Bacterial Blockade: How Gut Microbes Can Inactivate Cardiac Drugs

For decades, doctors have understood that microbes in the human gut can influence how certain drugs work in the body -- by either activating or inactivating specific compounds -- but questions have remained about exactly how the process works.

Harvard scientists are now beginning to provide those answers.
In a paper published July 19 in Science, Peter Turnbaugh, a Bauer Fellow at the Center for Systems Biology in the Faculty of Arts and Sciences (FAS), and Henry Haiser, a postdoctoral fellow, identify a pair of genes that appear to be responsible for allowing a specific strain of bacteria to break down a widely prescribed cardiac drug into an inactive compound, as well as a possible way to turn the process off.
"The traditional view of microbes in the gut relates to how they influence the digestion of our diet," Turnbaugh said. "But we also know that there are over 40 different drugs that can be influenced by gut microbes. What's really interesting is that although this has been known for decades, we still don't really understand which microbes are involved or how they might be processing these compounds."
To answer those questions, Turnbaugh and his colleagues chose to focus on digoxin, one of the oldest known cardiac glycosides. The medicine is typically prescribed to treat heart failure and cardiac arrhythmia.
"It's one of the few drugs that, if you look in a pharmacology textbook, it will say that it's inactivated by gut microbes," Turnbaugh said. "John Lindenbaum's group at Columbia showed that in the 1980s. They found that a single bacterial species, Eggerthella lenta, was responsible."
Researchers in the earlier study also tried -- but failed -- to show that testing bacterial samples from a person's gut could be used to predict whether the drug might be inactivated.
"To some degree the research was stalled there for a number of years, and the findings in our paper help to explain why," Turnbaugh said. "Originally, it was hoped that we would simply be able to measure the amount of E. lenta in a person's gut and predict whether the drug would be inactivated, but it's more complicated than that."
Beginning with lab-grown samples of E. lenta -- some cultured in the presence of digoxin, some in its absence -- Turnbaugh and Haiser tested to see if certain genes were activated by the presence of the drug.
"We identified two genes that were expressed at very low levels in the absence of the drug, but when you add the drug to the cultures … they come on really strong," Turnbaugh said. "What's encouraging about these two genes is that they both express what are called cytochromes -- enzymes that are likely capable of converting digoxin to its inactive form."
Though he warned that more genetic testing is needed before the results are definitive, Turnbaugh said other experiments support these initial findings.
The researchers found only a single strain of E. lenta -- the only one that contained the two genes they had earlier identified -- was capable of inactivating digoxin. In tests using human samples, bacterial communities that were able to inactivate the drug also showed high levels of these genes
"We were able to confirm that simply looking for the presence of E. lenta is not enough to predict which microbial communities inactivate digoxin," Turnbaugh said. "We found detectable E. lenta colonization in all the human fecal samples we analyzed. But by testing the abundance of the identified genes we were able to reliably predict whether or not a given microbial community could metabolize the drug."
In addition to being able to predict whether a given microbial community would inactivate the drug, Turnbaugh and colleagues identified a possible way to halt the process.
"It was previously shown that in the lab E. lenta grows on the amino acid arginine and that as you supply more and more arginine, you inhibit digoxin inactivation," he said.
Tests conducted with mice showed that animals fed a diet high in protein, and thereby arginine, had higher levels of the drug in their blood than mice fed a zero-protein diet.
"We think that this could potentially be a way to tune microbial drug metabolism in the gut," Turnbaugh said. "Our findings really emphasize the need to see if we can predict or prevent microbial drug inactivation in cardiac patients. If successful, it may be possible someday to recommend a certain diet, or to co-administer the drug with an inhibitor like arginine, ensuring a more reliable dosage."
 

Journal Reference:

1. H. J. Haiser, D. B. Gootenberg, K. Chatman, G. Sirasani, E. P. Balskus, P. J. Turnbaugh. Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta. Science, 2013; 341 (6143): 295 DOI: 10.1126/science.1235872

Courtesy: ScienceDaily
 

Bad Night's Sleep? The Moon Could Be to Blame

Many people complain about poor sleep around the full moon, and now a report appearing in Current Biology, a Cell Press publication, on July 25 offers some of the first convincing scientific evidence to suggest that this really is true. The findings add to evidence that humans -- despite the comforts of our civilized world -- still respond to the geophysical rhythms of the moon, driven by a circalunar clock.

