July 26, 2016
German Primate Center
Our hands are highly developed grasping organs that are in continuous use. Long before we stir our first cup of coffee in the morning, our hands have executed a multitude of grasps. Directing a pen between our thumb and index finger over a piece of paper with absolute precision appears as easy as catching a ball or operating a doorknob. Now neuroscientists have studied how the brain controls the different grasping movements. In their research with rhesus macaques, it was found that the three brain areas that are responsible for planning and executing hand movements, perform different tasks within their neural network.
Our hands are highly developed grasping organs that are in continuous use. Long before we stir our first cup of coffee in the morning, our hands have executed a multitude of grasps. Directing a pen between our thumb and index finger over a piece of paper with absolute precision appears as easy as catching a ball or operating a doorknob. The neuroscientists Stefan Schaffelhofer and Hansjörg Scherberger of the German Primate Center (DPZ) have studied how the brain controls the different grasping movements.
In their research with rhesus macaques, it was found that the three brain areas AIP, F5 and M1 that are responsible for planning and executing hand movements, perform different tasks within their neural network. The AIP area is mainly responsible for processing visual features of objects, such as their size and shape. This optical information is translated into motor commands in the F5 area. The M1 area is ultimately responsible for turning this motor commands into actions. The results of the study contribute to the development of neuroprosthetics that should help paralyzed patients to regain their hand functions.
The three brain areas AIP, F5 and M1 lay in the cerebral cortex and form a neural network responsible for translating visual properties of an object into a corresponding hand movement. Until now, the details of how this “visuomotor transformation” are performed have been unclear. During the course of his PhD thesis at the German Primate Center, neuroscientist Stefan Schaffelhofer intensively studied the neural mechanisms that control grasping movements. “We wanted to find out how and where visual information about grasped objects, for example their shape or size, and motor characteristics of the hand, like the strength and type of a grip, are processed in the different grasp-related areas of the brain,” says Schaffelhofer.
For this, two rhesus macaques were trained to repeatedly grasp 50 different objects. At the same time, the activity of hundreds of nerve cells was measured with so-called microelectrode arrays. In order to compare the applied grip types with the neural signals, the monkeys wore an electromagnetic data glove that recorded all the finger and hand movements. The experimental setup was designed to individually observe the phases of the visuomotor transformation in the brain, namely the processing of visual object properties, the motion planning and execution. For this, the scientists developed a delayed grasping task. In order for the monkey to see the object, it was briefly lit before the start of the grasping movement. The subsequent movement took place in the dark with a short delay. In this way, visual and motor signals of neurons could be examined separately.
The results show that the AIP area is primarily responsible for the processing of visual object features. “The neurons mainly respond to the three-dimensional shape of different objects,” says Stefan Schaffelhofer. “Due to the different activity of the neurons, we could precisely distinguish as to whether the monkeys had seen a sphere, cube or cylinder. Even abstract object shapes could be differentiated based on the observed cell activity.”
In contrast to AIP, area F5 and M1 did not represent object geometries, but the corresponding hand configurations used to grasp the objects. The information of F5 and M1 neurons indicated a strong resemblance to the hand movements recorded with the data glove. “In our study we were able to show where and how visual properties of objects are converted into corresponding movement commands,” says Stefan Schaffelhofer. “In this process, the F5 area plays a central role in visuomotor transformation. Its neurons receive direct visual object information from AIP and can translate the signals into motor plans that are then executed in M1. Thus, area F5 has contact to both, the visual and motor part of the brain.”
Knowledge of how to control grasp movements is essential for the development of neuronal hand prosthetics. “In paraplegic patients, the connection between the brain and limbs is no longer functional. Neural interfaces can replace this functionality,” says Hansjörg Scherberger, head of the Neurobiology Laboratory at the DPZ. “They can read the motor signals in the brain and use them for prosthetic control. In order to program these interfaces properly, it is crucial to know how and where our brain controls the grasping movements.” The findings of this study will facilitate to new neuroprosthetic applications that can selectively process the areas’ individual information in order to improve their usability and accuracy.
- Stefan Schaffelhofer, Hansjörg Scherberger. Object vision to hand action in macaque parietal, premotor, and motor cortices. eLife, 2016; 5 DOI: 10.7554/eLife.15278
Source: German Primate Center. “From vision to hand action: Neuroscientists decipher how our brain controls grasping movements.” ScienceDaily. ScienceDaily, 26 July 2016. <www.sciencedaily.com/releases/2016/07/160726094220.htm>.
July 25, 2016
Researchers have developed a new index based on rib and body weight measurements that predicts whether a mammal lived on land, in water, or both. When applied to extinct mammalian species, the index showed that some could not have supported their own weight while walking or crawling, and thus must have been restricted to an aquatic life. The index reveals the habitats of extinct species and enables reconstruction of their lifestyles and the anatomical changes that accompanied adoption of an exclusively aquatic lifestyle.
