Sparse halos of neutrinos within the hearts of exploding stars exert a previously unrecognized influence on the physics of the explosion and may alter which elements can be forged by these violent events.
John Cherry, a graduate student at UC San Diego, models stellar explosions, including a type called a core-collapse supernova. As these stars run out of fuel, their cores suddenly collapse to form a neutron star, which quickly rebounds sending seas of neutrinos through the surrounding stellar envelope and out into space.
Even as the collapsed core is rebounding, the rest of the star is still falling inward. Plumes of matter sink, accreting onto the core. “This matter is actually causing some small fraction of neutrinos to bounce at wide angles and cross the trajectories of neutrinos coming from the core,” Cherry said.
Astrophysicists knew that the heart of that envelope contained these scattered neutrinos, but because they are relatively few compared with the numbers streaming from the core, the scientists thought halo neutrinos’ influence on the physics of these explosions would be so minor it could be ignored. Not so, Cherry and colleagues demonstrated in a paper they published in Physics Review Letters. They showed that neutrinos streaming from the core interacted with halo neutrinos far more often than anticipated.
Cherry calculated how often that might occur and how large a difference it would make to their models of neutrinos within supernovae. “What was so startling about this is that nowhere was the correction less than 14 percent. That’s enough that you need to worry about it,” he said. Indeed, the some places in the outer regions of the envelope require as much as a 10 fold correction.
Neutrinos are famously aloof particles that seldom interact with other matter. “The way neutrinos interact in matter depends on what we call ‘flavor’,” said George Fuller, professor of physics at UC San Diego who leads the neutrino-modeling research group and is a co-author of the paper.
When neutrinos meet, they “scatter” off one another and in the process can change their flavor. The influence is much greater than physicists thought in the outer halo of neutrinos. “Even though few neutrinos are scattered in funny directions, they can completely dominate how the neutrinos change their flavors,” Fuller said.
And the balance of neutrino flavors determines many important things.“The neutrinos are the engine that drives the exploding star,” Cherry said. “What’s going on with neutrinos sets the entire stage for what’s happening in the explosion.”
These stars also forge new elements, and neutrino flavor influences this process as well.
“Those neutrino flavor states allow the neutrinos to change protons to neutrons or neutrons to protons.” Cherry said. “What matter is produced, what kinds of atoms, elements are produced by these supernovas are changed dramatically if you change the flavor content of neutrinos.”
A study led by researchers at the UC San Diego Stem Cell Research program and funded by the California Institute for Regenerative Medicine (CIRM) looks at an important RNA binding protein called LIN28, which is implicated in pluripotency and reprogramming as well as in cancer and other diseases. According to the researchers, their study – published in the September 6 online issue of Molecular Cell – will change how scientists view this protein and its impact on human disease.
Studying embryonic stem cells and somatic cells stably expressing LIN28, the researchers defined discrete binding sites of LIN28 in 25 percent of human transcripts. In addition, splicing-sensitive microarrays demonstrated that LIN28 expression causes widespread downstream alternative splicing changes –variations in gene products that can result in cancer or other diseases.
“Surprisingly, we discovered that LIN28 not only binds to the non-coding microRNAs, but can also bind directly to thousands of messenger RNAs,” said first author Melissa Wilbert, a doctoral student in the UC San Diego Biomedical Sciences graduate program.
Messenger RNA or mRNA, are RNA molecules that encode a chemical “blueprint” for the synthesis of a protein. MicroRNAs (miRNAs) are short snippets of RNA that are crucial regulators of cell growth, differentiation, and death. While they don’t encode for proteins, miRNAs are important for regulating protein production in the cell by repressing or “turning off” genes.
“The LIN28 protein is linked to growth and development and is important very early in human development,” said principal investigator Gene Yeo, PhD, MBA, of the Department of Cellular and Molecular Medicine, the Stem Cell Research Program and the Institute for Genomic Medicine at UC San Diego. “It is usually turned off in adult tissue, but can be reactivated, for instance, in certain cancers or metabolic disorders, such as obesity.”
Using genome-wide biochemical methods to look at the set of all RNA molecules across the transcriptome, the researchers found that LIN28 recognizes and binds to a known hairpin-like structure found on the let-7 family of miRNA, but surprisingly, this same structure is also found on mRNAs, allowing LIN28 to directly regulate thousands of targets.
