Scientists Sequence RNA of 750-Year-Old Barley Virus That Offers Genetic Evidence on Role of Farming In The Crusades

Researchers from the University of Warwick have for the first time sequenced an ancient RNA genome - of a barley virus - to reveal that intense farming at the time of the Crusades contributed to its spread. This virus was earlier believed to be only 150 years old. However, this research pushed its origin back at least 2,000 years. 

The genome sequence of the virus that scientists sequenced was Barley Stripe Mosaic Virus (BSMV) in a 750-year-old barley grain found found at a site near the River Nile in modern-day Egypt. Their study is published in the journal Scientific Reports.

  
BSMV virus was first discovered in 1950, while the earliest record of symptoms is just 100 years old. The new study challenges the presently held belief about the age of this virus. 

While ancient DNA genomes have been sequenced in past, this is the first time when ancient RNA genomes been sequenced. Sequencing RNA genomes can be quite challenging because they break down 50 times more rapidly than DNA. 

In case of the present study, the barley was found at the site in Qasr Ibrim in Lower Nubia. The scientists were able to sequence the RNA because it was better preserved at this site because of extremely dry conditions prevalent here. 

The researchers were able to trace the evolution of the Barley Stripe Mosaic Virus to a probable origin of around 2,000 years ago using the new medieval RNA to calibrate estimates of the rate of mutations. The potential of the origin could possibly go back to the domestication of barley in the Near East around 11,000 years ago.  

It is quite likely that the BSMV may have originally transferred from the wild grass population to an early cultivated form of barley while the seeds were stored through seed to seed contact.

"It is important to know as much as we can about virus evolution as emerging infectious plant diseases are a growing threat to global food security, and of those viruses account for almost half," said Dr Robin Allaby of the School of Life Sciences at the University of Warwick, who led the study. 

"History tells us about the devastation caused by the emergence of disease from wild hosts in disparate countries, such as the Central American origin of the oomycete that led to the Irish potato famine.

"We need to build up an accurate picture of the evolution of different types of virus so we can make better decisions about policies on plant movement.

"The medieval RNA from Qasr Ibrim gives us a vital clue to unlock the real age of the Barley Stripe Mosaic Virus.

"It is very difficult to understand how a plant disease evolved by solely relying on recent samples, however this 750-year-old example of the virus allows us to more accurately estimate its evolution rates and date of origin.

"Without the Medieval RNA evidence, the virus appears to be much younger than it actually is, when in fact its origins go back thousands of years.

"It's possible that other viruses that similarly appear to be very recent may in fact have a more ancient origin."

The Medieval BSMV genome may have come from a time of rapid expansion of the plant disease in the Near East and Europe, according to the researchers. This period could well have been the era of Crusades which witnessed a European Christianity up in arms against the Muslim territories of the Near East with their sights set on Jerusalem. The most closely aligned date of the origin of virus expansion coincides with the seventh Crusade of Louis IX in 1234. 

The virus may have likely spread due to massive war effort triggering intensification of farming to feed the armies involved in the campaign, according to researchers. This might have possibly brought wild grass in contact with cultivated barley making it possible for the virus to 'jump' into the crop. 

The possible split into an east and west BSMV lineage might have occurred 
around the end of the 15th century, around 100 years after the Mongol Empire stabilized the Silk Road, according to genetic evidence. It is likely that BSMV was transported to the east via trade routes such as the Silk Road in the late Medieval period. In more recent history, the virus appears to have spread to the US from Europe around 120-150 years ago.

Probiotics Can Keep Your Heart Healthy

In a recent study, it has been shown that certain probiotics have cholesterol-lowering potential. The new study titled "Effect of probiotics on biomarkers of cardiovascular disease: implications for heart-healthy diets," is published in the January issue of Nutrition Reviews. The study was designed to assess cholesterol-lowering potential of certain probiotics through examination of 26 clinical studies and two meta-analyses. More specifically, the scientists examined whether probiotics could reduce LDL-cholesterol. 

Among the several probiotics examined, the probiotics that best met therapeutic lifestyle change (TLC) dietary requirements was L. reuteri NCIMB 30242 (Cardioviva™). 

The researchers found that this probiotics significantly reduced LDL (bad) cholesterol and total cholesterol with robustness similar to that of existing TLC dietary options. It was also found to improve other coronary heart disease risk factors, such as inflammatory biomarkers, and it is, in addition, generally recognized as safe" (GRAS) status.

Although heart disease is a leading cause of death worldwide, and most adults (91 percent) claim to maintain a healthy cholesterol level for heart health, barely 37 percent actually get their cholesterol routinely tested. It is pretty well known that elevated LDL-cholesterol is a major risk factor for heart diseases. 

"People know probiotics for digestive health. They don't associate them with heart health," said Doug DiRienzo, PhD and lead author of the review. "It's time to recognize their potential role as a simple and natural tool in cholesterol management."

The scientists conducted randomized double-blinded, placebo-controlled, multi-center trials. These trials clearly demonstrated that Cardioviva™ healthy bacteria lowered total and LDL-cholesterol in hypercholesterolemic adults. 

One of these clinical trials involved 127 adults with high cholesterol. This trial demonstrated that those taking a supplement of L. reuteri NCIMB 30242 (Cardioviva™) twice a day had LDL levels 11.6 percent lower than those taking a placebo after nine weeks.

"It is exciting to think that certain probiotics, such as Cardioviva™, may have an impact on heart health through gut health," said Penny Kris-Etherton, PhD, RD, Distinguished Professor of Nutrition at the Pennsylvania State University and Fellow of the American Heart Association. "I would encourage consumers who are managing their heart health through diet and exercise to ask their health professionals about probiotics that have been proven effective in lowering cholesterol in clinical trials."

