early development." His team will next investigate if the exceptional persistence of centrioles extends to other systems, including human cells.
 

Journal Reference:

1. Fernando R Balestra, Lukas von Tobel, Pierre Gönczy. Paternally contributed centrioles exhibit exceptional persistence in C. elegans embryos. Cell Research, 2015; DOI: 10.1038/cr.2015.49 

Courtesy: ScienceDaily
 

Scientists announce final trial results of the world’s most advanced malaria vaccine

The first malaria vaccine candidate (RTS,S/AS01) to reach phase 3 clinical testing is partially effective against clinical disease in young African children up to 4 years after vaccination, according to final trial data, published in The Lancet. The results suggest that the vaccine could prevent a substantial number of cases of clinical malaria, especially in areas of high transmission.

The findings reveal that vaccine efficacy against clinical and severe malaria was better in children than in young infants, but waned over time in both groups. However, protection was prolonged by a booster dose, increasing the average number of cases prevented in both children and young infants.

Brian Greenwood, corresponding author and Professor of Clinical Tropical Medicine at London School of Hygiene & Tropical Medicine in the UK explains, "Despite the falling efficacy over time, there is still a clear benefit from RTS,S/AS01. An average 1363 cases of clinical malaria were prevented over 4 years of follow-up for every 1000 children vaccinated, and 1774 cases in those who also received a booster shot. Over 3 years of follow-up, an average 558 cases were averted for every 1000 infants vaccinated, and 983 cases in those also given a booster dose."

"Given that there were an estimated 198 million malaria cases in 2013, this level of efficacy potentially translates into millions of cases of malaria in children being prevented."

The RTS,S/AS01 vaccine was developed for use in sub-Saharan Africa where malaria still kills around 1300 children every day[1]. There is currently no licensed vaccine against malaria anywhere in the world.

The phase 3 randomised trial enrolled 15459 young infants (aged 6 to 12 weeks at first vaccination) and children (5 to 17 months at first vaccination) from 11 sites across seven sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and United Republic of Tanzania) with varying levels of malaria transmission. In 2014, initial phase 3 results at 18 months showed vaccine efficacy of about 46% against clinical malaria in children and around 27% among young infants [2].

In this study, members of the RTS,S Clinical Trials Partnership followed up the infants and children for a further 20 to 30 months, respectively, and assessed the impact of a fourth booster dose. Participants were each vaccinated three times with RTS,S/AS01 with or without a booster dose 18 months later, or given four doses of a comparator vaccine (control group).

In children who received 3 doses of RTS,S/AS01 plus a booster, the number of clinical episodes of malaria at 4 years was reduced by just over a third (36%). This is a drop in efficacy from the 50% protection against malaria seen in the first year.

Importantly, without a booster dose, significant efficacy against severe malaria was not shown in this age group. However, in children given a booster dose, overall protective efficacy against severe malaria was 32%, and 35% against malaria-associated hospitalisations.

In infants who received 3 doses of RTS,S/AS01 plus a booster, the vaccine reduced the risk of clinical episodes of malaria by 26% over 3 years follow-up. There was no significant protection against severe disease in infants.

Meningitis occurred more frequently in children given RTS,S/AS01 (11 children in the group who received the booster dose and 10 in those who did not) than in those given the control vaccine (1 child). RTS,S/AS02 produced more adverse reactions than the control vaccines. Convulsions following vaccination, although uncommon, occurred more frequently in children who received RTS,S/AS01 than in controls. The incidence of other serious adverse events was similar in all groups of participants.

According to Professor Greenwood, "The European Medicines Agency (EMA) will assess the quality, safety, and efficacy of the vaccine based on these final data. If the EMA gives a favorable opinion, WHO could recommend the use of RTS,S/AS01 as early as October this year. If licensed, RTS,S/AS01 would be the first licensed human vaccine against a parasitic disease."

Writing in a linked Comment, Vasee Moorthy and Jean Marie Okwo-Bele, from the Department of Immunization, Vaccines and Biologicals at WHO in Geneva, Switzerland say, "The donor community would need to coordinate any financing for the RTS,S/AS01 vaccine carefully, should it reach that stage. In particular, funding must not be redirected away from meeting adequate access to artemisinin-combination treatments, rapid diagnostic tests, longlasting insecticidal nets, and other malaria control measures already in place in certain settings."

Journal Reference:

1. RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. The Lancet, 2015 DOI: 10.1016/S0140-6736(15)60721-8 

Courtesy: ScienceDaily

Bacterial flora of remote tribespeople carries antibiotic resistance genes

 Scientists have found antibiotic resistance genes in the bacterial flora of a South American tribe that never before had been exposed to antibiotic drugs. The findings suggest that bacteria in the human body have had the ability to resist antibiotics since long before such drugs were ever used to treat disease.

These are huts in an isolated village inhabited by Yanomami Amerindians in a remote, mountainous area in southern Venezuela. Members of the tribe were isolated from the modern world and had never been exposed to antibiotic drugs, but the bacteria on their skin and in their mouths and intestines still had antibiotic resistance genes.

The research stems from the 2009 discovery of a tribe of Yanomami Amerindians in a remote mountainous area in southern Venezuela. Largely because the tribe had been isolated from other societies for more than 11,000 years, its members were found to have among the most diverse collections of bacteria recorded in humans. Within that plethora of bacteria, though, the researchers have identified genes wired to resist antibiotics.

The study, published April 17 in Science Advances, reports that the microbial populations on the skin and in the mouths and intestines of the Yanomami tribespeople were much more diverse than those found in people from the United States and Europe. The multicenter research was conducted by scientists at New York University School of Medicine, Washington University School of Medicine in St. Louis, the Venezuelan Institute of Scientific Research and other institutions.