“One of these targets actually encodes for the LIN28 protein itself. In other words, LIN28 helps to make more of itself,” said Yeo. This process, known as autoregulation, helps to maintain a so-called “steady-state” system in which a protein positively regulates its own production by binding to a regulatory element of the mRNA for the gene coding it.
“Since these mRNA targets include those known to be involved in gene splicing, we also implicate LIN28 in the regulation of alternative splicing,” said Wilbert, adding that abnormal variations in splicing are often implicated in cancer and other disorders.
In the splicing process, fragments that do not typically code for protein, called introns, are removed from gene transcripts, and the remaining sequences, called exons, are reconnected. The splicing factor proteins themselves, as well as the location where these proteins bind, dictate which pieces of the RNA are included or excluded in the final gene transcript – in much the same way that removing and inserting scenes, or splicing, can alter the plot of a movie.
The discovery of thousands of precise binding sites for LIN28 within human genes offers a novel look at the role this protein plays in development and disease processes. For example, scientists had looked at targeting a particular miRNA called let-7 to halt cancer growth. “But we now see that LIN28 can, in essence, bypass let-7 and find many, many other binding sites – perhaps with the same adverse effect of uncontrolled cell overgrowth,” said Yeo. “This suggests that LIN28 itself should be the therapeutic target for diseases, rather than let-7 or other miRNAs.”
This image from a scanning electron microscope shows a tiny mechanical device, an electrostatically actuated nanoresonator, that might ease congestion over the airwaves to improve the performance of cell phones and other portable devices. (Credit:- Purdue University)
Researchers have learned how to mass produce tiny mechanical devices that could help cell phone users avoid the nuisance of dropped calls and slow downloads. The devices are designed to ease congestion over the airwaves to improve the performance of cell phones and other portable devices.
“There is not enough radio spectrum to account for everybody’s handheld portable device,” said Jeffrey Rhoads, an associate professor of mechanical engineering at Purdue University.
The overcrowding results in dropped calls, busy signals, degraded call quality and slower downloads. To counter the problem, industry is trying to build systems that operate with more sharply defined channels so that more of them can fit within the available bandwidth.
“To do that you need more precise filters for cell phones and other radio devices, systems that reject noise and allow signals only near a given frequency to pass,” said Saeed Mohammadi, an associate professor of electrical and computer engineering who is working with Rhoads, doctoral student Hossein Pajouhi and other researchers.
The Purdue team has created devices called nanoelectromechanical resonators, which contain a tiny beam of silicon that vibrates when voltage is applied. Researchers have shown that the new devices are produced with a nearly 100 percent yield, meaning nearly all of the devices created on silicon wafers were found to function properly.
“We are not inventing a new technology, we are making them using a process that’s amenable to large-scale fabrication, which overcomes one of the biggest obstacles to the widespread commercial use of these devices,” Rhoads said.
Findings are detailed in a research paper appearing online in the journal IEEE Transactions on Nanotechnology. The paper was written by doctoral students Lin Yu and Pajouhi, Rhoads, Mohammadi, and graduate student Molly Nelis.
In addition to their use as future cell phone filters, such nanoresonators also could be used for advanced chemical and biological sensors in medical and homeland-defense applications and possibly as components in computers and electronics.
The devices are created using silicon-on-insulator, or SOI, fabrication – the same method used by industry to manufacture other electronic devices. The resonators can be readily integrated into electronic circuits and systems because SOI is compatible with complementary metal–oxide–semiconductor technology, or CMOS, another mainstay of electronics manufacturing used to manufacture computer chips.
The resonators are in a class of devices called nanoelectromechanical systems, or NEMS.
The new device is said to be “highly tunable,” which means it could enable researchers to overcome manufacturing inconsistencies that are common in nanoscale devices.
“Because of manufacturing differences, no two nanoscale devices perform the same rolling off of the assembly line,” Rhoads said. “You must be able to tune them after processing, which we can do with these devices.”