"The lunar cycle seems to influence human sleep, even when one does not 'see' the moon and is not aware of the actual moon phase," says Christian Cajochen of the Psychiatric Hospital of the University of Basel.
In the new study, the researchers studied 33 volunteers in two age groups in the lab while they slept. Their brain patterns were monitored while sleeping, along with eye movements and hormone secretions.
The data show that around the full moon, brain activity related to deep sleep dropped by 30 percent. People also took five minutes longer to fall asleep, and they slept for twenty minutes less time overall. Study participants felt as though their sleep was poorer when the moon was full, and they showed diminished levels of melatonin, a hormone known to regulate sleep and wake cycles.
"This is the first reliable evidence that a lunar rhythm can modulate sleep structure in humans when measured under the highly controlled conditions of a circadian laboratory study protocol without time cues," the researchers say.
Cajochen adds that this circalunar rhythm might be a relic from a past in which the moon could have synchronized human behaviors for reproductive or other purposes, much as it does in other animals. Today, the moon's hold over us is usually masked by the influence of electrical lighting and other aspects of modern life.
The researchers say it would be interesting to look more deeply into the anatomical location of the circalunar clock and its molecular and neuronal underpinnings. And, they say, it could turn out that the moon has power over other aspects of our behavior as well, such as our cognitive performance and our moods.
 

Journal Reference:

1. Christian Cajochen, Songül Altanay-Ekici, Mirjam Münch, Sylvia Frey, Vera Knoblauch, Anna Wirz-Justice. Evidence that the Lunar Cycle Influences Human Sleep. Current Biology, 2013; DOI: 10.1016/j.cub.2013.06.029

Courtesy: ScienceDaily
 

Interspecies Transplant Works in First Step for New Diabetes Therapy

In the first step toward animal-to-human transplants of insulin-producing cells for people with type 1 diabetes, Northwestern Medicine® scientists have successfully transplanted islets, the cells that produce insulin, from one species to another. And the islets survived without immunosuppressive drugs.

Northwestern scientists developed a new method that prevented rejection of the islets, a huge problem in transplants between species, called xenotransplantation.
"This is the first time that an interspecies transplant of islet cells has been achieved for an indefinite period of time without the use of immunosuppressive drugs," said study co-senior author Stephen Miller. "It's a big step forward."
"Our ultimate goal is to be able to transplant pig islets into humans, but we have to take baby steps," said Xunrong Luo, M.D., also co-senior author of the study that will be published online July 12 in the journal Diabetes. "Pig islets produce insulin that controls blood sugar in humans."
Luo is an associate professor of nephrology at Northwestern University Feinberg School of Medicine and medical director of the Human Islet Cell Transplantation Program at Northwestern Memorial Hospital. Miller is the Judy Gugenheim Research Professor of Microbiology-Immunology at Feinberg.
For people with hard-to-control type 1 diabetes, a transplant of insulin-producing islets from a deceased donor is one important way to control their chronic disease, in which their bodies do not produce insulin. However, there is a severe shortage of islet cells from deceased donors. Many patients on waiting lists don't receive the transplant or suffer damage to their heart, nerves, eyes and kidneys while they wait.
Using islets from another species would provide wider access to transplants for humans and solve the problem. But concerns about controlling rejection of transplants from a different species have made that approach seem insurmountable until now.
In the new study, scientists persuaded the immune systems of mice to recognize rat islets as their own and not reject them. Notably, the method did not require the long-term use of drugs to suppress the immune system, which have serious side effects. The islets lived and produced insulin in the mice for at least 300 days, which is as long as scientists followed the mice.
While the barrier from rats to mice is probably lower than from pigs to humans, the study showed interspecies islet transplants are possible and without immunosuppressive drugs, Luo said.
In the study, the rat splenocytes, a type of white blood cell located in the spleen, were removed and treated with a chemical that caused their deaths. Next, the dead splenocytes were injected into the mice. The cells entered the spleen and liver and were mopped up by scavenger cells. The scavengers processed the splenocytes and presented fragments of them on their cell surface, triggering a reaction that told the T cells to accept the subsequently transplanted rat islets and not attack them.
But rejection was still a threat. A unique challenge of an interspecies transplant is controlling the B cells, immune cells that are major producers of antibodies. Initially, when scientists transplanted the rat islets into the mice, the mouse immune system started producing antibodies against the rat cells causing rejection.
To solve the problem, Luo realized she needed to kill off the B-cells at the same time she injected the donor islets into the mice. Thus, she gave the mice B-cell depleting antibodies -- already used in a clinical setting in human transplants. When the B-cells naturally returned after the transplant, they no longer attacked the rat islets.
"With this method, 100 percent of the islets survived indefinitely," Luo said. "Now we're trying to figure out why the B-cells are different when they come back."
The study lead author is Shusen Wang, formerly a postdoctoral student in Luo's lab.
 