Fruit Flies With Longevity Mutation Can Reproduce More And Live Long

Researchers have for long suspected the role of a gene called "Indy", short for "I'm Not Dead Yet", in longevity. Mutations of this gene affect metabolism, life span, and reproductive fitness in both mammals and fruit flies. Up until now, mutations in this gene have been studied experimentally in the lab. A new study, however, claims that a particularly important variation of Indy gene with pretty much same life governing consequences has actually been widespread among fruit flies, judging by lines gathered from the wild across the entire globe for 60 years.

The variation in the gene is in fact naturally occurring when an invasive snippet of DNA inserts at a specific position on Indy. In this study, it was found that the transposable element, called Hoppel, was present to varying extents in 17 of 22 fruit fly lines gathered from all over the world as far back as the middle of last century. For instance, while Hoppel was found in 55 percent of flies descended from those gathered in Oahu, Hawaii, in 1955, it was present in 100 percent of a captive fly line started in 2006 in Mumbai, India. The researchers in this study included Brown University biology professors Dr. Stephen Helfand and Robert Reenan.  

Hefland first published a paper in Science in 2000 demonstrating the effect of Indy on life span. At that time, researchers wondered why a mutation that conveyed such advantages wasn't found in the wild.

However, the prevalence of Hoppel insertion, 14 years later suggests that it has been beneficial to flies in the wild and also persist during their evolution, according to Helfand of Brown's Department of Molecular Biology, Cellular Biology, and Biochemistry.

  

"It's kind of remarkable that just the Hoppel in Indy should affect fertility and life span because these flies from around the world are from such differing genetic backgrounds," said Helfand. "This suggests that we are correct that Indy does play a role in longevity. If it does it in the lab, that's great, but now we can show that it does it in the wild."

In the study, published online Jan. 31 in the journal Aging, the researchers, led by postdoctoral scholar Chen-Tseh Zhu, describe experiments that confirm that the Hoppel transposon's presence positively affected life span and fertility in the flies. What they found is that the optimal case for those two traits was heterozygosity: one allele, or copy, of the Indy gene in a fly having the insertion and the other not having it.

Life span and fertility

The researchers measured the physiological effects of Hoppel by looking at flies from three different lines: one from Oahu gathered in 1950s, another from Captain Cook, Hawaii, gathered in 2007, and one with its origin in Hidalgo, Mexico, in 2005. Each line had some flies with at least one copy of Indy with Hoppel and some with no Hoppel in Indy.

The heterozygous females in these lines ended up laying about 10 percent more eggs than flies that had no Indy alleles with Hoppel. Flies for whom both Indy alleles had Hoppel laid the fewest eggs. This demonstrates that one Indy allele with Hoppel had a strong selective advantage in reproductive fitness, Helfand said.

For life span, flies that had Hoppel on at least one Indy allele lived considerably longer than flies with no Hoppel on either chromosome. For example, among one group of females, by day 60, more than 80 percent of heterozygotes, and about 80 percent with Hoppel on both alleles were still alive. For those without any Hoppel insertion, less than 60 percent were still buzzing about by day 60.

Indy and Hoppel

For all the prior lab work, researchers are still not completely sure how Indy works, with our without mutations such as the Hoppel insertion. The protein the gene encodes appears to help gate metabolically important small nutrients such as citrate in the cell cytoplasm. Mutations in the gene appear to affect the concentration of these nutrients in the cell, effectively mimicking the effect of living on a calorie-restricted diet. Calorie restriction and certain Indy mutations have been shown to extend life span in flies and nematodes.

The hypothesis the scientists pursued is that mutations in Indy regulate the expression of the normal Indy gene, thereby leading to changes in the level of Indy activity in the body for better or worse. For that reason, the researchers measured levels of mRNA (the molecular means by which genes are expressed) in the flies. The more Hoppel insertion there was, they found, the more Indy expression there was. Heterozygotes lived longest and laid the most eggs, suggesting that the best level of expression might be the moderate one.

That the transposable element appears to confer benefits is a very exciting finding, Helfand said.

"It has often been suggested that the insertion of transposable elements into genes are largely detrimental to the organism," he said. "The present study is one of the few documented cases demonstrating insertion of a transposable element to have a positive benefit for the organism. Furthermore, it suggests that mutations due to transposable element insertion into genes may represent one of the ways by which new genetic material is produced, providing the raw material for natural selection and adaptive evolution."

Scientists Identify "Tumor Suppressor" Gene That Can Open New Possibilities For Cancer Therapy

In a recent study, researchers from Oregon State University have identified a genetic function that helps "tumor suppressor" genes to do its job better and prevent cancer.   

The gene identified is known as Grp1. Ways to maintain or increase the effectiveness of Grp1-associated scaffold protein or Grasp might possibly offer an important new avenue for cancer treatment, according to scientists. The findings are published in Photochemical and Photobiological Sciences, a journal of the Royal Society of Chemistry, by researchers from OSU and Oregon Health & Science University. The work was supported by the National Institute of Environmental Health Sciences.

The researchers studied Grasp gene in the skin of mice. However, studies have shown that Grasp gene is actually expressed at the highest levels in the brain, heart and lung. This gene is also shown to play a critical role in the operation of the p53 tumor suppressor gene, the focus of much modern cancer research. This is the gene that repairs damaged DNA. In case the damage is too great, p53 gene causes the mutated cell to die before it can cause further problems leading to cancer. More than half of all known cancers including skin, esophageal, colon, pancreatic, lung, ovarian, and head and neck cancers are linked to dysfunctional p53 genetic pathways.   

"DNA mutations occur constantly in our bodies just by ordinary stresses, something as simple as exposure to sunlight for a few seconds," said Mark Leid, professor of pharmacology and associate dean for research in the OSU College of Pharmacy, and one of the lead authors on this study.

"Just as constantly, the p53 gene and other tumor suppressors are activated to repair that damage," Leid said. "And in cases where the damage is too severe to be repaired, p53 will cause the apoptosis, or death of the mutated cell. Almost all of the time, when they are working right, these processes prevent the formation of cancers."