"This was an ideal opportunity to study how the connections between microbes and humans evolve when free of modern society's influences," said Gautam Dantas, PhD, associate professor of pathology and immunology at Washington University and one of the study's authors. "Such influences include international travel and exposure to antibiotics."

Intriguingly, in Dantas' lab, graduate student Erica Pehrsson searched for and found antibiotic resistance genes in bacteria on the skin and in the mouths and intestines of tribe members long isolated from such outside influences.

"These people had no exposure to modern antibiotics; their only potential intake of antibiotics could be through the accidental ingestion of soil bacteria that make naturally occurring versions of these drugs," Pehrsson said. "Yet we were able to identify several genes in bacteria from their fecal and oral samples that deactivate natural, semi-synthetic and synthetic drugs."

Thousands of years before people began using antibiotics to fight infections, soil bacteria began producing natural antibiotics to kill competitors. Similarly, microbes evolved defenses to protect themselves from the antibiotics their bacterial competitors would make, likely by acquiring resistance genes from the producers themselves through a process known as horizontal gene transfer.

In recent years, the abundance of antibiotics in medicine and agriculture has accelerated this process, stimulating the development and spread of genes that help bacteria survive exposure to antibiotics. Consequently, strains of human disease that are much harder to treat have emerged.

"We have already run out of drugs to treat some types of multidrug-resistant infections, many of which can be lethal, raising the bleak prospect of a post-antibiotic era," Dantas said.

Scientists don't really know whether the diversity of specific bacteria improves or harms health, Dantas said, but added that the microbiomes of people in industrialized countries are about 40 percent less diverse than what was found in the tribespeople never exposed to antibiotics.

"Our results bolster a growing body of data suggesting a link between, on one hand, decreased bacterial diversity, industrialized diets and modern antibiotics, and on the other, immunological and metabolic diseases -- such as obesity, asthma, allergies and diabetes, which have dramatically increased since the 1970s," said Maria Dominguez-Bello, PhD, associate professor of medicine at New York University Langone Medical Center and senior author of the study. "We believe there is something occurring in the environment during the past 30 years that has been driving these diseases, and we think the microbiome could be involved."

Dominguez-Bello said the research suggests a link between modern antibiotics, diets in industrialized parts of the world and a greatly reduced diversity in the human microbiome -- the trillions of bacteria that live in and on the body and that are increasingly being recognized as vital to good health.

The vast majority of human microbiome studies have focused on Western populations, so access to people unexposed to antibiotics and processed diets may shed light on how the human microbiome has changed in response to modern culture, and may point to therapies that can address disease-causing imbalances in the microbiome.

In the current study, when the researchers exposed cultured bacterial species from the tribe to 23 different antibiotics, the drugs were able to kill all of the bacteria. However, the scientists suspected that these susceptible bacteria might carry silent antibiotic resistance genes that could be activated upon exposure to antibiotics.

They tested for such activation, and the tests confirmed their suspicions. The bacterial samples contained many antibiotic resistance genes that can fend off many modern antibiotics. These genes may turn on in response to antibiotic exposure.

"However, we know that easily cultured bacteria represent less than 1 percent of the human microbiota, and we wanted to know more about potential resistance in the uncultured majority of microbes," Dantas said.

So the researchers applied the same method, called functional metagenomics, to identify functional antibiotic resistance genes from Yanomami fecal and oral samples without any prior culturing. From that experiment they were able to identify nearly 30 additional resistance genes. Many of these genes deactivated natural antibiotics, but the scientists also found multiple genes that could resist semi-synthetic and synthetic antibiotics.

"These include, for example, third- and fourth-generation cephalosporins, which are drugs we try to reserve to fight some of the worst infections," said Dantas. "It was alarming to find genes from the tribespeople that would deactivate these modern, synthetic drugs."

As for how bacteria could resist drugs that such microbes never before had encountered, the researchers point to the possibility of cross-resistance, when genes that resist natural antibiotics also have the ability to resist related synthetic antibiotics.

"We've seen resistance emerge in the clinic to every new class of antibiotics, and this appears to be because resistance mechanisms are a natural feature of most bacteria and are just waiting to be activated or acquired with exposure to antibiotics," Dantas said.

Funded by the C&D Fund, the Emch Fund, the Helmsley Charitable Trust, SUCCESS, NAKFI Synthetic Biology, a Washington University I-CARES award, the Diane Belfer Program for Human Microbial Ecology, an NDSEG graduate fellowship, a Howard Hughes Medical Institute Early Career Scientist Award, and grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences of the National Institutes of Health (NIH). NIH grants DK062429, DP2-DK098089, R01-GM099538 and UH2AR057506.

Journal Reference:

1. Jose C. Clemente, Erica C. Pehrsson, Martin J. Blaser, Kuldip Sandhu, Zhan Gao, Bin Wang, Magda Magris, Glida Hidalgo, Monica Contreras, Óscar Noya-Alarcón, Orlana Lander, Jeremy McDonald, Mike Cox, Jens Walter, Phaik Lyn Oh, Jean F. Ruiz, Selena Rodriguez, Nan Shen, Se Jin Song, Jessica Metcalf, Rob Knight, Gautam Dantas, M. Gloria Dominguez-Bello. The microbiome of uncontacted Amerindians. Science Advances, 2015 DOI: 10.1126/sciadv.1500183 

Courtesy: ScienceDaily

Nondestructive micron resolution 3-D imaging of biological cells with sound

Much like magnetic resonance imaging (MRI) is able to scan the interior of the human body, the emerging technique of "picosecond ultrasonics," a type of acoustic imaging, can be used to make virtual slices of biological tissues without destroying them.