The heart of the device is a silicon beam attached at two ends. The beam, which vibrates in the center like a jump rope, is about two microns long and 130 nanometers wide, or about 1,000 times thinner than a human hair. Applying alternating current to the beam causes it to selectively vibrate side-to-side or up and down and also allows the beam to be finely adjusted, or tuned.
The nanoresonators were shown to control their vibration frequencies better than other resonators. The devices might replace electronic parts to achieve higher performance and lower power consumption.
“A vivid example is a tunable filter,” Mohammadi said. “It is very difficult to make a good tunable filter with transistors, inductors and other electronic components, but a simple nanomechanical resonator can do the job with much better performance and at a fraction of the power.”
Not only are they more efficient than their electronic counterparts, he said, but they also are more compact.
“Because the devices are tiny and the fabrication has almost a 100 percent yield, we can pack millions of these devices in a small chip if we need to,” Mohammadi said. “It’s too early to know exactly how these will find application in computing, but since we can make these tiny mechanical devices as easily as transistors, we should be able to mix and match them with each other and also with transistors in order to achieve specific functions. Not only can you put them side-by-side with standard computer and electronic chips, but they tend to work with near 100 percent reliability.”
The new resonators could provide higher performance than previous MEMS, or microelectromechanical systems.
In sensing application, the design enables researchers to precisely measure the frequency of the vibrating beam, which changes when a particle lands on it. Analyzing this frequency change allows researchers to measure minute masses. Similar sensors are now used to research fundamental scientific questions. However, recent advances may allow for reliable sensing with portable devices, opening up a range of potential applications, Rhoads said.
Such sensors have promise in detecting and measuring constituents such as certain proteins or DNA for biological testing in liquids, gases and the air, and the NEMS might find applications in breath analyzers, industrial and food processing, national security and defense, and food and water quality monitoring.
“The smaller your system, the smaller the mass you can measure,” Rhoads said. “Most of the field-deployable sensors we’ve seen in the past have been based on microscale technologies, so this would be hundreds or thousands of times smaller, meaning we should eventually be able to measure things that much smaller.”
The work is based at the Dynamic Analysis of Micro- and Nanosystems Laboratory at the Birck Nanotechnology Center in Purdue’s Discovery Park. Other faculty members and graduate students also use the specialized facility.
The researchers have filed a patent application for the concept. The research is funded by the National Science Foundation.
A new study has found a gene that appears to make women happy, but it doesn’t work for men. The finding may help explain why women are often happier than men, the research team said.
Scientists at the University of South Florida (USF), the National Institutes of Health (NIH), Columbia University and the New York State Psychiatric Institute reported that the low-expression form of the gene monoamine oxidase A (MAOA) is associated with higher self-reported happiness in women. No such association was found in men.
The findings appear online in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry.
“This is the first happiness gene for women,” said lead author Henian Chen, MD, PhD, associate professor in the Department of Epidemiology and Biostatistics, USF College of Public Health.
“I was surprised by the result, because low expression of MAOA has been related to some negative outcomes like alcoholism, aggressiveness and antisocial behavior,” said Chen, who directs the Biostatistics Core at the USF Health Morsani College of Medicine’s Clinical and Translational Sciences Institute. “It’s even called the warrior gene by some scientists, but, at least for women, our study points to a brighter side of this gene.”
While they experience higher rates of mood and anxiety disorders, women tend to report greater overall life happiness than do men. The reason for this remains unclear, Chen said. “This new finding may help us to explain the gender difference and provide more insight into the link between specific genes and human happiness.”
The MAOA gene regulates the activity of an enzyme that breaks down serontin, dopamine and other neurotransmitters in the brain — the same “feel-good” chemicals targeted by many antidepressants. The low-expression version of the MAOA gene promotes higher levels of monoamine, which allows larger amounts of these neurotransmitters to stay in the brain and boost mood.
The researchers analyzed data from a population-based sample of 345 individuals – 193 women and 152 men – participating in Children in the Community, a longitudinal mental health study. The DNA of study subjects had been analyzed for MAOA gene variation and their self-reported happiness was scored by a widely used and validated scale.
After controlling for various factors, ranging from age and education to income, the researchers found that women with the low-expression type of MAOA were significantly happier than others. Compared to women with no copies of the low-expression version of the MAOA gene, women with one copy scored higher on the happiness scale and those with two copies increased their score even more.