However, the activity of p53 can fail at times, according to Leid leading to the development of cancer. The current research promises to pave way for cancer therapy based on stimulating or activating p53 protein to do its job. 

This study has identified the huge role that the Grasp gene plays in maintaining the proper function of p53. There could be occasions when Grasp gene does not get adequately expressed. In such cases the p53 protein that has entered the cell nucleus to either repair or destroy the cell comes back out of the nucleus before its work is finished.

"It appears that a primary function of Grasp is to form sort of a halo around the nucleus of a damaged skin cell, and act as kind of a plug to keep the p53 cell inside the nucleus until its work is done," Leid said. "A drug that could enhance Grasp function might also help enhance the p53 function, and give us a different way to keep this important tumor suppressor working the way that it is supposed to. "This could be important," he said.

The scientists created lab mice lacking Grasp gene. When the mice were reared in a perfect environment, they developed normally. However, even mild environmental stressor like UV light similar to moderate sun exposure, they began to develop cellular abnormalities much more rapidly than ordinary mice. Yet, the mutated skin cells did not die as they were expected to. 

OSU experts created laboratory mice that lacked the Grasp gene, and so long as the mice were reared in a perfect environment, they developed normally. But when they were exposed to even a mild environmental stress – ultraviolet light similar to moderate sun exposure – they began to develop cellular abnormalities much more rapidly than ordinary mice. Most significantly, mutated skin cells did not die as they should have.

In normal mice, the same moderate light exposure caused a rapid increase in expression of the Grasp gene, allowing the p53 protein to stay in the nucleus and normal protective mechanisms to do their work.

Most current cancer therapies related to the p53 tumor suppression process are directed toward activating the p53 protein, Leid said. A therapy directed toward improving the Grasp gene function would be a different approach toward the same goal, he said, and might improve the efficacy of treatment.

ScienceNews: Dormant Prostate Cancer Cells May Be Reawakened by...

ScienceNews: Dormant Prostate Cancer Cells May Be Reawakened by...: In a recent study conducted by researchers in  the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, it was found that dormant ...

Dormant Prostate Cancer Cells May Be Reawakened by Factors Produced in Inflammatory Cells

In a recent study conducted by researchers in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, it was found that dormant prostate cancer cells in bone tissue can get reawakened causing metastasis to other parts of the body. Understanding of this mechanism will help researchers to intervene before disease progression.   

"Understanding how and why dormant cells in bone tissue metastasize will aid us in preventing the spread of disease, prolonging survival and improving overall quality of life," said Chia-Yi "Gina" Chu, PhD, a researcher and postdoctoral fellow in the Uro-Oncology Research Program and lead author of the study published in the journal Endocrine-Related Cancer.

The researchers conducting the study found that exposure to RANKL triggered the reawakening of cancerous cells in the bone. RANKL is a signalling molecule commonly produced by inflammatory cells. Researchers genetically engineered cells to overproduce RANKL. They found in lab studies and in laboratory mice that these cells were equipped to significantly  alter the gene expression of surrounding dormant cells so that they transformed into aggressive cancerous cells. 

When researchers injected these genetically engineered RANKL cells directly into the blood circulation of laboratory mice, it caused dormant cells within the skeleton to reawaken, creating tumors within the bone. When the RANKL receptor or its downstream targets were blocked, tumors did not form.

"After examination, these engineered tumors were found to contain both RANKL-producing prostate cancer cells and dormant cells, which had been transformed to become cancerous," said Chu. "However, the transformed cells displayed aggressive traits that would metastasize to bone and become resistant to standard hormone therapies used to treat the disease."

Though findings are preliminary, researchers plan to identify other cells known to produce RANKL that may also recruit and reprogram dormant cells to colonize bone tissue. Investigators plan to embark into clinical research with human patients in collaboration with leading Cedars-Sinai researchers, including Edwin Posadas, MD, medical director of the Urologic Oncology Program.

"Though more work must be done to understand how RANKL reprograms dormant cells to become cancerous, we look forward to examining its influence on promoting metastasis and secondary tumors, as well as the possibility of 'deprogramming' metastatic cancer cells," said Leland Chung, PhD, director of the Uro-Oncology Research Program.

Researchers Have Found Possible Mechanism That May Help Develop New HIV Therapy

The current strategy against HIV symptoms is the use of drug cocktails that mainly target three enzymes produced by the virus. However, the periodically popping up resistant strains can thwart the drug combos. 

Researchers at the University of California, Berkeley, and the National Institutes of Health have identified a fourth protein, Nef or negative factor. This protein hijacks host proteins. The researchers have captured a high-resolution snapshot of Nef bound with a main host protein, and discovered a portion of the host protein that will make a promising target for the next-generation of anti-HIV drugs. It could be possible to slow or stop HIV by blocking the part of a key host protein to which Nef binds.  

The report comes a month after President Barack Obama pledged to redirect $100 million in the NIH budget to accelerate development of a cure for AIDS, though therapies to halt the symptoms of AIDS will remain necessary for the immediate future, Bonifacino said.

"We have imaged the molecular details for the first time," said structural biologist James H. Hurley, UC Berkeley professor of molecular and cell biology. "Having these details in hand puts us in striking distance of designing drugs to block the binding site and, in doing so, block HIV infectivity." The findings are reported in online journal eLife.

"For many patients, current drug therapies have transformed HIV infection into a chronic condition that doesn't lead to AIDS, but anything we can develop to further interfere with replication and propagation of the virus would help keep it in check until we find a way to completely eliminate the virus from the body," Hurley said.

There are a small number of genes within HIV that produce just about 15 proteins but each of them hijack some aspect of immune cells' internal machinery producing more copies of the virus. 