Fluorescence micrographs of fat and endothelial cells superimposed on differential-interference and phase-contrast images, respectively. The nuclei are stained blue in the micrographs. The image on the right is a picosecond-ultrasonic image of a single endothelial cell with approximately 1-micron lateral and 150-nanometer depth resolutions. Deep blue corresponds to the lowest ultrasonic amplitude.

Now a team of researchers in Japan and Thailand has shown that picosecond ultrasonics can achieve micron resolution of single cells, imaging their interiors in slices separated by 150 nanometers -- in stark contrast to the typical 0.5-millimeter spatial resolution of a standard medical MRI scan. This work is a proof-of-principle that may open the door to new ways of studying the physical properties of living cells by imaging them in vivo.
Picosecond ultrasonics has been used for decades as a method to explore the mechanical and thermal properties of materials like metals and semiconductors at submicron scales, and in recent years it has been applied to biological systems as well. The technique is suited for biology because it's sensitive to sound velocity, density, acoustic impedance and the bulk modulus of cells.
This week, in a story appearing on the cover of the journal Applied Physics Letters, from AIP Publishing, researchers from Walailak University in Thailand and Hokkaido University in Japan describe the first known demonstration of 3-D cell imaging using picosecond ultrasonics.
Their work centers on imaging two types of mammalian biological tissue -- a bovine aortic endothelial cell, a type of cell that lines a cow's main artery blood vessel, and a mouse "adipose" fat cell. Endothelial cells were chosen because they play a key role in the physiology of blood cells and are useful in the study of biomechanics. Fat cells, on the other hand, were studied to provide an interesting comparison with varying cell geometries and contents.
How the Work was Done
The team accomplished the imaging by first placing a cell in solution on a titanium-coated sapphire substrate and then scanning a point source of high-frequency sound generated by using a beam of focused ultrashort laser pulses over the titanium film. This was followed by focusing another beam of laser pulses on the same point to pick up tiny changes in optical reflectance caused by the sound traveling through the cell tissue.
"By scanning both beams together, we're able to build up an acoustic image of the cell that represents one slice of it," explained co-author Professor Oliver B. Wright, who teaches in the Division of Applied Physics, Faculty of Engineering at Hokkaido University. "We can view a selected slice of the cell at a given depth by changing the timing between the two beams of laser pulses."
The team's work is particularly noteworthy because "in spite of much work imaging cells with more conventional acoustic microscopes, the time required for 3-D imaging probably remains too long to be practical," Wright said. "Building up a 3-D acoustic image, in principle, allows you to see the 3-D relative positions of cell organelles without killing the cell. In our experiments in vitro, while we haven't yet resolved the cell contents -- possibly because cell nuclei weren't contained within the slices we viewed -- it should be possible in the future with various improvements to the technique."
So far, the team has used infrared light to generate sound waves within the cell, "limiting the lateral spatial resolution to about one micron," Wright explains. "By using an ultraviolet-pulsed laser, we could improve the lateral resolution by about a factor of three -- and greatly improve the image quality. And, switching to a diamond substrate instead of sapphire would allow better heat conduction away from the probed area, which, in turn, would enable us to increase the laser power and image quality."
So lowering the laser power or using substrates with higher thermal conductivity may soon open the door to in vivo imaging, which would be invaluable for investigating the mechanical properties of cell organelles within both vegetal and animal cells.
What's next for the team? "The method we use to image the cells now actually involves a combination of optical and elastic parameters of the cell, which can't be easily distinguished," Wright said. "But we've thought of a way to separate them, which will allow us to measure the cell mechanical properties more accurately. So we'll try this method in the near future, and we'd also like to try our method on single-celled organisms or even bacteria."
 

Journal Reference:

1. Sorasak Danworaphong, Motonobu Tomoda, Yuki Matsumoto, Osamu Matsuda, Toshiro Ohashi, Hiromu Watanabe, Masafumi Nagayama, Kazutoshi Gohara, Paul H. Otsuka, Oliver B. Wright. Three-dimensional imaging of biological cells with picosecond ultrasonics. Applied Physics Letters, 2015; 106 (16): 163701 DOI: 10.1063/1.4918275 

Courtesy: ScienceDaily
 

Drugs stimulate body’s own stem cells to replace the brain cells lost in multiple sclerosis

A pair of topical medicines already alleviating skin conditions each may prove to have another, even more compelling use: instructing stem cells in the brain to reverse damage caused by multiple sclerosis.

Led by researchers at Case Western Reserve, a multi-institutional team used a new discovery approach to identify drugs that could activate mouse and human brain stem cells in the laboratory. The two most potent drugs -- one that currently treats athlete's foot, and the other, eczema -- were capable of stimulating the regeneration of damaged brain cells and reversing paralysis when administered systemically to animal models of multiple sclerosis. The results are published online Monday, April 20, in the scientific journal Nature.

"We know that there are stem cells throughout the adult nervous system that are capable of repairing the damage caused by multiple sclerosis, but until now, we had no way to direct them to act," said Paul Tesar, PhD, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics, and associate professor in the Department of Genetics & Genome Sciences at the Case Western Reserve School of Medicine. "Our approach was to find drugs that could catalyze the body's own stem cells to replace the cells lost in multiple sclerosis."

The findings mark the most promising developments to date in efforts to help the millions of people around the world who suffer from multiple sclerosis. The disease is the most common chronic neurological disorder among young adults, and results from aberrant immune cells destroying the protective coating, called myelin, around nerve cells in the brain and spinal cord.

Without myelin, neural signals cannot be transmitted properly along nerves; over time, a patient's ability to walk, hold a cup or even see is inexorably eroded. Current multiple sclerosis therapies aim to slow further myelin destruction by the immune system, but the Case Western Reserve team used a new approach to create new myelin within the nervous system. Their work offers great promise of developing therapies that reverse disabilities caused by multiple sclerosis or similar neurological disorders.