While a substantial number of men carried a copy of the “happy” version of the MAOA gene, they reported no more happiness than those without it.
So, why the genetic gender gap in feeling good?
The researchers suspect the difference may be explained in part by the hormone testosterone, found in much smaller amounts in women than in men. Chen and his co-authors suggest that testosterone may cancel out the positive effect of MAOA on happiness in men.
The potential benefit of MAOA in boys could wane as testosterone levels rise with puberty, Chen said. “Maybe men are happier before adolescence because their testosterone levels are lower.”
Chen emphasizes that more research is needed to identify which specific genes influence resilience and subjective well-being, especially since studies of twins estimate genetic factors account for 35 to 50 percent of the variance in human happiness.
While happiness is not determined by a single gene, there is likely a set of genes that, along with life experiences, shape our individual happiness levels, Chen said. “I think the time is right for more genetic studies that focus on well-being and happiness.”
“Certainly it could be argued that how well-being is enhanced deserves at least as much attention as how (mental) disorders arise; however, such knowledge remains limited.”
The study by Chen and colleagues was supported by the National Institutes of Health and a USF proposal enhancement grant.
Source:- University of South Florida, (USF Health)
Figure 1a: Schematic illustration of the experimental set-up for surface plasmon resonance microscopy. A polarized laser beam is directed onto a gold-coated glass coverslip through an oil-immersion objective to create SPR on the gold surface, which is imaged with a CCD camera. 1b: From the bottom up, examples of bright-field, fluorescence (FL) and SPR images, respectively. (Credit:- Image Courtesy of Arizona State University)
Proteins adorning the surfaces of human cells perform an array of essential functions, including cell signaling, communication and the transport of vital substances into and out of cells. They are critical targets for drug delivery and many proteins are now being identified as disease biomarkers—early warning beacons announcing the pre-symptomatic presence of cancers and other diseases.
While study of the binding properties of membrane proteins is essential, detailed analysis of these complex entities is tricky. Now, Nongjian (NJ) Tao, Professor of Electrical Engineering, and director of the Center for Bioelectronics and Biosensors at Arizona State University’s Biodesign Institute has devised a new technique for examining the binding kinetics of membrane proteins.
“This is a very important but very difficult problem to solve,” Tao notes. “We demonstrate a new method of approaching the issue, which provides a quantitative analysis of protein interactions on the surface of a cell.”
The technique—known as SPR microscopy—holds the potential to simplify the study of membrane proteins, thereby streamlining the development of new drugs, aiding the identification of diagnostic biomarkers and improving the understanding of cell-pathogen interactions.
The group’s results appear in this week’s advanced online issue of the journal Nature Chemistry.
Typically, proteins attached to or embedded in the cell membrane’s lipid bilayer are either tagged with fluorescent markers or extracted from their locations, purified and immobilized on a glass surface in protein microarrays. These efforts may not accurately reflect native configuration and function.
Membrane proteins are complex structures whose subtle performance is often related to alterations in conformation and the particular binding kinetics at work. Existing techniques using florescent markers have been applied to pinpoint binding events, but these only permit the visualization of the protein before and after binding, omitting the dynamic processes evolving over time. Further, the use of fluorescent labels to tag protein molecules can interfere with the processes researchers hope to observe.
Alternately, proteins are extracted, purified and affixed to microarray slides—a labor-intensive process that removes proteins from their native environment, potentially affecting the shapes they naturally assume in situ and/or altering protein function.
In the current study, a label-free imaging technique is applied in situ to membrane proteins, which are visualized using a property known as surface plasmon resonance. This effect occurs when polarized light strikes the surface of a glass slide coated with a thin metallic film of gold. Under proper conditions of wavelength, polarization and incident angle, free electrons in the metal film absorb incident photons, converting them into plasmon waves, which propagate much like waves in water.
When nanoscale phenomena, including membrane proteins, interact and disrupt plasmon waves, they cause a measurable change in light reflectivity, which the new microscopy method converts into an image. (Figure 1a illustrates the basic setup of this technique.)