The anti-AIDS drugs currently available block three HIV enzymes. These are proteins that transcribe and insert virus' genetic material and snip some encoded proteins. Researchers are now looking for drugs to target the other proteins and thereby support current therapies. In other words, they are searching for ways to block sites on host proteins to which the virus proteins bind in order to stop HIV. This has to be done without interfering with normal cell function, however.  

Over two decades ago, scientists discovered that HIV is far less infective in the absence of the protein Nef. With a Nef-defective virus, patients can live for decades without complications. More details about Nef have been coming in over the years. HIV enters immune system cells via a receptor called CD4, but once "HIV gets into cells through the CD4 door, it slams the door shut behind itself to prevent unproductive re-infection," Hurley said. Scientists do not know why HIV slams door on other viruses. This could possibly be strategy to make viral replication more effective. 

The virus prevents further HIV infection by ridding the cell surface of all other CD4 receptors. Nef achieves this by tagging the CD4 receptor so that the cell thinks it is trash and carries it to the cell's incinerator, the lysosome, where it is destroyed. This was observed by Bonifacino and colleagues six years ago, when they found that Nef does this by directly binding to a host protein, AP2, that latches onto a protein called clathrin. This causes the cell membrane to bulge inward and pinch off to form a small membrane bubble that carries attached CD4 receptors to the lysosome for destruction.

"The new high-resolution image reveals a cavity at the site where Nef binds to AP2, that could be a good site for drug targeting," Bonifacino said.

"This cavity on AP2 is not known to be used by any other host protein, so if we interfere with the cavity we are not going to interfere with any host cell function, only the function of Nef," he said. "This will inform better searches for inhibitors."

Hurley cautioned, however, that the research "needs more validation to prove that the cavity is a target. But we are excited because it is a potential target, and these things don't come along every day."

"This work was an extension of our work on clathrin adaptors, an opportunity to do something relevant to fighting HIV that was based on the purely basic research we are doing on the sorting of proteins to lysosomes," Hurley said.

Parents Likely to Spank Less If They Know Spanking Is Linked to Short and Long Term Behavioral Problems Among Children

Parents who think spanking will discipline their kids need to rethink. Decades of research has found that spanking can give rise to short as well as long term behavioral problems among kids. 

Child psychologist George Holden favors humane alternatives to corporal punishment. He wanted to see if parents' positive views toward spanking could be reversed if they were made aware of the research. So Holden along with three colleagues at Southern Methodist University, Dallas designed a test for parents in which they were exposed to short research summaries detailing negative impact of spanking. The researchers claim that it is the first study to demonstrate that brief exposure to spanking research can alter people's views toward spanking. 

In addition, this study in contrast to the previous studies is efficient, less costly and less time consuming."Given the brevity of our intervention, the results are notable," said the authors. "Our Web-based approach is less expensive, potentially quicker, and more easily scaled up to use at a community level." The study is published online in the international journal of Child Abuse & Neglect.  

The researchers carried out two studies, one with parents and the other with non-parents and found that attitudes were significantly altered. 

"Parents spank with good intentions — they believe it will promote good behavior, and they don't intend to harm the child. But research increasingly indicates that spanking is actually a harmful practice," said Holden, lead author on the study. "These studies demonstrate that a brief exposure to research findings can reduce positive corporal punishment attitudes in parents and non-parents."

"If we can educate people about this issue of corporal punishment, these studies show that we can in a very quick way begin changing attitudes," said Holden, a professor in the SMU Department of Psychology who has carried out extensive research on spanking.

With spanking a public health concern, this approach offers a simple way to reach a large audience to change attitudes and reduce parents' reliance on corporal punishment, said Holden, who was recently elected president of Dallas' oldest child abuse prevention agency, Family Compass. 

Automated Osteoporosis Follow Up Plan Could Efficiently Identify High-Risk Osteoporosis Patients

Penn State College of Medicine researchers have developed an automated system that can identify high risk osteoporosis patients under treatment for fractures along with generating letters that generate follow up. This according to the researchers is an effective way to prevent future fractures and promote osteoporosis intervention. 

The researchers identified 103 patients that were at least 50 years old with fractures. All the patients identified were seeking medical help at the emergency department of Penn State Milton S. Hershey Medical Center. The researchers further went on to analyze treatment codes to find fractures that seemed to be from bone fragility -- a broken bone caused by a fall from standing height or less.

The researchers received data every month from the hospital's finance department. The data was used to autopopulate a spreadsheet created specifically to screen for osteoporosis. Further screening of the data base ensured elimination of those patients whose injuries were not consistent with fragility fractures. Finally, the computer generated letters were mailed to the final list. The researchers found that less than 30 percent of postmenopausal women and less than 10 percent of men with a prior fragility fracture are treated for osteoporosis. 

"Our almost fully automated osteoporosis system identifies these patients, requires minimal resources -- many of which are already currently in U.S. hospitals, but just need to be tapped -- and delivers substantially improved osteoporosis intervention results," said Edward Fox, professor of orthopedics.

Patients were sent a letter within three months of their emergency room visit that explained that they may be at risk for osteoporosis and encouraged them to schedule an appointment with their doctor or the hospital's bone health clinic. A follow-up phone call was placed three months after the letter, asking if follow-up treatment had occurred.

For comparison, a group of 98 patients who did not receive letters were also contacted by phone six months after being treated in the emergency department for a fragility fracture. These patients were asked if they were being treated or had plans for follow-up after their fracture.

Of those who received letters, 60 percent had followed up. Only 14 percent of those who did not receive a letter had, or planned, follow-up care. Results were published in Geriatric Orthopaedic Surgery & Rehabilitation.

Past research has been conducted on osteoporosis intervention programs, but the majority of programs have lacked automation or could be difficult to implement in an average hospital. Since it is automated, this system reduces the potential for human error in identifying high-risk patients.

Nationally, osteoporosis contributes to more than 2 million fractures per year.