Despite the extensive fossil record of mammals, it is often difficult to use fossil data to reconstruct the lifestyles and habitats of extinct species. The fact that some species spent all or part of their time underwater, respectively similar to modern-day whales and seals, further complicates this.
Konami Ando and Shin-chi Fujiwara, researchers at Nagoya University, addressed this by developing a new index for predicting if a species lived its entire life in the water. The index is based on how the ribs must be relatively strong for an animal to walk or crawl over land, but not for it to swim. After establishing the index via measurements of living terrestrial, semiaquatic, and exclusively aquatic species, Ando and Fujiwara used it to predict that some extinct species could not have supported themselves on land.
Although mammals originally evolved as terrestrial organisms, cladistics shows that some returned to aquatic lives, and that this sometimes occurred independently. Examples include whales, dolphins, and manatees, which never leave the water, and seals and hippopotamuses, which split time between land and water. Studies of fossils of extinct species also suggest some species spent all or some of their time in the water. However, inability to use fossil records alone to determine a species’ lifestyle has made this hard to confirm.
In their study, reported in the Journal of Anatomy, Ando and Fujiwara analyzed rib cages and their resistance to vertical compression in a range of mammalian species. This important factor represents an animal’s ability to support its body weight against gravity while walking or crawling; a trait aquatic organisms do not need. The researchers investigated 26 modern-day terrestrial, semiaquatic, and exclusively aquatic species, including the killer whale, polar bear, dugong, giraffe, and hippopotamus. They used their data to establish an index for differentiating between groups with different habitats. They then applied the index to four extinct mammalian species, all of which had retained their four limbs but showed signs of having been partially or completely aquatic, to shed light on their potential lifestyles.
“We selected mammals with different habitats from a range of taxa and analyzed fossils for which the bones in the thoracic region were well-preserved,” Fujiwara says. “We focused on the fracture loads of ribs. We found the sum of the fracture loads of all true ribs directly connected to the sternum divided by the body weight effectively separated the extant species groups by habitat. Exclusively aquatic species were clearly differentiated.”
After establishing that the index could correctly classify living species with known habitats and lifestyles, the researchers applied it to extinct groups:Ambulocetus, an early ancestor of whales, and three desmostylian species, which are the keens of elephants and sea cows. This was to confirm or reject earlier hypotheses about these groups’ lifestyles, which were based on other morphological findings.
“Our index lets us conclude that Ambulocetus and two desmostylians (Paleoparadoxia and Neoparadoxia) could not have supported themselves on land; they were exclusively aquatic,” Ando says. “But the findings were inconclusive for the third desmostylian (Desmostylus). We may need to perform additional studies on the intermediate group of semiaquatic species, include a bone density variable in our model, or improve our data on the body mass of extinct species to refine the index.”
The new index should help in both reconstructing the lifestyles and habitats of extinct mammals and clarifying anatomical changes associated with mammals shifting to a life partly or exclusively in the water.
- Konami Ando, Shin-ichi Fujiwara. Farewell to life on land – thoracic strength as a new indicator to determine paleoecology in secondary aquatic mammals. Journal of Anatomy, 2016; DOI:10.1111/joa.12518
Source: Nagoya University. “New index reveals likelihood of terrestrial or aquatic lifestyles of extinct mammals.” ScienceDaily. ScienceDaily, 25 July 2016. <www.sciencedaily.com/releases/2016/07/160725105228.htm>.
Linville Falls as Viewed at the Bottom of Linville Gorge – Great Place to Cool Off
Note from James Farley, colleague and photographer extraordinaire: Difficult day, as it was raining and there was thunder and lightning, while we hiked on the Plunge Basin Trail. Caught a brief moment, when the rain stopped, to get some stillness to the slower-moving water, and get a clear view through the water. Shot on my Canon 5D Mark III and 35mm f1.4 2nd Generation lens. 2 second exposure at f16 and ISO50. Lee Filters 0.6 ND Grad and Landscape Circular Polarizer used.
Linville Falls as Viewed at the Bottom of Linville Gorge ©JFarley Photography
Advice from the NIH: Summer is here and it’s blazing hot! So Please Stay Cool
It is important to be aware of the health risks that higher temperatures can bring. Older adults and people with chronic medical conditions are particularly susceptible to hyperthermia and other heat-related illnesses. Knowing the signs and recognizing the dangers to avoid problems is essential. The National Institute on Aging (NIA), part of the National Institutes of Health, offers advice to help combat the dangers of hot weather.
Heat fatigue, heat syncope (sudden dizziness after prolonged exposure to the heat), heat cramps, heat exhaustion and heat stroke are forms of hyperthermia, which is caused by a failure of the body’s heat-regulating mechanisms to deal with a hot environment. The combination of individual lifestyle, general health, and high temperatures can increase older adults’ risk for heat-related problems. Lifestyle factors can include not drinking enough fluids, living in housing without air conditioning, lack of mobility and access to transportation, overdressing, visiting overcrowded places and not understanding how to respond to hot weather conditions. On hot and humid days, older people, particularly those with chronic medical conditions like heart disease and diabetes, should stay indoors in cooler spaces, especially during an air pollution alert. People without air conditioners should go to places that do have air conditioning, such as senior centers, shopping malls, movie theaters and libraries. Cooling centers, which may be set up by local public health agencies, religious groups and social service organizations in many communities, are another option.