The above story is reprinted from materials provided by Northwestern University. The original article was written by Marla Paul.  

Courtesy: ScienceDaily

Stem Cell Clues Uncovered

Proper tissue function and regeneration is supported by stem cells, which reside in so-called niches. New work from Carnegie's Yixian Zheng and Haiyang Chen identifies an important component for regulating stem cell niches, with impacts on tissue building and function. The results could have implications for disease research. It is published by Cell Stem Cell.

Lamins are proteins that the major structural component of the material that lines the inside of a cell's nucleus. Lamins have diverse functions, including suppressing gene expression. It has been difficult to understand how mutations in lamins cause diseases in specific tissues and organs, such as skeletal muscles, heart muscle, and fat.

A group of human diseases called laminopathies, which include premature aging, are caused by defects in proteins called lamins. Zheng and her team, which included Xin Chen of Johns Hopkins University, decided to examine whether lamins would link stem cell niche function to healthy tissue building and maintenance.
To understand the tissue-specific effects of lamin mutations, the team focused on fruit fly testis, one of the best-studied stem cell niche systems. In the fruit fly testis, biochemical cross-signaling between the different types of cells that make up the niche environment ensures proper maintenance and differentiation of the testis system's stem cells.
Using an advanced array of techniques available in fruit fly studies, the team demonstrated that lamins were a necessary component of supporting niche organization, which in turn regulates proper proliferation and differentiation of germline stem cells in fruit fly testis.
"These results could have implications for the role of lamins in other types of stem cell niches," Zheng said. "These findings could contribute to the study of diseases caused by lamina-based tissue degeneration. For example, different lamin mutations could disrupt the organization of different niches in the body, which then leads to degeneration in tissues."
 

Journal Reference:

1. Haiyang Chen, Xin Chen, Yixian Zheng. The Nuclear Lamina Regulates Germline Stem Cell Niche Organization via Modulation of EGFR Signaling. Cell Stem Cell, 2013; 13 (1): 73 DOI: 10.1016/j.stem.2013.05.003

Courtesy: ScienceDaily
 

Artificial Sweetener a Potential Treatment for Parkinson's Disease

Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field -- it's approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.

Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain -- a process that is characteristic of Parkinson's disease.
These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this sweetener could be a novel therapy for the treatment of Parkinson's and other neurodegenerative diseases. The research was funded by a grant from the Parkinson's Disease Foundation and supported in part by the Lord Alliance Family Trust.
Seeing a significant difference
After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins' ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.
Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the "climbing assay," in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.
The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.
These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.
Delivering therapeutic compounds to the brain
The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson's in humans is needed, Prof. Segal says.
For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson's but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to "piggy-back" on mannitol's ability to open this barrier into the brain.
Although the results look promising, it is still not advisable for Parkinson's patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.
 