"Progressive bone fragility leads to greater risk for fractures," Fox said. "Hospitals treat fragility fractures, but they have no system in place to evaluate those same patients for osteoporosis to prevent the next fracture. This study's results are better than no letter or doing nothing, which is what most hospitals are doing, including the one piloting our program before it started this program."

Future studies should examine the effectiveness of using both a phone call and a letter to improve follow-up rates.

Scientists Find A Way to Identify Individuals Susceptible to Type 1 Diabetes Before the Actual Onset

Not everything is known about Type 1 diabetes even as it is pretty well known that it is a genetically driven autoimmune disease of pancreatic beta-cells. Yet its origin remains unknown. 

In a recent study, researchers from the Boston Medical Center (BMC) and Boston University School of Medicine (BUSM) found that skin cells from patients with type 1 diabetes display abnormal activity. This abnormal activity is triggered by immune response mechanisms to environmental stimuli like a viral infection. The findings are published online in PLoS One.

The researchers found that these skin cells when exposed to cytokines or fat have elevated levels of calcium. It is known that cytokines or cells signalling molecules essential to the body's immune response in humans increase with the onset of infection. This is quite similar to increased fatty acids when people stop eating or are sick. This is a common occurrence in children when they are infected with virus.  

"This is significant as it is known that a viral illness usually precedes the development of type 1 diabetes in children but no one knows why it should be related," says Barbara Corkey, PhD, Zoltan Kohn Professor of Medicine at BUSM and vice chair for Research in the Obesity Research Center at BMC. "Our findings that diabetic cells have a different sensitivity as indicated by higher levels of calcium to an environmental event such as a virus, may help to explain why the onset of type 1 diabetes might be triggered by an environmental stimulus as well as a genetic predisposition."

The data collected by scientists showed that skin cells of those relatives of someone with type 1 diabetes who do not have type 1 diabetes themselves show an intermediate calcium response to circulating signaling molecules. These data indicate that a genetic trait in combination with unique environmental stimulus may likely initiate diabetes. 

"Determination of this trait before development of diabetes could help to identify susceptible individuals prior to disease onset," Corkey said.

New Study Finds Permanent Changes in Brain Genes May Not be So Permanent After All

In a new study published in the January 28 issue of Nature Neuroscience, a team of researchers at Johns Hopkins a new gene control mechanism and how it may contribute to Rett Syndrome, a nervous system disorder affecting mostly girls that causes problems with movement and communication.

Normally cells turnoff genes they don't need by attaching a chemical methyl group to the DNA. This process is called methylation. Scientists for a long time believed that methyl groups could only stick to a particular DNA sequence - a cytosine followed by a guanine - called CpG. In recent years, however, it has been found that they can follow other sequences. The non-CpG methylation has been found in stem cells as well as in neurons in the brain. 

Johns Hopkins research team has discovered that non-CpG methylation occurs later and more dynamically in neurons than previously appreciated, and that it acts as a system of gene regulation, which can be independent of traditional CpG methylation.

The team, led by Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine's Institute for Cell Engineering's Stem Cell Program, had found non-CpG methylation prevalent in neurons. The finding is surprising because this wasn't found in any other cells besides stem cells.

The scientists examined the genes that were being transcribed in neurons and found that non-CpG methylation stops genes from being expressed  like the form of methylation scientists had seen in stem cells. On the basis of genome mapping, the scientists also identified the location of non-CpG methylation. It was also found that it carves out its own niche, and are distributed in regions without CpG methlyation. "That was the first hint that maybe it can function independently of CpG methylation," Song said.

The new kind of methylation also seems to operate under different rules. Scientists have long thought methylation was final. Once a cytosine gets a methyl stuck to it, so the story went, that gene is shut off forever. "This became dogma," Song said. "Once cells become the right type, they don't change their identity or DNA methylation."

However, non-CpG methylation was found to happen later, when the neuron is mature. The conventional wisdom said it was irreversible. The researchers learned this from an experiment in which they knocked out in adult mice the enzymes that attach methyl groups to DNA. They found the neurons still had just as much CpG methylation, but the non-CpG methylation dropped off. This suggests that non-CpG methylation is an active process, according to Song, with methyl groups continually being taken off and put back on, adding to evidence that non-CpG methylation may play more of a role in managing operations in mature cells.

The researchers also found a way that non-CpG methylation is similar to CpG methylation in one important way: it's read by MeCP2, an enzyme long identified as a player in methylation.

That's significant because a mutation in MeCP2 causes Rett Syndrome, and understanding DNA methylation is key to understanding this syndrome. The disorder occurs, Song says, when working copies of the gene for MeCP2 are silenced during development.

New Study Finds Aging Linked to Specific Diets

Which is the best diet for health and longevity? Whether you swear by Paleo diet, or Atkins or gluten free or any other, the scientists have found that nearly all diets are the best diets for health and longevity because scientists have identified a collection of genes that allow an organism to adapt to different diets. Otherwise, even minor tweaks to diet can cause premature aging and death. The new research conducted by USC scientists Sean Curran and Shanshan Pang is published this month in Cell Metabolism.  

In other words, scientists have found a genetic basis for an organism's dietary needs. Accordingly, it is suggested that different individuals may be genetically predisposed to thrive on different diets and therefore, in the current age of commercial gene sequencing, a simple blood test might reveal to people the diet that might work best for them.  

"These studies have revealed that single gene mutations can alter the ability of an organism to utilize a specific diet. In humans, small differences in a person's genetic makeup that change how well these genes function, could explain why certain diets work for some but not others," said Curran, corresponding author of the study and assistant professor with joint appointments in the USC Davis School of Gerontology, the USC Dornsife College of Letters, Arts and Sciences, and the Keck School of Medicine of USC.

