Doctors have long been mystified as to why HIV-1 rapidly sickens some individuals, while in others the virus has difficulties gaining a foothold. Now, a study of genetic variation in HIV-1 and in the cells it infects reported by University of Minnesota researchers in this week’s issue of PLOS Genetics has uncovered a chink in HIV-1′s armor that may, at least in part, explain the puzzling difference — and potentially open the door to new treatments.
HIV-1 harms people by invading immune system cells known as T lymphocytes, hijacking their molecular machinery to make more of themselves, then destroying the host cells — leaving the infected person more susceptible to other deadly diseases. T lymphocytes are not complete sitting ducks, however. Among their anti-virus defense mechanisms is a class of proteins known as APOBEC3s that have the ability to block the HIV-1′s ability to replicate. Not surprisingly, however, HIV-1 has a counter-defense mechanism — a protein called Vif that cons the T lymphocytes into destroying their own APOBEC3.
Suspecting differential susceptibility to HIV-1 might be related to genetic variations in this system, a research team led by doctoral student Eric Refsland and Reuben Harris of the University’s College of Biological Sciences and Medical School took a closer look. First, the researchers found that HIV-1 infection boosts the production of one kind of APOBEC3, APOBEC3H — suggesting it’s a key player in fighting back. Then, using an experimental technique known as separation of function mutagenesis, they discovered that different people have different strengths/potencies of APOBEC3H, with some proteins expressed stably and others inherently unstable. The stable variations, the researchers found, were able to successfully limit HIV-1′s ability to replicate if the infecting virus had a weak version of Vif — but not for HIV-1 viruses that had strong Vif.
“This work shows that the competition between the virus and the host is still ongoing,” Refsland says. “The virus hasn’t completely perfected its ability to replicate in humans.”
Armed with this clearer picture of the multifaceted interactions between Vif and APOBEC3, Harris says, the next step is to figure out how to stop Vif from disabling the APOBEC3 enzymes. “One could imagine drugs that stop Vif from binding with APOBEC,” he said. “This is a bonafide HIV killing pathway, and we just have to devise clever ways to activate it in infected persons. Such an approach could indefinitely suppress virus replication, and even result in curing it.”
A breakthrough in curing HIV-AIDS is not far behind. Manipulating genes, antibodies, other viruses or even developing novel drugs can be the next step. PCD Pharma companies lending monopoly franchise have diligent team of researchers who have developed various trade drugs with maximum efficacy like moxel-cv, loxim-oz, otflox-oz, etc
Driving to work becomes routine — but could you drive the entire way in reverse gear? Humans, like many animals, are accustomed to seeing objects pass behind us as we go forward. Moving backwards feels unnatural.
In a new study, scientists from The Scripps Research Institute (TSRI) reveal that moving forward actually trains the brain to perceive the world normally. The findings also show that the relationship between neurons in the eye and the brain is more complicated than previously thought — in fact, the order in which we see things could help the brain calibrate how we perceive time, as well as the objects around us.
“We were trying to understand how that happens and the rules used during brain development,” said the study’s senior author Hollis Cline, who is the Hahn Professor of Neuroscience and member of the Dorris Neuroscience Center at TSRI.
This research, published this week in the journal Proceedings of the National Academy of Sciences could have implications for treating sensory processing disorders such as autism.
Reversing the Map
The new study began when Masaki Hiramoto, a staff scientist in Cline’s lab, asked an important question: “How does the visual system of the brain get better “tuned” over time?”
Previous studies had shown that people use the visual system to create an internal map of the world. The key to creating this map is sensing the “optic flow” of objects as we walk or drive forward. “It’s natural because we’ve learned it,” said Cline.
To study how this system develops, Hiramoto and Cline used transparent tadpoles to watch as nerve fibers, called axons, developed between the retina and the brain. The scientists marked the positions of the axons using fluorescent proteins.
The tadpoles were split into groups and raised in small chambers. One group was shown a computer screen with bars of light that moved past the tadpoles from front to back — simulating a normal optic flow as if the animal were moving forward. A second group saw the bars in reverse — simulating an unnatural backwards motion. Using the TSRI Dorris Neuroscience Center microscopy facility, Hiramoto then captured high-resolution images of these neurons as they grew over time.
The researchers found that tadpoles’ visual map developed normally when shown bars moving from front to back. But tadpoles shown the bars in reverse order extended axons to the wrong spots in their map. With those axons out of order, the brain would perceive visual images as reversed or squished.