"To replace damaged cells, much of the stem cell field has focused on direct transplantation of stem cell-derived tissues for regenerative medicine, and that approach is likely to provide enormous benefit down the road," said Tesar, also a New York Stem Cell Foundation Robertson Investigator and member of the National Center for Regenerative Medicine. "But here we asked if we could find a faster and less invasive approach by using drugs to activate native stem cells already in the adult nervous system and direct them to form new myelin. Our ultimate goal was to enhance the body's ability to repair itself."

Tesar emphasized that much work remains before multiple sclerosis patients might benefit from the promising approach. Scientists still must find ways to transform the topical medications for internal use and determine their long-term efficacy and potential side effects. That said, using existing, federally approved drugs enhances the likelihood that the compounds can be made safe for human use.

Tesar and his colleagues could zero in on the two catalyzing medications only because of a breakthrough that his laboratory achieved in 2011. Specifically, the researchers developed a unique process to create massive quantities of a special type of stem cell called an oligodendrocyte progenitor cell (OPC). These OPCs are normally found throughout the adult brain and spinal cord, and therefore inaccessible to study. But once Tesar and his team could produce billions of the OPCs with relative ease, they could begin to test different existing drug formulations to determine which, if any, induced the OPCs to form new myelinating cells.
Using a state-of-the-art imaging microscope, the investigators quantified the effects of 727 previously known drugs, all of which have a history of use in patients, on OPCs in the laboratory. The most promising medications fell into two specific chemical classes. From there, the researchers found that miconazole and clobetasol performed best within the respective classes. Miconazole is found in an array of over-the-counter antifungal lotions and powders, including those to treat athlete's foot. Clobetasol, meanwhile, is typically available by prescription to treat scalp and other skin conditions such as dermatitis. Neither had been previously considered as a therapeutic for multiple sclerosis, but testing revealed each had an ability to stimulate OPCs to form new myelinating cells. When administered systemically to lab mice afflicted with a multiple sclerosis-like disease, both drugs prompted native OPCs to regenerate new myelin.
"It was a striking reversal of disease severity in the mice," said Robert Miller, PhD, a member of the neurosciences faculty at Case Western Reserve who, with Tesar, is a co-senior author of the Nature paper. The two collaborated on this project while Miller also served as Vice President for Research at Case Western Reserve; since June his primary appointments are at the George Washington University School of Medicine and Health Sciences, where he is Senior Associate Dean for Research and Vivian Gill Distinguished Research Chair. "The drugs that we identified are able to enhance the regenerative capacity of stem cells in the adult nervous system. This truly represents a paradigm shift in how we think about restoring function to multiple sclerosis patients."
While the drugs proved to have extraordinary effects on mice, their impact on human patients will not be known fully until actual clinical trials. Nevertheless, Tesar and his team already have added reason for optimism; in addition to the tests with animal cells, they also tested the drugs on human stem cells -- and saw the medication prompt a similar response as seen in the mouse cells. Both medications worked well, with miconazole demonstrating the more potent effects.
"We have pioneered technologies that enable us to generate both mouse and human OPCs in our laboratory," said Fadi Najm, MBA, the first author of the study and Research Scientist in the Department of Genetics & Genome Sciences at the Case Western Reserve School of Medicine. "This uniquely positioned us to test if these drugs could also stimulate human OPCs to generate new myelinating cells."
Tesar, who recently received the 2015 International Society for Stem Cell Research Outstanding Young Investigator Award, said investigators next will work to deepen their understanding of the mechanism by which these drugs act. Once these details are clear, researchers will modify the drugs to increase their effectiveness in people.
The team is enthusiastic that optimized versions of these two drugs can be advanced to clinical testing for multiple sclerosis in the future, but Tesar emphasized the danger of trying to use current versions for systemic human administration.
"We appreciate that some patients or their families feel they cannot wait for the development of specific approved medications," Tesar said, "but off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms. We are working tirelessly to ready a safe and effective drug for clinical use."
While multiple sclerosis is the initial focus for translating this research into the clinic, a number of other disorders involve myelin loss or dysfunction including cerebral palsy, age-related dementia, optic neuritis and schizophrenia. Any drugs developed that enhance myelination in multiple sclerosis also hold promise for benefiting these other disorders.
"The approach from Case Western Reserve University combines cutting-edge stem cell and drug screening technologies to develop new chemical therapeutics for myelin disorders," said Christopher Austin, MD, director of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH). NCATS researchers performed key external validation experiments as part of the study. "It is clear that the discovery of drugs that control the function of stem cells in the body represents a promising new era in regenerative medicine."

Journal Reference:

1. Fadi J. Najm, Mayur Madhavan, Anita Zaremba, Elizabeth Shick, Robert T. Karl, Daniel C. Factor, Tyler E. Miller, Zachary S. Nevin, Christopher Kantor, Alex Sargent, Kevin L. Quick, Daniela M. Schlatzer, Hong Tang, Ruben Papoian, Kyle R. Brimacombe, Min Shen, Matthew B. Boxer, Ajit Jadhav, Andrew P. Robinson, Joseph R. Podojil, Stephen D. Miller, Robert H. Miller, Paul J. Tesar. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature, 2015; DOI: 10.1038/nature14335 

Courtesy: ScienceDaily

New clinical platform may accelerate discovery of diagnostic and therapeutic agents

Researchers at University of British Columbia have developed a new technology that enables rapid discovery of aptamers, one of the fastest growing classes of diagnostic and therapeutic agents. Aptamers are short sequences of genetic material that fold into precise 3-D structures that bind target molecules and inhibit their biological functions.