The researchers Curran and Pang conducted their study on Caenorhabditis elegans. This is a one-milimeter-long worm that scientists have used as a model organism since the '70s. Decades of tests have shown that genes in C. elegans are likely to be mirrored in humans while its short lifespan allows scientists to do aging studies on it.

In this study, Curran and Pang identified a gene called alh-6, which delayed the effects of aging depending on what type of diet the worm was fed by protecting it against diet-induced mitochondrial defects. "This gene is remarkably well-conserved from single celled yeast all the way up to mammals, which suggests that what we have learned in the worm could translate to a better understanding of the factors that alter diet success in humans," Curran said.

Future work will focus on identifying what contributes to dietary success or failure, and whether these factors explain why specific diets don't work for everyone. This could be the start of personalized dieting based on an individual's genetic makeup, according to Curran.

"We hope to uncover ways to enhance the use of any dietary program and perhaps even figure out ways of overriding the system(s) that prevent the use of one diet in certain individuals," he said.

Study Finds High Level Of Food Insecurity Among Students

Oregon State University has set up a "Food Pantry " program that disburses community-donated food to assist students who have inadequate food supplies. Photo Courtesy: (Photo by Larry Pribyl, courtesy Oregon State University) 

A recent study by researchers from the Oregon State University, the Benton County Health Department, and Western Oregon University has found that a whopping 59 percent of college students at one Oregon university were at some point in the previous year were "food insecure" with several implications including academic success, physical and emotional health and other issues. The findings of the study appear in the Journal of Nutrition Education and Behavior   

These findings were based on a survey of 354 students at Western Oregon University, a mid-size public university in a small town near the state capitol in Salem, Ore. Students at Western Oregon supported and assisted in this research, and Doris Cancel-Tirado and Leticia Vazquez with Western Oregon co-authored the study.

In others words, concerns about obesity is not the entire truth. A large part of the truth is that many students do not get enough healthy food to eat as they face the challenges of costs, income, and unevenly distributed food and social support systems. The study surveyed the students at Western Oregon.

"Based on other research that's been done, we expected some amount of food concerns among college students," said Daniel López-Cevallos, associate director of research at OSU's Center for Latino/a Studies and Engagement. "But it was shocking to find food insecurity of this severity. Several recent trends may be combining to cause this."

Several factors including rising college costs, more low-income and first-generation students attending college, and changing demographic trends in combination have significant implications for the study. 

"For past generations, students living on a lean budget might have just considered it part of the college experience, a transitory thing," said Megan Patton-López, lead author of the study with Oregon's Benton County Health Department.

"But rising costs of education are now affecting more people," she said. "And for many of these students who are coming from low-income families and attending college for the first time, this may be a continuation of food insecurity they've known before. It becomes a way of life, and they don't have as many resources to help them out."

The study found that many students may not have enough money for healthy food at all times despite the fact that many of them work one or more jobs. The financial demands could be draining their meager resources. In addition, most college students are not eligible for food stamps and many among them already carry heavy debt load. 

Food insecurity means uncertain or limited availability of nutritionally adequate and safe foods in addition to the ability to acquire such food in acceptable ways. Food insecurity is associated with depression, stress, poor health and the trouble learning in the classroom. 

When food insecurity issues were addressed among elementary school students, improvements were seen in academic performance, behavior and retention of knowledge. However, these problems have received no attention among 19-24 year old demographic, a population that predominates in college, according to researchers. 

According to the findings of the study:

• While about 14.9 percent of all households in the nation report food insecurity, the number of college students voicing similar concerns in this report was almost four times higher, at 59 percent.
  
• In the past three decades the cost of higher education has steadily outpaced inflation, the cost of living and medical expenses.
  
• Food insecurity during college years could affect cognitive, academic and psychosocial development.
  
• Factors correlated with reports of food insecurity include fair to poor health, a lower grade point average, low income and employment.

Employment, by itself, is not adequate to resolve this problem, the researchers found. Students reporting food insecurity also worked an average of 18 hours a week – some as high as 42 – but the financial demands they faced more than offset that income.

The findings probably reflect similar concerns at colleges and universities across the nation, the researchers said, although more research is needed in many areas to determine the full scope of this problem.

"One thing that's clear is that colleges and universities need to be having this conversation and learning more about the issues their students may be facing," said López-Cevallos. "There may be steps to take locally that could help, and policies that could be considered nationally. But it does appear this is a very serious issue that has not received adequate attention, and we need to explore it further."

Development of Drug To Reverse the Spread of Breast Cancer Underway

A novel compound known to reverse the spread of malignant breast cancer is being developed by the researchers at Cardiff University. Most of the cancer deaths result from the progressive spread of malignant cells to vital organs known as metastasis. It is estimated that about 12,000 patients develop this form of disease, several years after the initial diagnosis of a breast lump.   

In a recent series of studies researchers identified a previously unknown critical role for a potential cancer causing gene, Bcl3, in metastatic breast cancer. "We showed that suppressing this gene reduced the spread of cancer by more than 80%," said Dr Richard Clarkson from Cardiff University's European Cancer Stem Cell Research Institute.

"Our next goal was to then find a way to suppress Bcl3 pharmacologically. Despite great improvements in therapy of early stage breast cancer, the current therapeutic options for patients with late stage metastatic disease are limited.

"There is therefore a clear unmet clinical need to identify new drugs to reverse or at least to slow down disease progression" he added.

Dr Clarkson and his team joined up with researchers Dr Andrea Brancale and Dr Andrew Westwell from the Cardiff University School of Pharmacy and Pharmaceutical Sciences, to develop small chemical inhibitors of the Bcl3 gene.

Computer aided modeling of how the Bcl3 gene functions inside the cell allowed the group to identify a pocket on the surface of Bcl3 essential for its function. By screening a virtual compound library for chemicals that could fit inside this pocket, using state-of-the-art computer software, they identified a drug candidate that potently inhibits Bcl3.