Rewriting the Rules
This discovery challenges a rule in neuroscience that dates back to 1949. Until now, researchers knew it was important that neighboring neurons fired at roughly the same time, but didn’t realize that the temporal sequence of firing was important.
“According to the old rule, if there was a stimulus that went backwards, the map would be fine,” said Cline.
The new study adds the element of order. The researchers showed that objects moving from front to back in the visual field activated retinal cells in a specific sequence.
Cline and Hiramoto believe that this sequence helps the brain perceive the passage of time. For example, if you drive for a few minutes and pass a street sign, your brain will map its position behind you. If you keep driving and you pass another street sign, your brain will map out not only the street signs’ positions relative to each other, but their distance in time as well.
This link between time and space in the visual system might also apply to hearing and the sense of touch. The original question of how the visual system gets “tuned” over time might be applicable across the entire brain.
The researchers believe this study could have implications for patients with sensory and temporal processing disorders, including autism and a mysterious disorder called Alice in Wonderland syndrome, where a person perceives objects as disproportionately big or small. Cline said the new study offers possibilities for retraining the brain to map the world correctly, for instance after stroke.
Support for the work came from the National Institutes of Health (EY011261 and DP1OD000458), the Nancy Lurie Marks Family Foundation and an endowment from the Hahn Family Foundation.
People exposed to Ebola vary in how the virus affects them. Some completely resist the disease, others suffer moderate to severe illness and recover, while those who are most susceptible succumb to bleeding, organ failure and shock.
In earlier studies of populations of people who have contracted Ebola, these differences are not related to any specific changes in the Ebola virus itself that made it more or less dangerous; instead, the body’s attempts to fight infection seems to determine disease severity.
In the Oct. 30 edition of Science, scientists describe strains of laboratory mice bred to test the role of an individual’s genetic makeup in the course of Ebola disease. Systems biologists and virologists Angela Rasmussen and Michael Katze from the Katze Laboratory at the University of Washington Department of Microbiology led the study in collaboration with the National Institutes of Health’s Rocky Mountain Laboratories in Montana and University of North Carolina at Chapel Hill.
Research on Ebola prevention and treatment has been hindered by the lack of a mouse model that replicates the main characteristics of human Ebola hemorrhagic fever. The researchers had originally obtained this genetically diverse group of inbred laboratory mice to study locations on mouse genomes associated with influenza severity.
The research was conducted in a highly secure, state-of-the-art biocontainment safety level 4 laboratory in Hamilton, Mont. The scientists examined mice that they infected with a mouse form of the same species of Ebola virus causing the 2014 West Africa outbreak. The study was done in full compliance with federal, state, and local safety and biosecurity regulations. This type of virus has been used several times before in research studies. Nothing was done to change the virus.
Interestingly, conventional laboratory mice previously infected with this virus died, but did not develop symptoms of Ebola hemorrhagic fever.
In the present study, all the mice lost weight in the first few days after infection. Nineteen percent of the mice were unfazed. They not only survived, but also fully regained their lost weight within two weeks. They had no gross pathological evidence of disease. Their livers looked normal.
Eleven percent were partially resistant and less than half of these died. Seventy percent of the mice had a greater than 50 percent mortality. Nineteen percent of this last group had liver inflammation without classic symptoms of Ebola, and thirty-four percent had blood that took too long to clot, a hallmark of fatal Ebola hemorrhagic fever in humans. Those mice also had internal bleeding, swollen spleens and changes in liver color and texture.
The scientists correlated disease outcomes and variations in mortality rates to specific genetic lines of mice.
“The frequency of different manifestations of the disease across the lines of these mice screened so far are similar in variety and proportion to the spectrum of clinical disease observed in the 2014 West African outbreak,” Rasmussen said.
While acknowledging that recent Ebola survivors may have had immunity to this or a related virus that saved them during this epidemic, Katze said, “Our data suggest that genetic factors play a significant role in disease outcome.”
In general, when virus infection frenzied the genes involved in promoting blood vessel inflammation and cell death, serious or fatal disease followed. On the other hand, survivors experienced more activity in genes that order blood vessel repair and the production of infection-fighting white blood cells.
The scientists note that certain specialized types of cells in the liver could also have limited virus reproduction and put a damper on systemic inflammation and blood clotting problems in resistant mice. Susceptible mice had widespread liver infection, which may explain why they had more virus in their bodies and poorly regulated blood coagulation. The researchers also noticed that spleens in the resistant and susceptible mice took alternate routes to try to ward off infection.