Journal Reference:

1. R. Shaltiel-Karyo, M. Frenkel-Pinter, E. Rockenstein, C. Patrick, M. Levy-Sakin, A. Schiller, N. Egoz-Matia, E. Masliah, D. Segal, E. Gazit. A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent  -Synuclein ( -syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD). Journal of Biological Chemistry, 2013; 288 (24): 17579 DOI: 10.1074/jbc.M112.434787

Courtesy: ScienceDaily
 

Molecular Switch That Kick Starts Formation of Arteries Identified

The ability to form blood vessels is one of evolution's crowning achievements, and something that separates vertebrates (animals with a backbone) from the rest of the animal kingdom. The two types of blood vessels, arteries and veins, are formed from the same precursor cell type -- endothelial cells -- that become committed to an arterial or venous cell fate during embryonic development. Yet precisely what drives this commitment, which is essential for shaping cardiovascular development, has long eluded researchers. Now, scientists at the Gladstone Institutes have identified the molecular signals that direct this process. In so doing, they illustrate how even the most complex of biological systems can be directed by the most subtle shifts in molecular signaling.

In the latest issue of Developmental Cell, researchers in the laboratory of Gladstone Senior Investigator Benoit Bruneau, PhD, describe the precise order and timing of signals that spur the formation of arteries. Specifically, they piece together a molecular signaling pathway by which a protein called vascular endothelial growth factor (Vegf) directs the activation of Delta-like 4 (Dll4), which is critical to artery formation.
Arteries and veins each have different identities and distinct functions. Arteries carry oxygenated blood from the heart out to tissues, while veins carry unoxygenated blood back to the heart. Understanding how arteries are made at the molecular level -- and specifically how they differ from veins -- is important not only for understanding diseases in which arteries and veins connect abnormally, but also to inform strategies for making new arteries, which could prove invaluable for treating coronary artery disease.
The key to this understanding lies with Dll4, one of the earliest known genes involved in artery formation. In fact, scientists currently use Dll4 as a marker to identify which cells will grow and differentiate into arteries, and which will not. Dll4 works by binding to another protein -- known as Notch -- which in turn promotes artery formation.
But there is a third player in this process: Vegf. It is secreted from cells in the embryo, which among other things activates Dll4. But exactly how Dll4, Notch and Vegf all work in concert to transform early embryonic cells into cells that form arteries has stumped researchers.
"We knew that Dll4, when activated, directs artery formation, but couldn't pinpoint how it is activated in the first place," said Dr. Bruneau, who is also a professor of pediatrics at the University of California, San Francisco, with which Gladstone is affiliated. "Here, we've mapped the series of steps that precede Dll4 activation and that set the stage for the formation of arteries -- shedding light into a so-called 'black box' of embryonic development."
In this study, the team delved deep into the nucleus of cells belonging to mouse and zebrafish embryos -- two important animal models of embryonic development -- in order to determine how the Dll4 gene is turned on. They used sophisticated molecular biology approaches, together with experiments that deleted specific genes from the animal models, to fill in the steps that led from Vegf signaling to Dll4 activation. And what they found was surprising.
"Vegf sets off a signaling cascade that eventually activates a group of proteins, called Mitogen Activated Protein Kinases, or MAPKs," said Gladstone Staff Scientist Joshua Wythe, PhD, the paper's lead author. "This, in turn, activates another group of proteins, called ETS transcription factors, and it is this signaling relay -- from Vegf to MAPKs to ETS factors -- that turns on an maintains Dll4 activity, helping the arterial cells grow and gain their cellular identity over time."
In biology, a signaling cascade is a series of chain reactions that help cells amplify a particular signal -- like a domino effect. Here, the research team identified Vegf as being the first domino, followed by the activation of MAPKs, then ETS factors and so on.
"Interestingly, the ETS factors aren't specific to soon-to-be arterial cells, but rather they are present throughout the embryo," explained Jason Fish, PhD, a former Gladstone postdoctoral fellow, now at the University of Toronto, who collaborated with the Gladstone team. "Instead, the Vegf signaling cascade alerts only those MAPKs and ETS factors within the realm of Dll4 -- assuring only the correct cells grow and differentiate over time to form arteries."
This research is important not only because it uncovers the molecular link between Vegf and Dll4, but also because it shows how signaling cascades like this one can direct genes -- which are normally active throughout the embryo -- to perform tasks only in specific cell types.
"In the future we will refine our approach to see whether this signaling cascade regulates other arterial genes in the developing embryo," said Dr. Bruneau. "We hope this research will help inform clinicians into congenital defects related to the formation and maintenance of arteries and veins, and may also yield new strategies that can coax the development of arteries from stem cells -- which may prove useful for treating coronary artery disease."
Research Scientist W. Patrick Devine, MD, PhD, and Research Associate Daniel He also participated in this research at Gladstone, which was supported by the American Heart Association, the California Institute of Regenerative Medicine, the DeGeorge Charitable Trust, the William H. Younger, Jr., Foundation and the National Institutes of Health.
 