There are many things that can increase risk for hyperthermia, including:
Dehydration; Age-related changes to the skin such as poor blood circulation and inefficient sweat production; use of multiple medications; reduced sweating caused by medications such as diuretics, sedatives, tranquilizers and certain heart and blood pressure drugs; high blood pressure or other health conditions that require changes in diet; people on salt-restricted diets may be at increased risk, however, salt pills should not be used without first consulting a doctor; heart, lung and kidney diseases, as well as any illness that causes general weakness or fever; being substantially overweight or underweight; and alcohol use.
Heat stroke is a life-threatening form of hyperthermia. It occurs when the body is overwhelmed by heat and unable to control its temperature. Signs and symptoms of heat stroke include a significant increase in body temperature (generally above 104 degrees Fahrenheit), mental status changes (like confusion or combativeness), strong rapid pulse, dry flushed skin, lack of sweating, feeling faint, staggering or coma. It is critical to seek immediate emergency medical attention for a person with heat stroke symptoms, especially an older adult.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.
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Impressive Immune System Discoveries
Maps of the lymphatic system: old (left) and updated to reflect UVA’s discovery.
Credit: University of Virginia Health System; ScienceDaily.com
In a discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the 1) ___ is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer’s disease to multiple sclerosis. Instead of asking, ‘How do we study the immune response of the brain?’ And, ‘Why do multiple sclerosis patients have the immune attacks?’ now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral 2) ___ through meningeal lymphatic vessels, said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG). It changes entirely the way we perceive the neuro-immune interaction. We always perceived it before as something esoteric that can’t be studied. But now we can ask mechanistic questions. We believe that for every neurological disease that has an immune component to it, these vessels may play a major role, Kipnis said. Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component.
New Discovery in Human Body
Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, described his reaction to the discovery by Kipnis’ lab: The first time these guys showed me the basic result, I just said one sentence: ?They’ll have to change the textbooks.’ There has never been a lymphatic system for the central 3) ___ system, and it was very clear from that first singular observation — and they’ve done many studies since then to bolster the finding — that it will fundamentally change the way people look at the central nervous system’s relationship with the immune system. Even Kipnis was skeptical initially. I really did not believe there are structures in the body that we are not aware of. I thought the body was mapped, he said. I thought that these discoveries ended somewhere around the middle of the last 4) ___. But apparently they have not. The discovery was made possible by the work of Antoine Louveau, PhD, a postdoctoral fellow in Kipnis’ lab. The vessels were detected after Louveau developed a method to mount a mouse’s meninges — the membranes covering the brain — on a single slide so that they could be examined as a whole. It was fairly easy, actually, he said. There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn’t have worked. After noticing vessel-like patterns in the distribution of immune 5) ___ on his slides, he tested for lymphatic vessels and there they were. The impossible existed. The soft-spoken Louveau recalled the moment: I called Jony [Kipnis] to the microscope and I said, ?I think we have something.’
As to how the brain’s lymphatic vessels managed to escape notice all this time, Kipnis described them as very well hidden and noted that they follow a major 6) ___ vessel down into the sinuses, an area difficult to image. It’s so close to the blood vessel, you just miss it, he said. If you don’t know what you’re after, you just miss it. Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris, Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the phenomenal surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study. The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. In Alzheimer’s, there are accumulations of big 7) ___ chunks in the brain, Kipnis said. We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels. He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.
Interesting Developments Based on the Initial Discovery
In a startling discovery (discussed above) that raises fundamental questions about human behavior, researchers at the University of Virginia School of Medicine have determined, based on their research last year, that the immune system directly affects — and even controls — creatures’ social behavior, such as their desire to interact with others. So could immune system problems contribute to an inability to have normal social interactions? The answer appears to be yes, and that finding could have great implications for neurological conditions such as autism-spectrum disorders and schizophrenia.
The brain and the adaptive immune system were thought to be isolated from each other, and any immune activity in the brain was perceived as sign of a pathology. And now, not only are we showing that they are closely interacting, but some of our behavior traits might have evolved because of our immune response to pathogens, explained Jonathan Kipnis, PhD, chairman of UVA’s Department of Neuroscience. It’s crazy, but maybe we are just multicellular battlefields for two ancient forces: pathogens and the immune system. Part of our personality may actually be dictated by the immune system.