The compound was then trialed on mice with metastatic disease. The resulting effect was that the drug completely inhibited the development of the mice's metastatic tumours.

With financial backing from Tiziana Pharmaceuticals*, work is now underway to progress the compound to clinical trials. The aim is to develop a therapeutic agent capable of blocking metastatic disease in breast cancer and a variety of tumour types.

Cleveland Researchers Discover Why Good Cholesterol Becomes Bad

Can high density lipoprotein (HDL) or good cholesterol become dysfunctional, loses its cardio-protective properties, and instead promote inflammation and atherosclerosis, or the clogging and hardening of the arteries? The answer is yes, and the way this happens is discovered by Cleveland Clinic researchers. The study is published in the journal Nature Medicine.

The beneficial and cardio-protective properties of HDL have been studied and reported extensively. However, all clinical trials of pharmaceuticals designed to raise HDL levels have so far failed to show that they significantly improve cardiovascular health. Therefore, a research team led by Stanley Hazen, M.D., Ph.D., Vice Chair of Translational Research for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at Cleveland Clinic  have attempted to explain this disconnect. They have also gone on to demonstrate that a protein abundant in HDL is present in an oxidized form in diseased artery walls. 

Apolipoprotein A1 (apoA1) is the primary protein present in HDL, providing the structure of the molecule that allows it to transfer cholesterol out of the artery wall and deliver it to the liver, from which cholesterol is excreted. It's apoA1 that normally gives HDL its cardio-protective qualities, but Dr. Hazen and his colleagues have discovered that in the artery wall during atherosclerosis, a large proportion of apoA1 becomes oxidized and no longer contributes to cardiovascular health, but rather, contributes to the development of coronary artery disease.

Over the course of more than five years, Dr. Hazen and his colleagues developed a method for identifying dysfunctional apoA1/HDL and discovered the process by which it is oxidized and turned dysfunctional in the artery wall. They then tested the blood of 627 Cleveland Clinic cardiology patients for the dysfunctional HDL and found that higher levels raised the patient's risk for cardiovascular disease.

"Identifying the structure of dysfunctional apoA1 and the process by which it becomes disease-promoting instead of disease-preventing is the first step in creating new tests and treatments for cardiovascular disease," said Dr. Hazen. 

"Now that we know what this dysfunctional protein looks like, we are developing a clinical test to measure its levels in the bloodstream, which will be a valuable tool for both assessing cardiovascular disease risk in patients and for guiding development of HDL-targeted therapies to prevent disease."

The research also points toward new therapeutic targets for pharmaceuticals, such as those designed to prevent the formation of dysfunctional HDL and the development or progression of atherosclerosis.

How Does Brain Create Meaningful Sequences?

In an article published in Nature Neuroscience, datelined January 26, 2014, neuroscientist Rui Costa, and his postdoctoral fellow, Fatuel Tecuapetla, both working at the Champalimaud Neuroscience Programme (CNP) in Lisbon, Portugal, and Xin Jin, an investigator at the Salk Institute, in San Diego, USA, reveal that neurons in the basal ganglia can signal the concatenation of individual elements into a behavioral sequence.

When you learn how to play the piano, first you have to learn notes, scales and chords and only then will you be able to play a piece of music. The same principle applies to speech and to reading, where instead of scales you have to learn the alphabet and the rules of grammar.

But how do separate small elements come together to become a unique and meaningful sequence?

It has been shown that a specific area of the brain, the basal ganglia, is implicated in a mechanism called chunking, which allows the brain to efficiently organize memories and actions. Until now little was known about how this mechanism is implemented in the brain.

"We trained mice to perform gradually faster sequences of lever presses, similar to a person who is learning to play a piano piece at an increasingly fast pace." explains Rui Costa. "By recording the neural activity in the basal ganglia during this task we found neurons that seem to treat a whole sequence of actions as a single behavior."

The basal ganglia encompass two major pathways, the direct and the indirect pathways. The authors found that although activity in these pathways was similar during the initiation of movement, it was rather different during the execution of a behavioral sequence.

"The basal ganglia and these pathways are absolutely crucial for the execution of actions. These circuits are affected in neural disorders, such as Parkinson or Huntington's disease, in which learning of action sequences is impaired", adds Xin Jin.

The work published in this article "is just the beginning of the story", says Rui Costa. The Neurobiology of Action laboratory at the CNP, a group of around 20 researchers headed by Rui Costa, will continue to study the functional organisation of the basal ganglia during learning and execution of action sequences. Earlier this year, Rui Costa was awarded a 2 million euro consolidation Grant by the European Research Council to study the mechanism of Chunking.

Breast Stem Cells Live Long And May Trigger Cancer Decades Later

(Breast cancer research team Professor Jane Visvader, Dr. Nai Yang Fu, Dr. Anne Rios and Professor Geoff Lindeman (left to right) have found that breast stem cells and their 'daughter' progenitor cells are long-lived in the breast.  Photo Courtesy: Walter and Eliza Hall Institute)

                                                   
A new research has found out that breast stem cells and their daughters have much longer life span than previously thought. In addition, they are active in puberty and throughout life, according to researchers from Melbourne's Walter and Eliza Hall Institute. The research is published in the journal Nature.
                                
The implication of the longevity of breast stem cells and their daughters is that the genetic defects or damage could progress to cancer decades later while shifting back the timeline of breast cancer development. The finding may also possibly identify the cells from which breast cancer originates and help develop new treatments and diagnostics for breast cancer. 

Professors Jane Visvader and Geoff Lindeman and their colleagues at the Walter and Eliza Hall Institute isolated breast stem cells in 2006. Now in another project led by Dr Anne Rios and Dr Nai Yang Fu, it was found that breast stem cells actively maintain breast tissue for most of the life of the individual and contribute to all major stages of breast development. 