Journal Reference:

1. Joshua D. Wythe, Lan T.H. Dang, W. Patrick Devine, Emilie Boudreau, Stanley T. Artap, Daniel He, William Schachterle, Didier Y.R. Stainier, Peter Oettgen, Brian L. Black, Benoit G. Bruneau, Jason E. Fish. ETS Factors Regulate Vegf-Dependent Arterial Specification. Developmental Cell, 2013; DOI: 10.1016/j.devcel.2013.06.007

Courtesy: ScienceDaily
 

Why Some Women Don't Have Enough Breastmilk for Baby: Important Role of Insulin in Making Breast Milk Identified

Why do so many mothers have difficulty making enough milk to breastfeed? A new study by scientists at Cincinnati Children's Hospital Medical Center and the University of California Davis adds to their previous research implicating insulin's role in lactation success.

The study is the first to describe how the human mammary gland becomes highly sensitive to insulin during lactation. It is also the first study to get an accurate picture of how specific genes are switched on in the human mammary gland during lactation.
The researchers used next generation sequencing technology, RNA sequencing, to reveal "in exquisite detail" the blueprint for making milk in the human mammary gland, according to Laurie Nommsen-Rivers, PhD, RD, IBCLC, a scientist at Cincinnati Children's and corresponding author of the study, published online in PLOS ONE, a journal of the Public Library of Science.
Nommsen-Rivers' previous research had shown that for mothers with markers of sub-optimal glucose metabolism, such as being overweight, being at an advanced maternal age, or having a large birth-weight baby, it takes longer for their milk to come in, suggesting a role for insulin in the mammary gland. The new research shows how the mammary gland becomes sensitive to insulin during lactation.
For a long time, insulin was not thought to play a direct role in regulating the milk-making cells of the human breast, because insulin is not needed for these cells to take in sugars, such as glucose. Scientists now, however, appreciate that insulin does more than facilitate uptake of sugars.

"This new study shows a dramatic switching on of the insulin receptor and its downstream signals during the breast's transition to a biofactory that manufactures massive amounts of proteins, fats and carbohydrates for nourishing the newborn baby," says Dr. Nommsen-Rivers.

"Considering that 20 percent of women between 20 and 44 are prediabetic, it's conceivable that up to 20 percent of new mothers in the United States are at risk for low milk supply due to insulin dysregulation."

Dr. Nommsen-Rivers and her colleagues were able to use a non-invasive method to capture mammary gland RNA -- a chain of molecules that are blueprints for making specified proteins -- in samples of human breast milk. They then created the first publicly accessible library of genes expressed in the mammary gland based on RNA-sequencing technology.

This approach revealed a highly sensitive portrait of the genes being expressed in human milk-making cells. They discovered an orchestrated switching on and off of various genes as the mammary gland transitions from secreting small amounts of immunity-boosting colostrum in the first days after giving birth to the copious production of milk in mature lactation.

In particular, the PTPRF gene, which is known to suppress intracellular signals that are usually triggered by insulin binding to its receptor on the cell surface, may serve as a biomarker linking insulin resistance with insufficient milk supply. These results lay the foundation for future research focused on the physiological contributors to mothers' milk supply difficulties.

Now that they've demonstrated the significance of insulin signaling in the human mammary gland, they are planning a phase I/II clinical trial with a drug used to control blood sugar in type 2 diabetes to determine whether it improves insulin action in the mammary gland, thus improving milk supply. While a drug is not an ideal way to solve the problem of sub-optimal glucose metabolism impairing breastfeeding, according to Dr. Nommsen-Rivers, it is excellent for establishing proof-of-concept through the use of a placebo controlled randomized clinical trial.