Evolutionary Forces at Work
The follow-up finding is equally illuminating, shedding light on both the workings of the brain and on evolution itself. The relationship between people and pathogens, the researchers suggest, could have directly affected the development of our social behavior, allowing us to engage in the social interactions necessary for the survival of the species while developing ways for our immune systems to protect us from the diseases that accompany those interactions. Social behavior is, of course, in the interest of8) ___, as it allows them to spread. The UVA researchers have shown that a specific immune molecule, interferon gamma, seems to be critical for social behavior and that a variety of creatures, such as flies, zebrafish, mice and rats, activate interferon gamma responses when they are social. Normally, this molecule is produced by the immune system in response to bacteria, viruses or parasites. Blocking the molecule in mice using genetic modification made regions of the brain hyperactive, causing the mice to become less social. Restoring the molecule restored the brain connectivity and behavior to normal. In a paper outlining theirfindings, the researchers note the immune 9) ___ plays a profound role in maintaining proper social function.
It’s extremely critical for an organism to be social for the survival of the species. It’s important for foraging, sexual reproduction, gathering, hunting, said Anthony J. Filiano, PhD, Hartwell postdoctoral fellow in the Kipnis lab and lead author of the study. So the hypothesis is that when organisms come together, you have a higher propensity to spread infection. So you need to be social, but [in doing so] you have a higher chance of spreading pathogens. The idea is that interferon gamma, in evolution, has been used as a more efficient way to both boost social behavior while boosting an anti-pathogen response.
The researchers note that a malfunctioning immune system may be responsible for social deficits in numerous neurological and psychiatric disorders. But exactly what this might mean for autism and other specific conditions requires further investigation. It is unlikely that any one molecule will be responsible for disease or the key to a cure, the researchers believe; instead, the causes are likely to be much more complex. But the discovery that the immune system — and possibly germs, by extension — can control our interactions raises many exciting avenues for scientists to explore, both in terms of battling neurological disorders and understanding human 10) ___. Immune molecules are actually defining how the brain is functioning. So, what is the overall impact of the immune system on our brain development and function? Kipnis said. I think the philosophical aspects of this work are very interesting, but it also has potentially very important clinical implications. Kipnis and his team worked closely with UVA’s Department of Pharmacology and the group of Vladimir Litvak, PhD, at the University of Massachusetts Medical School. Litvak’s team developed a computational approach to investigate the complex dialogue between immune signaling and brain function in health and disease. Using this approach we predicted a role for interferon gamma, an important cytokine secreted by T lymphocytes, in promoting social brain functions, Litvak said. Our findings contribute to a deeper understanding of social dysfunction in neurological disorders, such as autism and schizophrenia, and may open new avenues for therapeutic approaches.
Source: University of Virginia School of Medicine; University of Massachusetts Medical School; NIH.gov; ScienceDaily.com
- Antoine Louveau, Igor Smirnov, Timothy J. Keyes, Jacob D. Eccles, Sherin J. Rouhani, J. David Peske, Noel C. Derecki, David Castle, James W. Mandell, Kevin S. Lee, Tajie H. Harris, Jonathan Kipnis. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015; DOI: 10.1038/nature14432
- The findings have been published online in the journal Nature. The article was written by Filiano, Yang Xu, Nicholas J. Tustison, Rachel L. Marsh, Wendy Baker, Igor Smirnov, Christopher C. Overall, Sachin P. Gadani, Stephen D. Turner, Zhiping Weng, Sayeda Najamussahar Peerzade, Hao Chen, Kevin S. Lee, Michael M. Scott, Mark P. Beenhakker, Litvak and Kipnis.
This work was supported by the National Institutes of Health (grants No. AG034113, NS081026 and T32-AI007496) and the Hartwell Foundation.
ANSWERS: 1) brain; 2) system; 3) nervous; 4) century; 5) cells; 6) blood; 7) protein; 8) pathogens; 9) molecule; 10) behavior
Emil Adolf von Behring MD: Antitoxins and Passive Serum Therapy
Emil Adolf von Behring MD (1854-1917)
Source: Public Domain, Wikimedia Commons.org
One of the most important pieces of evidence to support the earlier theory of antibodies came from Emil von Behring, who received the first-ever Nobel Prize in Medicine, in 1901. His Nobel Prize medal is now kept on display at the International Red Cross and Red Crescent Museum in Geneva.
Emil von Behring and his colleagues discovered in 1890 that animals, when injected with tiny, weakened doses of the bacteria that cause tetanus or diphtheria, produce chemicals in their blood that neutralize these microbes’ disease-causing toxins. Not only that, but von Behring established that transferring blood containing these antitoxin chemicals to other animals granted them immunity from the same disease. As opposed to ?active’ immunity, that is, the defense provided by a host’s immune system, receiving these antitoxins from another animal was said to provide ?passive immunity’. Taking this a stage further, von Behring showed that children injected with antitoxin-containing serum were cured of their diphtheria symptoms, and did not die of the disease. This was a hugely important discovery: the vaccines created by Jenner and Pasteur prevented diseases, but von Behring’s discoveries showed how a disease that had already taken hold could be cured. Von Behring was hailed as a savior of children and of soldiers, and the mass-produced form of his serum saved tens of thousands of lives every year in his native Germany alone. Unfortunately, this method of treatment – passive serum therapy – turned out to be useful for only a limited number of diseases. However, anyone who has ever received an anti-venom injection for snakebites has benefited directly from von Behring’s discoveries.
