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.