"The ideal approach is a preventive one," she says. "Modifications in diet and exercise are more powerful than any drug. After this clinical trial, we hope to study those interventions."

Dr. Nommsen-Rivers began her quest to understand why so many U.S. mothers today struggle with low milk supply when she was a doctoral student at the University of California Davis.

The lead author of the study is Danielle Lemay, PhD, of the University of California Davis Research Center.

Journal Reference:

1. Danielle G. Lemay, Olivia A. Ballard, Maria A. Hughes, Ardythe L. Morrow, Nelson D. Horseman, Laurie A. Nommsen-Rivers. RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation. PLoS ONE, 2013; 8 (7): e67531 DOI: 10.1371/journal.pone.0067531

Courtesy: ScienceDaily

Bacteria Communicate to Help Each Other Resist Antibiotics

New research from Western University unravels a novel means of communication that allows bacteria such as Burkholderia cenocepacia (B. cenocepacia) to resist antibiotic treatment. B. cenocepacia is an environmental bacterium that causes devastating infections in patients with cystic fibrosis (CF) or with compromised immune systems.

Dr. Miguel Valvano and first author Omar El-Halfawy, PhD candidate, show that the more antibiotic resistant cells within a bacterial population produce and share small molecules with less resistant cells, making them more resistant to antibiotic killing. These small molecules, which are derived from modified amino acids (the building blocks used to make proteins), protect not only the more sensitive cells of B. cenocepacia but also other bacteria including a highly prevalent CF pathogen, Pseudomonas aeruginosa, and E. coli. The research is published in PLOS ONE.
"These findings reveal a new mechanism of antimicrobial resistance based on chemical communication among bacterial cells by small molecules that protect against the effect of antibiotics," says Dr. Valvano, adjunct professor in the Department of Microbiology and Immunology at Western's Schulich School of Medicine & Dentistry, currently a Professor and Chair at Queen's University Belfast. "This paves the way to design novel drugs to block the effects of these chemicals, thus effectively reducing the burden of antimicrobial resistance."
"These small molecules can be utilized and produced by almost all bacteria with limited exceptions, so we can regard these small molecules as a universal language that can be understood by most bacteria," says El-Halfawy, who called the findings exciting. "The other way that Burkholderia communicates its high level of resistance is by releasing small proteins to mop up, and bind to lethal antibiotics, thus reducing their effectiveness." The next step is to find ways to inhibit this phenomenon.
The research, conducted at Western, was funded by a grant from Cystic Fibrosis Canada and also through a Marie Curie Career Integration grant.
 

Journal Reference:

1. Omar M. El-Halfawy, Miguel A. Valvano. Chemical Communication of Antibiotic Resistance by a Highly Resistant Subpopulation of Bacterial Cells. PLoS ONE, 2013; 8 (7): e68874 DOI: 10.1371/journal.pone.0068874

Courtesy: ScienceDaily
 

Brain's 'Garbage Truck' May Hold Key to Treating Alzheimer's and Other Disorders

In a perspective piece appearing today in the journal Science, researchers at University of Rochester Medical Center (URMC) point to a newly discovered system by which the brain removes waste as a potentially powerful new tool to treat neurological disorders like Alzheimer's disease. In fact, scientists believe that some of these conditions may arise when the system is not doing its job properly.