In a recent Biotechnology and Bioengineering article, the investigators describe their aptamer selection platform, called high-fidelity systematic evolution of ligands by exponential enrichment (Hi-Fi SELEX), that accelerates and improves selection of DNA aptamers by ameliorating several limitations of current methods used for aptamer discovery. The platform is engineered to greatly enhance the diversity of the starting collection of aptamers and the ability to rapidly enrich aptamers of therapeutic relevance, while also enabling their high-fidelity amplification and regeneration.
"As a technology development lab, we looked under-the-hood of available aptamer discovery platforms to determine precisely why they often do not yield functionally or therapeutically useful reagents. Through that effort we identified a number of issues that greatly limit performance and then worked to ameliorate those impediments using a combination of chemical modification methods and advanced enzymatic and processing strategies available in our labs," said senior author Dr. Charles Haynes. "One of the great strengths of the resulting Hi-Fi SELEX platform is its ability to enhance the functional diversity of the library, which greatly improves the odds of discovering useful molecules."
 

Journal Reference:

1. Eric Ouellet, Jonathan H. Foley, Edward M. Conway, Charles Haynes. Hi-Fi SELEX: A high-fidelity digital-PCR based therapeutic aptamer discovery platform. Biotechnology and Bioengineering, 2015; DOI: 10.1002/bit.25581 

Courtesy: ScienceDaily

 

Researchers at University of British Columbia have developed a new technology that enables rapid discovery of aptamers, one of the fastest growing classes of diagnostic and therapeutic agents. Aptamers are short sequences of genetic material that fold into precise 3-D structures that bind target molecules and inhibit their biological functions.

 

Your pain reliever may also be diminishing your joy

Researchers studying the commonly used pain reliever acetaminophen found it has a previously unknown side effect: It blunts positive emotions.

Acetaminophen is the most common drug ingredient in the United States, found in more than 600 medicines, according to the Consumer Healthcare Products Association.

In the study, participants who took acetaminophen reported less strong emotions when they saw both very pleasant and very disturbing photos, when compared to those who took placebos.
Acetaminophen, the main ingredient in the over-the-counter pain reliever Tylenol, has been in use for more than 70 years in the United States, but this is the first time that this side effect has been documented.
Previous research had shown that acetaminophen works not only on physical pain, but also on psychological pain. This study takes those results one step further by showing that it also reduces how much users actually feel positive emotions, said Geoffrey Durso, lead author of the study and a doctoral student in social psychology at The Ohio State University.
"This means that using Tylenol or similar products might have broader consequences than previously thought," Durso said.
"Rather than just being a pain reliever, acetaminophen can be seen as an all-purpose emotion reliever."
Durso conducted the study with Andrew Luttrell, another graduate student in psychology at Ohio State, and Baldwin Way, an assistant professor of psychology and the Ohio State Wexner Medical Center's Institute for Behavioral Medicine Research. Their results appear online in the journal Psychological Science.
Way said people in the study who took the pain reliever didn't appear to know they were reacting differently. "Most people probably aren't aware of how their emotions may be impacted when they take acetaminophen," he said.
Acetaminophen is the most common drug ingredient in the United States, found in more than 600 medicines, according to the Consumer Healthcare Products Association, a trade group.
Each week about 23 percent of American adults (about 52 million people) use a medicine containing acetaminophen, the CHPA reports.
There were two studies of college students. The first involved 82 participants, half of whom took an acute dose of 1000 milligrams of acetaminophen and half who took an identical-looking placebo. They then waited 60 minutes for the drug to take effect.
Participants then viewed 40 photographs selected from a database (International Affective Picture System) used by researchers around the world to elicit emotional responses.
The photographs ranged from the extremely unpleasant (crying, malnourished children) to the neutral (a cow in a field) to the very pleasant (young children playing with cats).
After viewing each photo, participants were asked to rate how positive or negative the photo was on a scale of -5 (extremely negative) to +5 (extremely positive). They then viewed the same photos again and were asked to rate how much the photo made them feel an emotional reaction, from 0 (little or no emotion) to 10 (extreme amount of emotion).
Results in both studies showed that participants who took acetaminophen rated all the photographs less extremely than did those who took the placebo.
In other words, positive photos were not seen as positively under the influence of acetaminophen and negative photos were not seen as negatively.
The same was true of their emotional reactions.
"People who took acetaminophen didn't feel the same highs or lows as did the people who took placebos," Way said.
For example, people who took the placebo rated their level of emotion relatively high (average score of 6.76) when they saw the most emotionally jarring photos of the malnourished child or the children with kittens.
People taking acetaminophen didn't feel as much in either direction, reporting an average level of emotion of 5.85 when they saw the extreme photos.
Neutral photos were rated similarly by all participants, regardless of whether they took the drug or not.
These findings seem dramatic, but one possibility is that acetaminophen changes how people judge magnitude. In other words, acetaminophen may blunt individuals' broader judgments of everything, not just things having emotional content, Durso said.
So the researchers did a second study in which they had 85 people view the same photos and make the same judgments of evaluation and emotional reactions as in the prior study. Additionally, participants in this second study also reported how much blue they saw in each photo.
Once again, individuals who took acetaminophen (compared to placebo) had evaluations and emotional reactions to both negative and positive photographs that were significantly blunted. However, judgments of blue color content were similar regardless of whether the participants took acetaminophen or not.
The results suggest that acetaminophen affects our emotional evaluations and not our magnitude judgments in general.
At this point, the researchers don't know if other pain relievers such as ibuprofen and aspirin have the same effect, although they plan on studying that question, Durso said.
Acetaminophen, unlike many other pain relievers, is not a nonsteroidal anti-inflammatory drug, or NSAID. That means it not thought to control inflammation in the body. Whether that fact has any relevance to possible emotional effects of the drugs is still an open question, Durso said.
These results may also have an impact on psychological theory, Way said. An important question in psychological research is whether the same biochemical factors control how we react to both positive and negative events in our lives. A common theory is that certain factors control how we react to the bad things that happen in life -- for example, how devastated people feel when they go through a divorce.
But this study offers support to a relatively new theory that says that common factors may influence how sensitive we are to both the bad as well as the good things in life.
That means the person who is more devastated by a divorce may thrive more than others when they get a promotion at work or have some other extremely positive event happen.
In this study, acetaminophen may have tapped into the sensitivity that makes some people react differently to both positive and negative life events.
"There is accumulating evidence that some people are more sensitive to big life events of all kinds, rather than just vulnerable to bad events," Durso said.
 