The achievements of von Behring, and of Metchnikov and Ehrlich, helped to establish a brand-new field of science called immunology, one that sought to explore the mysterious workings of the body’s inner defense mechanisms. And once anti-toxins had provided convincing experimental proof for Ehrlich’s antibodies, scientists rushed to investigate these toxin-neutralizing molecules in greater detail. Many diseases are caused by microorganisms, but the body can use its immune system to defend itself against attacks and become immune to new attacks. As part of its defenses, the immune system forms antibodies that neutralize poisons, or toxins, that are formed by bacteria. Emil von Behring and other researchers showed that by means of blood plasma, or serum, antibodies could be transferred from one person or animal to another person, who also then became immune. In 1900 Emil von Behring introduced serum from immune horses as a method to cure and prevent diphtheria.
Emil Adolf von Behring (15 March 1854 – 31 March 1917) was a German physiologist, born in Hansdorf, now Lawice, IIawa County, Poland. Between 1874 and 1878, he studied medicine at the Akademie fur das militararztliche Bildungswesen, Berlin. He was mainly a military doctor and then became Professor of Hygienics within the Faculty of Medicine at the University of Marburg (against the initial strenuous opposition of the faculty council), a position he would hold for the rest of his life. He and the pharmacologist Hans Horst Meyer had their laboratories in the same building, and Behring stimulated Meyer’s interest in the mode of action of tetanus toxin. Behring was the discoverer of diphtheria antitoxin in 1890 and attained a great reputation by that means and by his contributions to the study of immunity. He won the first Nobel Prize in Physiology or Medicine in 1901 for the development of serum therapies against diphtheria (which Kitasato Shibasaburo and Emile Roux also contributed to) and tetanus. Diphtheria had been a scourge of the population, especially children, whereas tetanus was a leading cause of death in wars, killing the wounded. He was elected a Foreign Honorary Member of the American Academy of Arts and Sciences in 1902. At the International Tuberculosis Congress in 1905 he announced that he had discovered a substance proceeding from the virus of tuberculosis. This substance, which he designated T C, plays the important part in the immunizing action of Professor Behring’s bovivaccine, which prevents bovine tuberculosis. He tried unsuccessfully to obtain a protective and therapeutic agent for humans. His diphtheria serum was developed by repeatedly injecting the deadly toxin into a horse. The serum was used effectively during an epidemic in Germany. A chemical company preparing to undertake commercial production and marketing of the diphtheria serum offered him a contract.
In December 1896, Behring married the then eighteen-year-old Else Spinola, who was a daughter of Bernhard Spinola, the director of the Charite hospital in Berlin, and a Jewish-born mother who had converted to Christianity upon her marriage. They had six sons. They held their honeymoon at villa Behring on Capri 1897, where Behring owned a vacation home. In 1909-1911, the Russian writer Maxim Gorky lived at this villa. Behring died at Marburg, Hessen-Nassau, on 31 March 1917. His name survived with: the Dade Behring, organization, at the time, the world’s largest company dedicated solely to clinical diagnostics, (now part of the Siemens Healthcare Division), in CSL Behring, a manufacturer of plasma-derived biotherapies, in Behringwerke AG in Marburg, in Novartis Behring and in the Emil von Behring Prize of the University of Marburg, the highest endowed medicine award in Germany.
Sources: Nobelprize.org; Wikipedia
Advances in Possible Treatments for Gaucher and Parkinson’s Diseases
Gaucher disease affects an estimated 1 in 50,000 to 1 in 100,000 people in the general population. People of Eastern and Central European (Ashkenazi) Jewish heritage are more likely to get Gaucher disease. Parkinson’s disease affects 1.5-2% of people over age 60, and the incidence increases with age. In the United States, about 60,000 new cases are identified each year. Parkinson’s disease affects more than 1 million people in North America and 7-10 million people worldwide.
Gaucher disease occurs when GBA1, the gene that codes for the protein glucocerebrosidase, is mutated. This protein normally helps cells dispose of certain fats (lipids), a type of waste produced by all cells. When a person inherits two mutated copies of GBA1, lipids accumulate and can cause symptoms such as enlargement of the spleen, frequent bleeding and bruising, weakened bones and, in the most severe cases, neurological disease. People with even one mutated copy of GBA1 are at higher risk of developing Parkinson’s disease, a common disorder characterized by tremors, muscular rigidity and slowed movements.
According to an article published on line (12 June 2016) in the Journal of Neuroscience, with assistance from a high tech robot known at Tox21, National Institutes of Health researchers have identified and tested a molecule that shows promise as a possible treatment for Gaucher disease and Parkinson’s disease.