Surface plasmon resonance had already been applied to extracted proteins to study binding kinetics, though Tao explains that many steps are required and proteins may lose their proper conformational characteristics. This is particularly true for proteins normally embedded in a cell membrane’s lipid matrix.
Another important consideration for the study of membrane proteins is the fact that that they arrange themselves heterogeneously across membrane surfaces and modify their distribution during various cellular activities. This behavior is particularly important during a process known as chemotaxis, when cells direct their movements under the influence of chemicals in the surrounding environment. For this reason, a tool allowing for both spatial and temporal study of membrane protein distribution in real time is highly desirable.
Tao’s method uses surface plasmon resonance to provide high-resolution spatial and temporal information, and also allows for simultaneous optical and fluorescence observation of the sample, combining the advantages of both label-based and label-free methods.
High spatial resolution proved particularly useful for observing the ways polarized membrane proteins (bearing hydrophobic and hydrophilic regions) rearrange themselves, assisting cell migration directed by surrounding chemicals. The phenomenon also plays an important role during immune recognition. Using SPR microscopy, the spatial distribution of membrane proteins in single cells during chemotaxis could be mapped in detail for the first time, using a chemoattractant to induce cell migration.
Cells for study are cultured directly on a gold-coated slide, which can be subjected to simultaneous bright-field, florescent and SPR imaging. A liquid containing binding ligands is then applied over cells and the binding events with cell surface proteins monitored with SPR.
The technique permits millisecond resolution of temporal events and sub-micron scale analysis of spatial distribution. (See Figure 1b). In the current study, the method examined the binding of membrane glycoproteins with lectin ligands, the spatial distribution of membrane receptor molecules and membrane protein polarization and redistribution events.
The versatility of the new method, allowing for simultaneous imaging in optical, fluorescent and SPR modes, promises to significantly expand the study of membrane proteins in their native state, improving the understanding of protein binding kinetics and speeding the development of drugs targeting membrane proteins.
Tao stresses that such techniques—by more closely approximating in vivo conditions— provide a valuable window into biological processes relevant to health and disease: “Cells are different from tissues which are different from human beings, but at least now we can move from a system on the surface of a glass slide to an actual cell surface.”
By modifying the rate at which chemical reactions take place, nanoparticle catalysts fulfill myriad roles in industry, the biomedical arena and everyday life. They may be used for the production of polymers and biofuels, for improving pollution and emission control devices, to enhance reactions essential for fuel cell technology and for the synthesis of new drugs. Finding new and more effective nanoparticle catalysts to perform these useful functions is therefore vital.
Now Nongjian (NJ) Tao—a researcher at Arizona State University’s Biodesign Institute—has found a clever way to measure catalytical reactions of single nanoparticles and multiple particles printed in arrays, which will help characterize and improve existing nanoparticle catalysts, and advance the search for new ones.
Most catalytic materials synthesized in labs contain particles with different sizes and shapes, each having different electrocatalytical activities, but the conventional methods measure the average properties of many nanoparticles, which smear out the properties of individual nanoparticles.
“The capability of measuring single nanoparticle catalytical reactions allows for determining the relationship between the efficiency of a catalytical reaction and the size, shape, and composition of the nanoparticle.” Tao explained. “Such an imaging capability also makes it possible to image arrays of nanoparticle catalytical reactions, which may be used for fast screening of different nanoparticles,” he added.
In the current study, platinum nanoparticles acting as electrochemical catalysts are investigated by means of the new technique, known as plasmonic electrochemical imaging. The method combines the spatial resolution of optical detection with the high sensitivity and selectivity of electrochemical recognition.
Results of the study appear in this week’s advanced online edition of the journal Nature Nanotechnology.
Scanning electrochemical microscopy (SECM) has been used to image electrochemical reactions by mechanically scanning a sample surface using a microelectrode. In this process however, imaging speed is limited and the presence of the microelectrode itself may impinge on the sample and alter results.
The new method relies instead on imaging electrochemical reactions optically based on the phenomenon of surface plasmon resonance. Surface plasmons are oscillations of free electrons in a metal electrode, and can be created and detected with light. Every electrochemical reaction is accompanied by the exchange of electrons between reactants and electrodes, and the conventional electrochemical methods, including SECM, detect the electrons.