Journal Reference:

1. G. R. O. Durso, A. Luttrell, B. M. Way. Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli. Psychological Science, 2015; DOI: 10.1177/0956797615570366 

Courtesy: ScienceDaily
 

Make your home a home for the birds

The landscaping plants chosen by residents for their yards plays a much greater role in the diversity of native birds in suburban neighborhoods than do the surrounding parks, forest preserves, or streetside trees, say biologists at the University of Illinois at Chicago.

Their findings are published in the journal Ecological Applications.
The combined effects of a neighborhood's small yards has a greater impact on the variety of native birds than larger landscape features, says Amy Belaire, UIC doctoral candidate in biological science, who is first author on the study.
"We were surprised by the diversity of species we found in people's neighborhoods--36 species in all," Belaire said. But areas with bird-friendly yards had nearly twice as many species, she said, as neighborhoods whose private yards were less attractive to birds.
The UIC biologists surveyed 25 neighborhoods in the Chicago area, in June's peak breeding season, scoring the number and type of birds and "bird-friendly" landscaping features, such as berry bushes, evergreens and certain other trees -- along with bird feeders, bird-baths or ponds.
Because backyards are private, their impact on bird populations hasn't been previously studied, said Emily Minor, UIC associate professor of biological sciences and principal investigator on the study.
"The backyards are where people feel more comfortable landscaping things that they think are important," said Minor. "So a lot of people's bird-friendly efforts are in the backyards."
Belaire walked one kilometer down 25 selected streets near forest preserves throughout Cook County, stopping every 100 meters to look for birds and listen for birdsongs. She identified and counted the birds in each area based on these observations.
Going house-to-house, Belaire, along with UIC undergraduate student Hannah Gin, asked people to fill out a survey of their yards, identifying environmental characteristics including bird-friendly landscaping. They also asked if cats or dogs lived outside.
The researchers found that the neighborhoods most attractive to birds were those in which many yards had fruit or berry-bearing trees and shrubs; a mix of evergreen and other types of trees; and, to a lesser extent, other environmental features. They found that the presence of outdoor animals, especially cats, kept birds away.
The research, Minor said, grew from wondering how many birds from the forest preserves flew into nearby neighborhoods. Many do so, they found.
"Birds are really living out in the neighborhood," Minor said. "We found that there were simple guidelines for people to follow to increase bird diversity in their own backyards."
 

Journal Reference:

1. J. Amy Belaire, Christopher J. Whelan, Emily S. Minor. Having our yards and sharing them too: the collective effects of yards on native bird species in an urban landscape. Ecological Applications, 2014; 24 (8): 2132 DOI: 10.1890/13-2259.1 

Courtesy: ScienceDaily
 

Cigarette smoke makes superbugs more aggressive

Methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant superbug, can cause life-threatening skin, bloodstream and surgical site infections or pneumonia. Researchers at the University of California, San Diego School of Medicine now report that cigarette smoke may make matters worse. The study, published March 30 by Infection and Immunity, shows that MRSA bacteria exposed to cigarette smoke become even more resistant to killing by the immune system.

"We already know that smoking cigarettes harms human respiratory and immune cells, and now we've shown that, on the flipside, smoke can also stress out invasive bacteria and make them more aggressive," said senior author Laura E. Crotty Alexander, MD, assistant clinical professor of medicine at UC San Diego and staff physician at the Veterans Affairs San Diego Healthcare System.
Crotty Alexander is a pulmonologist who sees many patients who smoke cigarettes. She also sees many MRSA infections, and that got her wondering if one might influence the other. To test the hypothesis, Crotty Alexander and her team infected macrophages, immune cells that engulf pathogens, with MRSA. Some of the bacteria were grown normally and some were grown with cigarette smoke extract. They found that while the macrophages were equally able to take up the two bacterial populations, they had a harder time killing the MRSA that had been exposed to cigarette smoke extract.
To better understand why, the Crotty Alexander team tested the bacteria's susceptibility to individual mechanisms macrophages typically employ to kill bacteria. Once inside macrophages, smoke-exposed MRSA were more resistant to killing by reactive oxygen species, the chemical burst that macrophages use to destroy their microbial meals. The team also discovered that smoke-exposed MRSA were more resistant to killing by antimicrobial peptides, small protein pieces the immune system uses to poke holes in bacterial cells and trigger inflammation. The effect was dose-dependent, meaning that the more smoke extract they used, the more resistant the MRSA became.
MRSA treated with cigarette smoke extract were also better at sticking to and invading human cells grown in the lab. In a mouse model, MRSA exposed to cigarette smoke survived better and caused pneumonia with a higher mortality rate.
The data suggest that cigarette smoke strengthens MRSA bacteria by altering their cell walls in such a way that they are better able to repel antimicrobial peptides and other charged particles.
"Cigarette smokers are known to be more susceptible to infectious diseases. Now we have evidence that cigarette smoke-induced resistance in MRSA may be an additional contributing factor," Crotty Alexander said.