To better understand the connection between Gaucher and Parkinson’s diseases, the authors used a labor-intensive technology to develop pluripotent stem cells (unspecialized cells that can develop into various specialized body cells). The stem cells were created in the lab from the skin cells of Gaucher patients with and without Parkinson’s disease. The stem cells were then converted into neurons that had features that were identical to those in people with Gaucher disease. Results showed that the neurons from Gaucher patients, who also had Parkinson’s disease, had elevated levels of alpha-synuclein. This is the protein that accumulates in the brains of people with Parkinson’s disease impacting neurons responsible for controlling movement.
The authors then looked for a molecule that would help patients with mutant GBA1 break down cellular waste. In a process known as high-throughput drug screening, the authors used the Tox21 robot to evaluate hundreds of thousands of different molecules. The authors identified a promising molecule, NCGC607which helps to chaperone the mutated protein so that it can still function. In the patients’ stem cell-derived neurons, NCGC607 reversed the lipid accumulation and lowered the amount of alpha-synuclein, suggesting a possible treatment strategy for Parkinson’s disease.
Daniel Kastner, M.D., Ph.D., NHGRI scientific director and director of the institute’s Division of Intramural Research said that This research constitutes a major advance as it demonstrates how insights from a rare disorder such as Gaucher disease can have direct relevance to the treatment of common disorders like Parkinson’s disease. the authors will next test the new molecule to see if it might be developed into an appropriate prototype drug for patients with Gaucher disease and Parkinson’s disease.
Brain Circuits that Help People Cope with Stress
People encounter stressful situations and stimuli everywhere, every day, and studies have shown that long-term stress can contribute to a broad array of health problems. However, some people cope with stress better than others, and scientists have long wondered why.
According to a study published online (19 July 2016) in the Proceedings of the National Academy of Sciences, brain patterns in humans have been identified that appear to underlie resilient coping. Resilient coping encompasses the healthy emotional and behavioral responses to stress that help some people handle stressful situations better than others.
In a study of human volunteers, the authors used a brain scanning technique called functional magnetic resonance imaging (fMRI) to measure localized changes in brain activation during stress. Study participants were given fMRI scans while exposed to highly threatening, violent and stressful images followed by neutral, non-stressful images for six minutes each. While conducting the scans, the authors also measured non-brain indicators of stress among study participants, such as heart rate, and levels of cortisol, a stress hormone, in blood.
The brain scans revealed a sequence of three distinct patterns of response to stress, compared to non-stress exposure. The first pattern was characterized by sustained activation of brain regions known to signal, monitor and process potential threats. The second response pattern involved increased activation, and then decreased activation, of a circuit connecting brain areas involved in stress reaction and adaptation, perhaps as a means of reducing the initial distress to a perceived threat. The third pattern helped predict those who would regain emotional and behavioral control to stress. This pattern involved what the authors described as neuroflexibility, in a circuit between the brain’s medial prefrontal cortex and forebrain regions including the ventral striatum, extended amygdala, and hippocampus during sustained stress exposure. The authors explained that this neuroflexibility was characterized by initially decreased activation of this circuit in response to stress, followed by its increased activation with sustained stress exposure. The authors noted that previous research has consistently shown that repeated and chronic stress damages the structure, connections, and functions of the brain’s prefrontal cortex. The prefrontal cortex is the seat of higher order functions such as language, social behavior, mood, and attention, and which also helps regulate emotions, and more primitive areas of the brain.
In the current study, the authors reported that participants who did not show the neuroflexibility response in the prefrontal cortex during stress had higher levels of self-reported binge drinking, anger outbursts, and other maladaptive coping behaviors. They hypothesize that such individuals might be at increased risk for alcohol use disorder or emotional dysfunction problems, which are hallmarks of chronic exposure to high levels of stress.
FDA Approves First Intraocular Lens with Extended Range of Vision for Cataract Patients
Cataracts are a common eye condition where the natural lens becomes clouded, impairing a patient’s vision. According to the National Eye Institute, more than 20% of Americans will have cataracts by the age of 65, and the prevalence increases with age. In cataract surgery, the clouded natural lens is removed and replaced with an intraocular lens (IOL).
The FDA has approved the first IOL that provides cataract patients with an extended depth-of-focus, which helps improve their sharpness of vision (visual acuity) at near, intermediate and far distances. Traditional monofocal IOLs have been limited to improving distance vision. The Tecnis Symfony IOL improves visual acuity at close, intermediate and far ranges and, therefore, may reduce the need for patients to wear contact lenses or glasses after cataract surgery.