“Our approach is to measure electrochemical reactions without directly detecting the electrons.” Tao said. “The trick is to detect the conversion of the reactant into reaction products associated with the exchange of electrons.” Such conversion in the vicinity of the electrode affects the plasmon, causing changes in light reflectivity, which the technique converts to an optical image.
Using plasmonic electrochemical current imaging, Tao’s group examined the electrocatalytic activity of platinum nanoparticles printed in a microarray on a gold thin-film electrode, demonstrating for the first time the feasibility of high-throughput screening of the catalytic activities of nanoparticles.
Additionally, the new study shows that the same method can be used to investigate individual nanoparticles. As an electrical potential is applied to the electrode and cycled through a range of values, nanoparticles clearly appear as spots on the array. The effect can be seen in accompanying videos, where nanoparticle spots ‘develop’ over time as the potential changes, much like a polaroid picture gradually appears.
Microarrays featuring different surface densities of nanoparticles were also produced for the study. Results showed that electrocatalytic current at a given potential increases proportionally with nanoparticle density. Further, when individual nanoparticles were characterized using SPR microscopy, atomic force microscopy (AFM) and transmission electron microscopy (TEM), good agreement was shown between the results, further validating the new technique.
Tao notes that in principle, plasmonic electrochemical imaging— a rapid and non-invasive technique offering the combined benefits of optical and electrochemical detection—may be applied to other phenomena for which conventional electrochemical detection methods are currently used.
Stroke is the fourth leading cause of death and a common cause of long-term disability in the United States, but doctors have very few proven treatment methods. Now a new device that mechanically removes stroke-causing clots from the brain is being hailed as a game-changer.
In a recent clinical trial, the SOLITAIRE Flow Restoration Device dramatically outperformed the standard mechanical treatment. Findings from the trial, called SOLITAIRE With the Intention for Thrombectomy (SWIFT), are published online today in the journal The Lancet and will also appear in a later print edition of the journal.
SOLITAIRE, which was approved by the U.S. Food and Drug Administration in March, is among an entirely new generation of devices designed to remove blood clots from blocked brain arteries in patients experiencing an ischemic stroke. It has a self-expanding, stent-like design, and once inserted into a blocked artery using a thin catheter tube, it compresses and traps the clot. The clot is then removed by withdrawing the device, reopening the blocked blood vessel.
“This new device is significantly changing the way we can treat ischemic stroke,” said the study’s lead author, Dr. Jeffrey L. Saver, director of the UCLA Stroke Center and a professor of neurology at the David Geffen School of Medicine at UCLA. “We are going from our first generation of clot-removing procedures, which were only moderately good in reopening target arteries, to now having a highly effective tool.”
Results of the study showed that the device opened blocked vessels without causing symptomatic bleeding in or around the brain in 61 percent of patients. The standard FDA–approved mechanical device — a corkscrew-type clot remover called the MERCI Retriever — was effective in 24 percent of cases.
The use of SOLITAIRE also led to better survival three months after a stroke. There was a 17.2 percent mortality rate with the new device, compared with a 38.2 percent rate with the older one.
About 87 percent of all strokes are caused by blood clots blocking a blood vessel supplying the brain. The stroke treatment that has received the most study is an FDA–approved clot-busting drug known as tissue plasminogen activator, but this drug must be given within four-and-a-half hours of the onset of stroke symptoms, and even more quickly in older patients.
When clot-busting drugs cannot be used or are ineffective, the clot can sometimes be mechanically removed during, or beyond, the four-and-a-half–hour window. The current study, however, did not compare mechanical clot removal to drug treatment.
For the trial, researchers randomly assigned 113 stroke patients at 18 hospitals to receive either SOLITAIRE or MERCI therapy within eight hours of stroke onset, between January 2010 and February 2011. The patients’ average age was 67, and 68 percent were male. The time from the beginning of stroke symptoms to the start of the clot-retriever treatment averaged 5.1 hours. Forty percent of the patients had not improved with standard clot-busting medication prior to the study, while the remainder had not received it.
At the suggestion of a safety monitoring committee, the trial was ended nearly a year earlier than planned due to significantly better outcomes with the experimental device.
Other statistically significant findings included:
2 percent of SOLITAIRE-treated patients had symptoms of bleeding in the brain, compared with 11 percent of MERCI patients.