“We hope that medical researchers will be able to rapidly apply these findings to candidate therapeutics and vaccines,” Katze said. They believe this mouse model can be promptly implemented to find genetic markers, conduct meticulous studies on how symptoms originate and take hold, and evaluate drugs and that have broad spectrum anti-viral activities against all Zaire ebolaviruses, including the one responsible for the current West African epidemic.
In the future, working up a sweat by exercising may not only be good for your health, but it could also power your small electronic devices. Researchers will report today that they have designed a sensor in the form of a temporary tattoo that can both monitor a person’s progress during exercise and produce power from their perspiration.
In general, the more intense the exercise, the more lactate the body produces. During strenuous physical activity, the body needs to generate more energy, so it activates a process called glycolysis. Glycolysis produces energy and lactate, the latter of which scientists can detect in the blood.
Professional athletes monitor their lactate levels during performance testing as a way to evaluate their fitness and training program. In addition, doctors measure lactate during exercise testing of patients for conditions marked by abnormally high lactate levels, such as heart or lung disease. Currently, lactate testing is inconvenient and intrusive because blood samples must be collected from the person at different times during the exercise regime and then analyzed.
Jia, a postdoctoral student in the lab of Joseph Wang, D.Sc., at the University of California San Diego, and her colleagues developed a faster, easier and more comfortable way to measure lactate during exercise. They imprinted a flexible lactate sensor onto temporary tattoo paper. The sensor contained an enzyme that strips electrons from lactate, generating a weak electrical current. The researchers applied the tattoo to the upper arms of 10 healthy volunteers. Then the team measured the electrical current produced as the volunteers exercised at increasing resistance levels on a stationary bicycle for 30 minutes. In this way, they could continuously monitor sweat lactate levels over time and with changes in exercise intensity.
The team then went a step further, building on these findings to make a sweat-powered biobattery. Batteries produce energy by passing current, in the form of electrons, from an anode to a cathode. In this case, the anode contained the enzyme that removes electrons from lactate, and the cathode contained a molecule that accepts the electrons.
When 15 volunteers wore the tattoo biobatteries while exercising on a stationary bike, they produced different amounts of power. Interestingly, people who were less fit (exercising fewer than once a week) produced more power than those who were moderately fit (exercising one to three times per week). Enthusiasts who worked out more than three times per week produced the least amount of power. The researchers say that this is probably because the less-fit people became fatigued sooner, causing glycolysis to kick in earlier, forming more lactate. The maximum amount of energy produced by a person in the low-fitness group was 70 microWatts per cm2 of skin.
“The current produced is not that high, but we are working on enhancing it so that eventually we could power some small electronic devices,” Jia says. “Right now, we can get a maximum of 70 microWatts per cm2, but our electrodes are only 2 by 3 millimeters in size and generate about 4 microWatts — a bit small to generate enough power to run a watch, for example, which requires at least 10 microWatts. So besides working to get higher power, we also need to leverage electronics to store the generated current and make it sufficient for these requirements.”
Biobatteries offer certain advantages over conventional batteries: They recharge more quickly, use renewable energy sources (in this case, sweat), and are safer because they do not explode or leak toxic chemicals.
“These represent the first examples of epidermal electrochemical biosensing and biofuel cells that could potentially be used for a wide range of future applications,” Wang says.
During the winter of 1944, the Nazis blocked food supplies to the western Netherlands, creating a period of widespread famine and devastation. The impact of starvation on expectant mothers produced one of the first known epigenetic “experiments” — changes resulting from external rather than genetic influences — which suggested that the body’s physiological responses to hardship could be inherited. The underlying mechanism, however, remained a mystery.
In a paper published recently in the journal Cell, Dr. Oded Rechavi, Dr. Leah Houri-Ze’ev, and Dr. Sarit Anava of Tel Aviv University’s Faculty of Life Sciences and Sagol School of Neuroscience, Prof. Oliver Hobert and Dr. Sze Yen Kerk of Columbia University Medical Center and the Howard Hughes Medical Institute, and Dr. Wee Siong Sho Goh and Dr. Gregory J. Hannon of the Cold Spring Harbor Laboratory and the Howard Hughes Medical Institute, explore a genetic mechanism that passes on the body’s response to starvation to subsequent generations of worms, with potential implications for humans also exposed to starvation and other physiological challenges, such as anorexia nervosa.