The approval is based on a review of results from a randomized clinical trial comparing 148 cataract patients implanted with the Tecnis Symfony IOL to 151 cataract patients implanted with a monofocal IOL. The study evaluated visual acuity at near, intermediate and far ranges; contrast sensitivity (the ability to distinguish small differences between light and dark); and adverse events for six months after implantation. Of the patients implanted with the Tecnis Symfony IOL, 77% had good vision (20/25), without glasses at intermediate distances, compared to 34% of those with the monofocal IOL. For near distances, patients with the Tecnis Symfony IOL were able to read two additional, progressively smaller lines on a standard eye chart than those with the monofocal IOL. Both sets of patients had comparable results for good distance vision.
Patients implanted with the Tecnis Symfony IOL may experience worsening of or blurred vision, bleeding or infection. The device may also cause reduced contrast sensitivity that becomes worse under poor visibility conditions such as dim light or fog. Some patients may experience visual halos, glare or starbursts. The device is not intended for use on patients who have had previous trauma to their eye.
The Tecnis Symfony Extended Range of Vision IOL, manufactured by Abbott Medical Optics, Inc. of Santa Ana, California, and is also available in four toric models, which are indicated for the reduction of residual refractive astigmatism or imperfections in the curvature of the eye.
Perfect Summer Slaw: Carrots, Cilantro, Dill, Honey, Lime, Toasted Mustard Seeds, Raisins, Peanuts
Tossed with raisins. ©Joyce Hays, Target Health Inc.
Tossed without raisins. ©Joyce Hays, Target Health Inc.
Zest of 1/2 a fresh lime
Juice of 1/2 fresh lime
2.5 cups unsalted pre-roasted peanuts
1/2 to 1 cup raisins (optional)
4 cloves garlic, minced
2 Tablespoons white vinegar, more later, to your taste
3 Tablespoons rice wine vinegar, more later, to your taste
1 Tablespoon honey
2 Tablespoon toasted sesame oil
1/2 cup black mustard seeds, toasted
Pinch chili flakes
Pinch Kosher salt
Pinch black pepper
1 ? to 2 pounds carrots, scrubbed, then peeled julienne,
lengthwise into long thin strands.
1 cup tightly packed cilantro leaves, very finely chopped
1 cup fresh dill, very finely chopped
These ingredients will hold up in warmer weather. Besides, this is a very tasty summer slaw. ©Joyce Hays, Target Health Inc.
Toast the black mustard seeds, then set aside.
Here, I’m toasting black mustard seeds with enough sesame seeds for this salad and another recipe I’m working on at the same time. ©Joyce Hays, Target Health Inc.
Make the carrot strands: Scrub, then julienne all the carrots. Swipe the julienne peeler from the thick end of carrot, to tip of carrots, to make long thin strips. Make the strips as thin as you can. If you don’t have one, a julienne peeler, is a good investment for your kitchen, to make the thin strands of any veggie.
Scrub, then julienne all the carrots. ©Joyce Hays, Target Health Inc.
In a wooden salad serving bowl, mash the garlic with a fork, until it looks like a paste. Add the two types of vinegar, honey, sesame oil, sesame (optional) & black mustard seeds, chili flakes, pinch black pepper and pinch salt. Combine all of these dressing ingredients together, well.
Chop everything that needs chopping at the same time, on the same board. This is the cilantro & dill. ©Joyce Hays, Target Health Inc.
Mashing the garlic with a fork. ©Joyce Hays, Target Health Inc.
Add the finely chopped cilantro & finely chopped dill, to the dressing in the wooden salad bowl and toss again to distribute the herbs well.
Everything except the carrots has been added to salad bowl. ©Joyce Hays, Target Health Inc.
Finally, add all of the carrot strips and toss once again, until each carrot strand is completely coated with dressing.
Add the unsalted, pre-roasted peanuts, half and whole pieces. I’ve experimented with different sizes of peanut in this recipe. Leaving them in halves and whole, works the best for this particular salad. No need to chop them at all.
Finally, add the raisins and toss. Add 1/2 cup, 1 cup or more. It’s your taste that counts.
This is such a delicious salad and perfect for summer weather. It’s easy to make and left-overs store well. This slaw is packed with vitamins and minerals, so on a warm evening, you might just want to have it for the whole meal, along with an icy drink and rolls warmed up in a toaster oven or microwave.
We have been experimenting with lighter cooler drinks this summer and one of these is the effervescent Sofia Blanc de Blanc, tasting of fresh juicy pears, melon and honeysuckle. Zesty, cool and fun, as you see above. This light fizzy wine comes from the vineyards of director Francis Ford Coppola.
Next week the heat wave continues so try to stay cool. Walk, don’t run, drink lots of icy water all day, and do your best to avoid stressful situations.
From Our Table to Yours !
July 21, 2016
University of Pennsylvania
Scientists have mathematically modeled the coevolutionary processes that describe how antibodies and viruses interact and adapt to one another over the course of a chronic infection, such as HIV/AIDS.
It has remained frustratingly difficult to develop a vaccine for HIV/AIDS, in part because the virus, once in our bodies, rapidly reproduces and evolves to escape being killed by the immune system.