At the 90-day follow-up, overall adverse event rates, including bleeding in the brain, were similar for the two devices.
58 percent of SOLITAIRE-treated patients had good mental/motor functioning at 90 days, compared with 33 percent of MERCI patients.
The SOLITARE device also opened more vessels when used as the first treatment approach, necessitating fewer subsequent attempts with other devices or drugs.
Open an undergraduate biochemistry textbook and you will learn that enzymes are highly efficient and specific in catalyzing chemical reactions in living organisms, and that they evolved to this state from their “sloppy” and “promiscuous” ancestors to allow cells to grow more efficiently. This fundamental paradigm is being challenged in a new study by bioengineers at the University of California, San Diego, who reported in the journal Science what a few enzymologists have suspected for years: many enzymes are still pretty sloppy and promiscuous, catalyzing multiple chemical reactions in living cells, for reasons that were previously not well understood.
In this study, the research team, led by Bernhard Palsson, Galetti Professor of Bioengineering at the UC San Diego Jacobs School of Engineering, brought together decades of work on the behavior of individual enzymes to produce a genome-scale model of E. coli metabolism and report that at least 37 percent of its enzymes catalyze multiple metabolic reactions that occur in an actively growing cell.
“We’ve been able to stitch all of the enzymes together into one giant model, giving us a holistic view of what has been driving the evolution of enzymes and found that it isn’t quite what we’ve thought it to be,” said Palsson.
When organisms evolve, it is the genes or proteins that change. Therefore, gene and protein evolution has classically been studied one gene at a time. However in this work, Palsson and his colleagues, introduce an important paradigm shift by demonstrating that the evolution of individual proteins and enzymes is influenced by the function of all of the other enzymes in an organism, and how they all work together to support the growth rate of the cell.
Using a whole-cell model of metabolism, the research team found that the more essential an enzyme is to the growth of the cell, the more efficient it needs to be; meanwhile, enzymes that only weakly contribute to cell growth can remain ‘sloppy.’ The study found three major reasons why some enzymes have evolved to be so efficient, while others have not:
Enzymes that are used more extensively by the organism need to be more efficient to avoid waste. To increase efficiency, they evolve to catalyze one specific metabolic reaction.
When enzymes are responsible for catalyzing reactions that are necessary for cell growth and survival, they are specific in order to avoid interference from molecules that are not needed for cell growth and survival.
Since organisms have to adapt to dynamic and noisy environments, they sometimes need to have careful control of certain enzyme activities in order to avoid wasting energy and prepare for anticipated nutrient changes. Evolving higher specificity makes these enzymes easier to control.
“Our study found that the functions of promiscuous enzymes are still used in growing cells, but the sloppiness of these enzymes is not detrimental to growth. They are much less sensitive to changes in the environment and not as necessary for efficient cell growth,” said Nathan Lewis, who earned a Ph.D. in bioengineering at the Jacobs School in March and is now a postdoctoral fellow at Harvard Medical School.
This study is also a triumph in the emerging field of systems biology, which leverages the power of high-performance computing and an enormous amount of available data from the life sciences to simulate activities such as the rates of reactions that break down nutrients to make energy and new cell parts. “This study sheds light on the vast number of promiscuous enzymes in living organisms and shifts the paradigm of research in biochemistry to a holistic level,” said Lewis. “The insights found in our work also clearly show that fine-grained knowledge can be obtained about individual proteins while using large-scale models.” This concept will yield immediate and more distant results.
“Our team’s findings could also inform other research efforts into which enzymes require further study for overlooked promiscuous activities,” said Hojung Nam, a postdoctoral researcher in Palsson’s lab. “Besides testing and characterizing more enzymes for potential promiscuous activities, enzyme promiscuity could have far-reaching impacts as scientists try to understand how unexpected promiscuous activities of enzymes contribute to diseases such as leukemia and brain tumors,” said Nam.
Men who have been treated for prostate cancer, either with surgery or radiation, could benefit from taking aspirin regularly, says a new study that includes a researcher at UT Southwestern Medical Center.