“There are possibly several different genetic mechanisms that enable inheritance of traits in response to changes in the environment. This is a new field, so these mechanisms are only now being discovered,” said Dr. Rechavi. “We identified a mechanism called ‘small RNA inheritance’ that enables worms to pass on the memory of starvation to multiple generations.”
Does RNA have a memory?
RNA molecules are produced from DNA templates in response to the needs of specific cells. “Messenger” RNA molecules (mRNAs) contain instructions for the production of proteins, which service cells and allow them to function. But other RNA molecules have different regulatory functions. Small RNAs are one species of these regulatory RNAs — short molecules that regulate gene expression, mostly by shutting genes off, but sometimes by turning them on.
Dr. Rechavi first became interested in studying starvation-induced epigenetic responses following a discovery made as a post doctorate in Prof. Hobert’s lab at Columbia University Medical Center in New York. “Back then, we found that small RNAs were inherited, and that this inheritance affected antiviral immunity in worms. It was obvious that this was only the tip of the iceberg,” he said.
In the course of the new study, worms (C.elegans nematodes) were starved early in their development. They responded by producing small RNAs, which function by regulating genes through a process that is known as RNA interference (RNAi). The researchers discovered that the starvation-responsive small RNAs target genes that are involved in nutrition. More important, the starvation-induced small RNAs were inherited by at least three subsequent generations of worm specimens.
“We were also surprised to find that the great-grandchildren of the starved worms had an extended life span,” said Dr. Rechavi. “To the best of our knowledge, our paper provides the first concrete evidence that it’s enough to simply experience a particular environment — in this case, an environment without food — for small RNA inheritance and RNA interference to ensue. In this case, the environmental challenge is starvation, a very physiologically relevant challenge, and it is likely that other environments induce transgenerational inheritance of small RNAs as well.
“We identified genes that are essential for production and for the inheritance of starvation-responsive small RNAs. RNA inheritance could prove to be an important genetic mechanism in other organisms, including humans, acting parallel to DNA. This could possibly allow parents to prepare their progeny for hardships similar to the ones that they experience,” Dr. Rechavi said.
The researchers are currently researching a wide variety of traits affected by inherited small RNAs.
Reducing the amount of alcoholic beverages consumed, even for light-to-moderate drinkers, may improve cardiovascular health, including a reduced risk of coronary heart disease, lower body mass index (BMI) and blood pressure, according to a new multi-center study published in The BMJ and co-led by the Perelman School of Medicine at the University of Pennsylvania. The latest findings call into question previous studies which suggest that consuming light-to-moderate amounts of alcohol (0.6-0.8 fluid ounces/day) may have a protective effect on cardiovascular health.
The new research reviewed evidence from more than 50 studies that linked drinking habits and cardiovascular health for over 260,000 people. Researchers found that individuals who carry a specific gene which typically leads to lower alcohol consumption over time have, on average, superior cardiovascular health records. Specifically, the results show that individuals who consume 17 percent less alcohol per week have on average a 10 percent reduced risk of coronary heart disease, lower blood pressure and a lower Body Mass Index.
“These new results are critically important to our understanding of how alcohol affects heart disease. Contrary to what earlier reports have shown, it now appears that any exposure to alcohol has a negative impact upon heart health,” says co-lead author Michael Holmes, MD, PhD, research assistant professor in the department of Transplant Surgery at the Perelman School of Medicine at the University of Pennsylvania. “For some time, observational studies have suggested that only heavy drinking was detrimental to cardiovascular health, and that light consumption may actually be beneficial. This has led some people to drink moderately based on the belief that it would lower their risk of heart disease. However, what we’re seeing with this new study, which uses an investigative approach similar to a randomized clinical trial, is that reduced consumption of alcohol, even for light-to-moderate drinkers, may lead to improved cardiovascular health.”
In the new study, researchers examined the cardiovascular health of individuals who carry a genetic variant of the ‘alcohol dehydrogenase 1B’ gene, which is known to breakdown alcohol at a quicker pace. This rapid breakdown causes unpleasant symptoms including nausea and facial flushing, and has been found to lead to lower levels of alcohol consumption over time. By using this genetic marker as an indicator of lower alcohol consumption, the research team was able to identify links between these individuals and improved cardiovascular health.
The study was funded by the British Heart Foundation and the Medical Research Council, and was an international collaboration that included 155 investigators from the UK, continental Europe, North America, and Australia.