“The viruses are constantly producing mutants that evade detection,” said Joshua Plotkin, a professor in the University of Pennsylvania’s Department of Biology in the School of Arts & Sciences. “A single person with HIV may have millions of strains of the virus circulating in the body.”
Yet the body’s immune system can also evolve. Antibody-secreting B-cells compete among themselves to survive and proliferate depending on how well they bind to foreign invaders. They dynamically produce diverse types of antibodies during the course of an infection.
In a new paper in PLOS Genetics, Plotkin, along with postdoctoral researcher Jakub Otwinowski and Princeton University research scholar Armita Nourmohammad, mathematically modeled these dueling evolutionary processes to understand the conditions that influence how antibodies and viruses interact and adapt to one another over the course of a chronic infection.
Notably, the researchers considered the conditions under which the immune system gives rise to broadly neutralizing antibodies, which can defeat broad swaths of viral strains by targeting the most vital and immutable parts of the viral genome. Their findings, which suggest that presenting the immune system with a large diversity of viral antigens may be the best way to encourage the emergence of such potent antibodies, have implications for designing vaccines against HIV and other chronic infections.
“This isn’t a prescription for how to design an HIV vaccine,” Plotkin said, “but our work provides some quantitative guidance for how to prompt the immune system to elicit broadly neutralizing antibodies.”
The biggest challenge in attempting to model the co-evolution of antibodies and viruses is keeping track of the vast quantity of different genomic sequences that arise in each population during the course of an infection. So the researchers focused on the statistics of the binding interactions between the virus and antibodies.
“This is the key analytical trick to simplify the problem,” said Otwinowski. “It would otherwise be impossible to track and write equations for all the interactions.”
The researchers constructed a model to examine how mutations would affect the binding affinity between antibodies and viruses. Their model calculated the average binding affinities between the entire population of viral strains and the repertoire of antibodies over time to understand how they co-evolve.
“It’s one of the things that is unique about our work,” said Nourmohammad. “We’re not only looking at one virus binding to one antibody but the whole diversity of interactions that occur over the course of a chronic infection.”
What they saw was an S-shaped curve, in which sometimes the immune system appeared to control the infection with high levels of binding, but subsequently a viral mutation would arise that could evade neutralization, and then binding affinities would go down.
“The immune system does well if there is active binding between antibodies and virus,” Plotkin said, “and the virus does well if there is not strong binding.”
Such a signature is indicative of a system that is out of equilibrium where the viruses are responding to the antibodies and vice versa. The researchers note that this signature is likely common to many antagonistically co-evolving populations.
To see how well their model matched with data from an actual infection, the researchers looked at time-shifted experimental data from two HIV patients, in which their antibodies were collected at different time points and then “competed” against the viruses that had been in their bodies at different times during their infections.
They saw that these patient data are consistent with their model: Viruses from earlier time points would be largely neutralized by antibodies collected at later time points but could outcompete antibodies collected earlier in infection.
Finally, the researchers used the model to try to understand the conditions under which broadly neutralizing antibodies, which could defeat most strains of virus, would emerge and rise to prominence.
“Despite the effectiveness of broadly neutralizing antibodies, none of the patients with these antibodies has been cured of HIV,” Plotkin said. “It’s just that by the time they develop them, it’s too late and their T-cell repertoire is depleted. This raises the intriguing idea that, if only they could develop these antibodies earlier in infection, they might be prepared to combat an evolving target.”
“The model that we built,” Nourmohammad said, “was able to show that, if viral diversity is very large, the chance that these broadly neutralizing antibodies outcompete more specifically targeted antibodies and proliferate goes up.”
The finding suggests that, in order for a vaccine to elicit these antibodies, it should present a diverse set of viral antigens to the host. That way no one specialist antibody would have a significant fitness advantage, leaving room for the generalist, broadly neutralizing antibodies to succeed.
The researchers said that there has been little theoretical modeling of co-evolutionary systems such as this one. As such, their work could have implications for other co-evolution scenarios.
“Our theory can also apply to other systems, such as bacteria-phage co-evolution,” said Otwinowski, in which viruses infect bacteria, a process that drives bacterial evolution and ecology.
“It could also shed light on the co-evolution of the influenza virus in the context of evolving global immune systems,” Nourmohammad said.
The work was supported by funding from the U.S. National Science Foundation, James S. McDonnell Foundation, David and Lucile Packard Foundation, U.S. Army Research Office and U.S. Department of the Interior.
- Armita Nourmohammad, Jakub Otwinowski, Joshua B. Plotkin. Host-Pathogen Coevolution and the Emergence of Broadly Neutralizing Antibodies in Chronic Infections. PLOS Genetics, 2016; 12 (7): e1006171 DOI: 10.1371/journal.pgen.1006171
Source: University of Pennsylvania. “How the immune system might evolve to conquer HIV.” ScienceDaily. ScienceDaily, 21 July 2016. <www.sciencedaily.com/releases/2016/07/160721180333.htm>.