"Essentially all neurodegenerative diseases are associated with the accumulation of cellular waste products," said Maiken Nedergaard, M.D., D.M.Sc., co-director of the URMC Center for Translational Neuromedicine and author of the article. "Understanding and ultimately discovering how to modulate the brain's system for removing toxic waste could point to new ways to treat these diseases."
The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this "blood-brain barrier" was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by URMC scientists last August in the journal Science Translational Medicine.
The removal of waste is an essential biological function and the lymphatic system -- a circulatory network of organs and vessels -- performs this task in most of the body. However, the lymphatic system does not extend to the brain and, consequently, researchers have never fully understood what the brain does its own waste. Some scientists have even speculated that these byproducts of cellular function where somehow being "recycled" by the brain's cells.
One of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, Nedergaard and her colleagues were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain.
The brain is surrounded by a membrane called the arachnoid and bathed in cerebral spinal fluid (CSF). CSF flows into the interior of the brain through the same pathways as the arteries that carry blood. This parallel system is akin to a donut shaped pipe within a pipe, with the inner ring carrying blood and the outer ring carrying CSF. The CSF is draw into brain tissue via a system of conduits that are controlled by a type support cells in the brain known as glia, in this case astrocytes. The term glymphatic was coined by combining the words glia and lymphatic.
The CSF is flushed through the brain tissue at a high speed sweeping excess proteins and other waste along with it. The fluid and waste are exchanged with a similar system that parallels veins which carries the waste out of the brain and down the spine where it is eventually transferred to the lymphatic system and from there to the liver, where it is ultimately broken down.
While the discovery of the glymphatic system solved a mystery that had long baffled the scientific community, understanding how the brain removes waste -- both effectively and what happens when this system breaks down -- has significant implications for the treatment of neurological disorders.
One of the hallmarks of Alzheimer's disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain's inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key 'players' in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.
"The idea that 'dirty brain' diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders," said Nedergaard. "It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions."
 

Journal Reference:

1. M. Nedergaard. Garbage Truck of the Brain. Science, 2013; 340 (6140): 1529 DOI: 10.1126/science.1240514

Courtesy: ScienceDaily
 

Global Warming May Affect Soil Microbe Survival, With Unknown Consequences On Soil Fertility and Erosion

Arizona State University researchers have discovered for the first time that temperature determines where key soil microbes can thrive -- microbes that are critical to forming topsoil crusts in arid lands. And of concern, the scientists predict that in as little as 50 years, global warming may push some of these microbes out of their present stronghold in colder U.S. deserts, with unknown consequences to soil fertility and erosion.

The findings are featured as the cover story of the June 28 edition of the journal Science.
An international research team led by Ferran Garcia-Pichel, microbiologist and professor with ASU's School of Life Sciences, conducted continental-scale surveys of the microbial communities that live in soil crusts. The scientists collected crust samples from Oregon to New Mexico, and Utah to California and studied them by sequencing their microbial DNA.
While there are thousands of microbe species in just one pinch of crust, two cyanobacteria -- bacteria capable of photosynthesis -- were found to be the most common. Without cyanobacteria, the other microbes in the crust could not exist, as every other species depends on them for food and energy.
"We wanted to know which microbes are where in the crust and whether they displayed geographic distribution patterns at the continental scale," said Garcia-Pichel, also dean of natural sciences in ASU's College of Liberal Arts and Sciences. "To our surprise, where we thought a single cyanobacterium would dominate, we found that two had neatly split the territory between themselves. We used to think that one, called Microcoleus vaginatus, was the most important and dominant, but now we know that Microcoleus steenstrupii, the other one, is just as important, particularly in warmer climates," he added.
While the two look very much alike, M. vaginatus and M. steenstrupii are not even closely related. They have evolved to appear alike because their shape and behavior help them stabilize soil and form soil crusts.
Crusts are crucial to the ecological health of arid lands, as they protect the soil from erosion and contribute to land fertility by fixing carbon and nitrogen into the soil and by extracting other nutrients from trapped dust.
Temperature affects microbial communities After considering data about soil types and chemistry, rainfall, climate and temperature, researchers used a mathematical model that showed temperature best explained the geographic separation of the two microbes. While both are found throughout the studied area, M. vaginatus dominate the crusts in cooler deserts and M. steenstrupii are more prevalent in the southern deserts.
"But this was just a correlation," Garcia-Pichel explained. "To prove the role temperature plays, we tested cultivated forms of the microbes and confirmed that it does indeed make a difference -- temperature is what keeps them apart. The point now is that temperature is no longer stable because of global warming."
In the U.S. Southwest, where the study took place, climate models predict about one degree of warming per decade.
Change is on the horizon "By using our data with current climate models, we can predict that in 50 years, the cyanobacterium that fares better in warmer temperatures will push the cold-loving one off our map. M. steenstrupii could completely dominate the crusts everywhere in our study area by then. Unfortunately, we simply don't know much about this microbe or what will happen to the ecosystem in the absence of M. vaginatus," Garcia-Pichel added.
Should microbe distribution indeed change due to increasing temperatures, scientists do not know what effect that will have on soil fertility and erosion.
These microbes are hundreds of millions of years old and can be found in many places around the globe. No matter where individuals of M. vaginatus are found in the world, they are very closely related and practically indistinguishable genetically. By contrast, individual variation within M. steenstrupii is greater, and this more genetically diverse species is thought to be much older in evolutionary terms.
Garcia-Pichel believes the pattern of temperature segregation detected in the U.S. is likely to be similar worldwide, and that it will not be easy for M. vaginatus to evolve quickly enough to tolerate higher temperatures.
The team is calling for climate researchers to include the study of microbes when considering global warming.
"Our study is relevant beyond desert ecology. It exemplifies that microbial distributions and the partitioning of their habitats can be affected by global change, something we've long known for plants and animals. This study tells us clearly that we can no longer neglect microbes in our considerations," added Garcia-Pichel.
The ASU research team includes Yevgeniy Marusenko, School of Life Sciences graduate student, and ASU research technician Ruth Potrafka. Professor Pilar Mateo and graduate student Virginia Loza, both with the Universidad Autónoma de Madrid, contributed to the project as visiting scholars. The research project is funded by a National Science Foundation grant.
 