Journal Reference:

1. Elisa K. McEachern, John H. Hwang, Katherine M. Sladewski, Shari Nicatia, Carola Dewitz, Denzil P. Mathew, Victor Nizet, Laura E. Crotty Alexander. Analysis of the Effects of Cigarette Smoke on Staphylococcal Virulence Phenotypes. Infection and Immunity, 2015; IAI.00303-15 DOI: 10.1128/IAI.00303-15 

 Courtesy: ScienceDaily

Ebola virus diagnostic tool developed by physician who worked in Liberia

Adam C. Levine, M.D., an emergency medicine physician at Rhode Island Hospital and The Miriam Hospital who treated Ebola-infected patients in Liberia last year, used his field experience to create a tool to determine the likelihood that patients presenting with Ebola symptoms will actually carry the virus. His research was published in the Annals of Emergency Medicine.

Ebola Virus Disease (EVD) has affected 24,000 persons during the current epidemic, which is the largest recorded outbreak of EVD in history. Over 10,000 people have died in West Africa, mainly in Sierra Leone, Liberia and Guinea. Because the initial symptoms are not specific to EVD, diagnosing EVD remains a significant challenge. This is the first time that researchers scientifically derived a clinical prediction model, the Ebola Prediction Score, for patients with suspected EVD who await laboratory confirmation.
"There is a lag time between a suspected case and a confirmation," said Levine, who volunteered in Liberia through the humanitarian organization, International Medical Corps, helping set up their first Ebola Treatment Unit (ETU) in Bong County. "The Ebola Prediction Score will help clinicians risk-stratify patients already meeting one or more suspect definitions of EVD."
Typical predictors for EVD include fever, nausea/vomiting, diarrhea, fatigue, abdominal pain, loss of appetite, muscle pain, joint pain, headache, difficulty breathing, difficulty swallowing, hiccups, unexplained bleeding, and exposure to a suspected or confirmed EVD patient within 21 days. In Levine's Ebola Prediction Score tool, six of those symptoms create the model--sick contact, diarrhea, loss of appetite, muscle pain, difficulty swallowing and absence of abdominal pain. A scoring system based on these signs may help clinicians determine who is most likely to require isolation while laboratory tests confirm diagnosis.
"Admitting a patient to an ETU in a rural setting or to a community-based isolation center who is unlikely to have EVD puts that patient at risk for exposure," said Levine. "Determining which patients to admit for definitive testing and treatment required balancing the epidemiologic imperative to break the train of transmission in the community against the ethical imperative to 'do no harm' to each individual patient, all within the context of severe resource constraints."
Patient data was collected during routine clinical care at the 52-bed Bong County ETU in Liberia during its first 16 weeks of operation. EVD testing results were available for 382 of the 395 patients admitted to the ETU during the study period. Forty-two percent, or 160 patients, tested positive for EVD.
According to Levine, while the Ebola Prediction Score can help determine who is more likely to have EVD and treat them accordingly, better testing needs to be a focus. "Given the inherent limitations of clinical prediction models...a low-cost, point-of-care test that can rapidly and definitively exclude EVD in patients should be a research priority," he said.

Journal Reference:

1. Adam C. Levine, MD, MPH et al. Derivation and Internal Validation of the Ebola Prediction Score for Risk Stratification of Patients With Suspected Ebola Virus Disease. Annals of Emergency Medicine, April 2015 DOI: 10.1016/j.annemergmed.2015.03.011

 Courtesy: ScienceDaily

DNA can't explain all inherited biological traits, research shows

Characteristics passed between generations are not decided solely by DNA, but can be brought about by other material in cells, new research shows.

A histone is a protein that provides structural support to a chromosome. In order for very long DNA molecules to fit into the cell nucleus, they wrap around complexes of histone proteins, giving the chromosome a more compact shape. Some variants of histones are associated with the regulation of gene expression.

Scientists studied proteins found in cells, known as histones, which are not part of the genetic code, but act as spools around which DNA is wound. Histones are known to control whether or not genes are switched on.
Researchers found that naturally occurring changes to these proteins, which affect how they control genes, can be sustained from one generation to the next and so influence which traits are passed on.
The finding demonstrates for the first time that DNA is not solely responsible for how characteristics are inherited. It paves the way for research into how and when this method of inheritance occurs in nature, and if it is linked to particular traits or health conditions.
It may also inform research into whether changes to the histone proteins that are caused by environmental conditions -- such as stress or diet -- can influence the function of genes passed on to offspring.
The research confirms a long-held expectation among scientists that genes could be controlled across generations by such changes. However, it remains to be seen how common the process is, researchers say.
Scientists tested the theory by carrying out experiments in a yeast with similar gene control mechanisms to human cells. They introduced changes to a histone protein, mimicking those that occur naturally, causing it to switch off nearby genes. The effect was inherited by subsequent generations of yeast cells.
The study, published in Science, was supported by the Wellcome Trust and the EC EpiGeneSys Network.
Professor Robin Allshire, of the University of Edinburgh's School of Biological Sciences, who led the study, said: "We've shown without doubt that changes in the histone spools that make up chromosomes can be copied and passed through generations. Our finding settles the idea that inherited traits can be epigenetic, meaning that they are not solely down to changes in a gene's DNA."

Journal Reference:

1. Pauline N. C. B. Audergon, Sandra Catania, Alexander Kagansky, Pin Tong, Manu Shukla, Alison L. Pidoux, Robin C. Allshire. Restricted epigenetic inheritance of H3K9 methylation. Science, 2015 DOI: 10.1126/science.1260638

CourtesyL: ScienceDaily

MRI based on a sugar molecule can tell cancerous from noncancerous cells

Imaging tests like mammograms or CT scans can detect tumors, but figuring out whether a growth is or isn't cancer usually requires a biopsy to study cells directly. Now results of a Johns Hopkins study suggest that MRI could one day make biopsies more effective or even replace them altogether by noninvasively detecting telltale sugar molecules shed by the outer membranes of cancerous cells.