Taking aspirin is associated with a lower risk of death from prostate cancer, especially in men with high risk disease, according to a multicenter study published in today’s issue of the Journal of Clinical Oncology. Dr. Kevin Choe, assistant professor of radiation oncology at UT Southwestern, is first author of the paper.
Preclinical studies have shown that aspirin and other anticoagulation medications may inhibit cancer growth and metastasis, but clinical data have been limited previously. The study looked at almost 6,000 men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database who had prostate cancer treated with surgery or radiotherapy.
About 2,200 of the men involved – 37 percent – were receiving anticoagulants (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of death from prostate cancer was compared between those taking anticoagulants and those who were not.
The findings demonstrated that 10-year mortality from prostate cancer was significantly lower in the group taking anticoagulants, compared to the non-anticoagulant group – 3 percent versus 8 percent, respectively. The risks of cancer recurrence and bone metastasis also were significantly lower. Further analysis suggested that this benefit was primarily derived from taking aspirin, as opposed to other types of anticoagulants.
The suggestion that aspirin, a frequently prescribed and relatively well-tolerated medication, may improve outcomes in prostate cancer is of particular interest, Dr. Choe said, since prostate cancer is the most common non-skin cancer among men and the second-leading cancer killer in the U.S.
“The results from this study suggest that aspirin prevents the growth of tumor cells in prostate cancer, especially in high-risk prostate cancer, for which we do not have a very good treatment currently,” Dr. Choe said. “But we need to better understand the optimal use of aspirin before routinely recommending it to all prostate cancer patients.”
Other scientists involved with the study include Janet Cowan, Drs. June Chan, and Peter Carroll of the University of California, San Francisco; Dr. Anthony D’Amico of Harvard University; and senior author Dr. Stanley Liauw of the University of Chicago.
Being physically fit during your 30s, 40s, and 50s not only helps extend lifespan, but it also increases the chances of aging healthily, free from chronic illness, investigators at UT Southwestern Medical Center and The Cooper Institute have found.
For decades, research has shown that higher cardiorespiratory fitness levels lessen the risk of death, but it previously had been unknown just how much fitness might affect the burden of chronic disease in the most senior years – a concept known as morbidity compression.
“We’ve determined that being fit is not just delaying the inevitable, but it is actually lowering the onset of chronic disease in the final years of life,” said Dr. Jarett Berry, assistant professor of internal medicine and senior author of the study available online in the Archives of Internal Medicine.
Researchers examined the patient data of 18,670 participants in the Cooper Center Longitudinal Study, research that contains more than 250,000 medical records maintained over a 40-year span. These data were linked with the patients’ Medicare claims filed later in life from ages 70 to 85. Analyses during the latest study showed that when patients increased fitness levels by 20 percent in their midlife years, they decreased their chances of developing chronic diseases – congestive heart failure, Alzheimer’s disease, and colon cancer – decades later by 20 percent.
“What sets this study apart is that it focuses on the relationship between midlife fitness and quality of life in later years. Fitter individuals aged well with fewer chronic illnesses to impact their quality of life,” said Dr. Benjamin Willis of The Cooper Institute, first author on the study.
This positive effect continued until the end of life, with more-fit individuals living their final five years of life with fewer chronic diseases. The effects were the same in both men and women.
These data suggest that aerobic activities such as walking, jogging, or running translates not only into more years of life but also into higher quality years, compressing the burden of chronic illness into a shorter amount of time at the end of life, Dr. Berry said.
According to the National Heart, Lung, and Blood Institute (NHLBI), adults should get at least 2 ½ hours of moderate to intense aerobic activity each week to ensure major heart and overall health benefits.
UT Southwestern has a partnership with The Cooper Institute, the preventive medicine research and educational nonprofit located at the Cooper Aerobics Center, to develop a joint scientific medical research program aimed at improving health and preventing a wide range of chronic diseases. One of the world’s most extensive databases, the Cooper Center Longitudinal Study includes detailed information from clinic visits that has been collected since Dr. Kenneth Cooper founded the institute and clinic in 1970.
Other UT Southwestern researchers involved in the study include Dr. David Leonard, assistant professor of clinical sciences, and Ang Gao, a biostatistical consultant in internal medicine.
The study was funded with support from the NHLBI and the American Heart Association.