Journal Reference:

1. F. Garcia-Pichel, V. Loza, Y. Marusenko, P. Mateo, R. M. Potrafka. Temperature Drives the Continental-Scale Distribution of Key Microbes in Topsoil Communities. Science, 2013; 340 (6140): 1574 DOI: 10.1126/science.1236404

Courtesy: ScienceDaily
 

Inactivation of Taste Genes Causes Male Sterility

Scientists from the Monell Center report the surprising finding that two proteins involved in oral taste detection also play a crucial role in sperm development.

"This paper highlights a connection between the taste system and male reproduction," said lead author Bedrich Mosinger, MD, PhD, a molecular biologist at Monell. "It is one more demonstration that components of the taste system also play important roles in other organ systems."
While breeding mice for taste-related studies, the researchers discovered that they were unable to produce offspring that were simultaneously missing two taste-signaling proteins.
As reported online in advance of print in the Proceedings of the National Academy of Sciences, the critical proteins were TAS1R3, a component of both the sweet and umami (amino acid) taste receptors, and GNAT3, a molecule needed to convert the oral taste receptor signal into a nerve cell response.
Breeding experiments determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.
In order to explore the reproductive function of the two proteins, the research team engineered mice that were missing genes for the mouse versions of TAS1R3 and GNAT3 but expressed the human form of the TAS1R3 receptor. These mice were fertile.
However, when the human TAS1R3 receptor was blocked in the engineered mice by adding the drug clofibrate to the rodents' diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm. The sterility was quickly reversed after clofibrate was removed from the diet.
Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies from the Monell team had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.
Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor, Mosinger speculates that these compounds could be negatively affecting human fertility, an increasing problem worldwide.
He in turn notes positive implications related to the research. "If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive."
Previous work from Monell and other groups has shown that some taste genes can be found in other parts of the body, including stomach, intestines, pancreas, lungs, and brain, where they are increasingly thought to have important physiological functions.
"Like much good science, our current findings pose more questions than answers," comments Monell molecular neurobiologist Robert Margolskee, MD, PhD, also an author on the paper. "We now need to identify the pathways and mechanisms in testes that utilize these taste genes so we can understand how their loss leads to infertility."
Journal Reference:

1. Bedrich Mosinger, Kevin M. Redding, M. Rockwell Parker, Valeriya Yevshayeva, Karen K. Yee, Katerina Dyomina, Yan Li, and Robert F. Margolskee. Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility. PNAS, July 1, 2013 DOI: 10.1073/pnas.1302827110

Courtesy: ScienceDaily