Normal cells (left) have far more sugar attached to mucin proteins than do cancerous cells (right). Mucin-attached sugar generates a high MRI signal, shown in red.

The MRI technique, so far tested only in test tube-grown cells and mice, is described in a report published March 27 in the online journal Nature Communications.
"We think this is the first time scientists have found a use in imaging cellular slime," says Jeff Bulte, Ph.D., a professor of radiology and radiological science in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. "As cells become cancerous, some proteins on their outer membranes shed sugar molecules and become less slimy, perhaps because they're crowded closer together. If we tune the MRI to detect sugars attached to a particular protein, we can see the difference between normal and cancerous cells."
Bulte's research builds on recent findings by others that indicate glucose can be detected by a fine-tuned MRI technique based on the unique way it interacts with surrounding water molecules without administering dyes. Other researchers have used MRI but needed injectable dyes to image proteins on the outside of cells that lost their sugar. In this study, Bulte's research team compared MRI readings from proteins known as mucins with and without sugars attached to see how the signal changed. They then looked for that signal in four types of lab-grown cancer cells and detected markedly lower levels of mucin-attached sugars than in normal cells.
Xiaolei Song, Ph.D., the lead author on the study and a research associate in Bulte's laboratory, explains that this is the first time a property integral to cancer cells, rather than an injected dye, has been used to detect those cells. "The advantage of detecting a molecule already inside the body is that we can potentially image the entire tumor," she says. "This often isn't possible with injected dyes because they only reach part of the tumor. Plus, the dyes are expensive."
Bulte cautions that much more testing is needed to show that the technique has value in human cancer diagnosis. His team's next step will be to see if it can distinguish more types of cancerous tumors from benign masses in live mice.
If further testing does show such success, Bulte and Song suggest the technique could be used to detect cancer at an early stage, monitor response to chemotherapy, guide biopsies to ensure sampling of the most malignant part of a tumor and eventually make at least some biopsies unnecessary.
Other authors on the paper are Raag D. Airan, Dian R. Arifin, Amnon Bar-Shir, Deepak K. Kadayakkara, Guanshu Liu, Assaf A. Gilad, Peter C.M. van Zijl and Michael T. McMahon, all of The Johns Hopkins University.
This project was supported by the National Institute of Biomedical Imaging and Bioengineering (grant numbers R01 EB015032 and R01 EB015031), the National Cancer Institute (grant number U54 CA151838), the Maryland Stem Cell Research Foundation (grant number MSCRFII-0042), and the Pearl and Yueh-Heng Yang Foundation.
 

Journal Reference:

1. Xiaolei Song, Raag D. Airan, Dian R. Arifin, Amnon Bar-Shir, Deepak K. Kadayakkara, Guanshu Liu, Assaf A. Gilad, Peter C. M. van Zijl, Michael T. McMahon, Jeff W. M. Bulte. Label-free in vivo molecular imaging of underglycosylated mucin-1 expression in tumour cells. Nature Communications, 2015; 6: 6719 DOI: 10.1038/ncomms7719

---

 

Courtesy: ScienceDaily

 

Crossing fingers can reduce feelings of pain

How you feel pain is affected by where sources of pain are in relation to each other, and so crossing your fingers can change what you feel on a single finger, finds new UCL research.

The research, published in Current Biology, used a variation on an established pain experiment, known as the "thermal grill illusion." In the thermal grill illusion, a pattern of warm-cold-warm temperatures applied to the index, middle and ring finger respectively causes a paradoxical, sometimes painful, sensation of burning heat on the middle finger -- even though this finger is actually presented with a cold stimulus.
"The thermal grill is a useful component in our scientific understanding of pain," says Angela Marotta (UCL Institute of Cognitive Neuroscience), co-lead author in the research, "It uses a precisely-controlled stimulus to activate the brain's pain systems. This can certainly feel painful, but doesn't actually involve any tissue damage."
The thermal grill produces burning heat sensations because of a three-way interaction between the nerve pathways that tell the brain about warmth, cold and pain. The warm temperature on the ring and index fingers blocks the brain activity that would normally be driven by the cold temperature on the middle finger.
"Cold normally inhibits pain, so inhibiting the input from the cold stimulus produces an increase in pain signals," explains co-lead author Dr Elisa Ferrè (UCL Institute of Cognitive Neuroscience). "It's like two minuses making a plus."
The researchers showed that this interaction was based on the spatial arrangement of the fingers. When the middle finger was crossed over the index finger, the paradoxical sensation of burning heat on the middle finger was reduced.
However, if the index finger was cooled and the middle and ring fingers were warmed, the burning heat sensation was now increased when the middle finger was crossed over the index finger.
"Our results showed that a simple spatial pattern determined the burning heat sensation," says Dr Ferrè. "When the cold finger was positioned in between the two warm fingers, it felt burningly hot. When the cold finger was moved to an outside position, the burning sensation was reduced. The brain seemed to use the spatial arrangement of all three stimuli to produce the burning heat sensation on just one finger."
"Interactions like these may contribute to the astonishing variability of pain," says senior author Professor Patrick Haggard (UCL Institute of Cognitive Neuroscience). "Many people suffer from chronic pain, and the level of pain experienced can be higher than would be expected from actual tissue damage. Our research is basic laboratory science, but it raises the interesting possibility that pain levels could be manipulated by applying additional stimuli, and by moving one part of the body relative to others. Changing the spatial pattern of interacting inputs could have an effect on the brain pathways that underlie pain perception."
 

Journal Reference:

1. Patrick Haggard et al. Transforming the Thermal Grill Effect by Crossing the Fingers. Current Biology, March 2015 DOI: 10.1016/j.cub.2015.02.055

 Courtesy: ScienceDaily