"Given that these stem cells – and their 'daughter' progenitor cells – can live for such a long time and are capable of self renewing, damage to their genetic code could lead to breast cancer 10 or 20 years later," Professor Lindeman said. "This finding has important applications for our understanding of breast cancer. We hope that it will lead to the development of new treatment and diagnostic strategies in the clinic to help women with breast cancer in the future," said Professor Lindeman, who is also an oncologist at The Royal Melbourne Hospital. 

In order to understand why and how breast cells become cancerous, it is important to understand the hierarchy and development of breast cells, according to Professor Visvader. "Without knowing the precise cell types in which breast cancer originates, we will continue to struggle in our efforts to develop new diagnostics and treatments for breast cancer, or developing preventive strategies," Professor Visvader said.

Immature breast cells were already implicated in cancer development in an earlier research by scientists from the same institute. "In 2009, we showed that luminal progenitor cells, the daughters of breast stem cells, were the likely cell of origin for the aggressive BRCA1-associated basal breast cancers," Professor Visvader said. "The meticulous work of Anne and Nai Yang, using state-of-the-art three-dimensional imaging, has significantly improved our understanding of normal breast development and will have future applications for breast cancer." 

The current project may likely settle a debate on the issue, confirming once for all that breast cells were 'true' stem cells capable of renewing themselves and making all the cells of the mammary gland.

Researchers Discover Potential Drug Targets For Early Onset Glaucoma

Scientists have for the first time identified molecules that block the accumulation of a toxic eye protein leading to early onset of glaucoma using a novel high-throughput screening process. 

Glaucoma is actually a groups of eye diseases leading to vision loss and blindness as it damages the optic nerve. 

The increased eye pressure, according to researchers is actually caused by a mutant form of protein called myocilin. Mutant myocilin impacts with its toxicity to cells in the part of the eye that regulates pressure. These genetically inherited mutants of myocilin clump together in the front of the eye, preventing fluid flow out of the eye, which then raises eye pressure. This cascade of events can lead to early onset-glaucoma, which affects several million people from childhood to age 35.

The researchers designed a simple, high-throughput assay to find molecules that bind to mutant myocilin and block its aggregation. Thereafter they screened a library of compounds. Eventually, two molecules were identified which can be useful for future drug development to treat early onset glaucoma.  

"These are really the first potential drug targets for glaucoma," said Raquel Lieberman, an associate professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology in Atlanta, whose lab led the research.

The study was published on Nov. 26, 2013, in the journal ACS Chemical Biology. The National Institutes of Health and the Pew Scholar in Biomedical Sciences program provided support for the research. The work was a collaboration involving Georgia Tech, Emory University and the University of South Florida.

At the heart of the study was an assay that Lieberman's lab created to take advantage of the fundamental principles of ligand binding. In their assay, mutant myocilin is mixed with a fluorescent compound that emits more light when the protein is unwound. When a molecule from the library screen binds to myocilin, the pair becomes highly stable – tightly wound – and the fluorescent light emitted decreases. By measuring fluorescence, researchers were able to identify molecules that bound tightly to mutant myocilin.

The researchers then added these molecules to cultured human cells that were making the toxic aggregating myocilin. Treating the cells with the newly identified molecules blocked the aggregation and caused the mutated version of myocilin to be released from the cells, reducing toxicity.

"We found two molecules from that initial screen that bound to our protein and also inhibited the aggregation," Lieberman said. "When we saw that these compounds inhibited aggregation then we knew we were onto something good because aggregation underlies the pathogenesis of this form of glaucoma."

In a separate study, Lieberman's lab characterized the toxic myocilin aggregates. That study was published in December 2013 in the Journal of Molecular Biology. The study found that myocilin aggregates are similar to the protein deposits called amyloid, which are responsible for Alzheimer's disease and other neurodegenerative diseases.

"In Alzheimer's disease, the deposits are extracellular and kill neurons. In glaucoma the aggregates are not directly killing neurons in the retina to cause vision loss, but they are cytotoxic in the pressure-regulating region of the eye," Lieberman said. "It's parallel to all these other amyloids that are out there in neurodegenerative disease."

The researchers are now focusing on mapping the structure of myocilin to learn more about what myocilin does and why it is in the eye in the first place.

"The underlying problem with myocilin is that for 14 years it has been studied and still nobody really knows what its biological role is inside the eye," Lieberman said.

(Image Courtesy: Hill, et al., 2013.)

Asthma Treatment Likely With Salmonella

This is the research that can pave way for effective asthma treatment. Researchers from Germany experimenting on mice have found that Salmonella infections can reduce the incidence of asthma. The research is published in the journal Infection and Immunity. The research may likely lead to treatments. 

There has been a dramatic increase in incidence of allergies in recent years. The surge in allergies is explained with the help of a leading theory known as "hygiene hypothesis". According to this theory, the surge results from modern obsession with cleanliness resulting in improperly developed immune systems. Earlier researches had indicated that there is a reduced incidence of asthma in children infected with Salmonella. 

The study based on previous research the investigators found that Salmonella infection correlated with reduced airway inflammation, according to first author Venkateswaran Ganesh. The reduction in inflammation, according to Ganesh is linked to reduced production of an inflammatory compound called interleukin-4, which is produced by T helper-2 cells. The researchers found that the T helper-2 cells is regulated by a certain  type of "myelod" immune cell which can induce lesser production of less interleukin-4. Myeloid cells include an array of immune cells, and are ultimately derived from the bone marrow.   

"By performing cell culture assays and studies in rodents, we could determine the influence of myeloid cells on Th2 cells," he explained. The research could lead to treatments based on the use of commensal bacteria (harmless, oft-helpful inhabitants of the body) resembling Salmonella as probiotics, or the application of myeloid cells as therapeutics, Ganesh said.

Roughly 26 million Americans, 8.2 percent of the population, have asthma, including 7.1 million (9.5%) children, according to the US Centers for Disease Control and Prevention.