Nature-inspired synthetic membranes could aid water purification, energy, and healthcare needs
July 19, 2016
DOE/Pacific Northwest National Laboratory
Materials scientists have created a new material that performs like a cell membrane found in nature. Such a material has long been sought for applications as varied as water purification and drug delivery. The material can assemble itself into a sheet thinner but stabler than a soap bubble, the researchers report.
Materials scientists have created a new material that performs like a cell membrane found in nature. Such a material has long been sought for applications as varied as water purification and drug delivery.
Referred to as a lipid-like peptoid (we’ll unpack that in a second), the material can assemble itself into a sheet thinner, but more stable, than a soap bubble, the researchers report July 12 in Nature Communications. The assembled sheet can withstand being submerged in a variety of liquids and can even repair itself after damage.
“Nature is very smart. Researchers are trying to make biomimetic membranes that are stable and have certain desired properties of cell membranes,” said chemist Chun-Long Chen at the Department of Energy’s Pacific Northwest National Laboratory. “We believe these materials have potential in water filters, sensors, drug delivery and especially fuel cells or other energy applications.”
The amazing membrane
Cell membranes are amazing materials. Made from thin sheets of fatty molecules called lipids, they are at least ten times thinner than an iridescent soap bubble and yet allow cells to collectively form organisms as diverse at bacteria, trees and people.
Cell membranes are very selective about what they let pass through, using tiny embedded proteins as gatekeepers. Membranes repair dings to their structure automatically and change thickness to pass signals from the outside environment to the cell’s interior, where most of the action is.
Scientists would like to take advantage of membrane properties such as gatekeeping to make filters or signaling to make sensors. A cell-membrane-like material would have advantages over other thin materials such as graphene. For example, mimicking a cell membrane’s efficient gatekeeping could result in water purifying membranes that don’t require a lot of pressure or energy to push the water through.
Synthetic molecules called peptoids have caught the interest of researchers because they are cheap, versatile and customizable. They are like natural proteins, including those that embed themselves in cell membranes, and can be designed to have very specific forms and functions. So Chen and colleagues decided to see if they could design peptoids to make them more lipid-like.
Lipid molecules are long and mostly straight: They have a fatty end that prefers to hang out with other fats, and a water-like end that prefers the comfort of water. Because of this chemistry, lipid molecules arrange themselves with the fatty ends pointed toward each other, sandwiched between the water-loving ends pointed out. Scientists call this a lipid bilayer, essentially a sheet that envelops the contents of a cell. Proteins or carbohydrate molecules embed themselves in the membranous sheet.
Inspired by this, Chen and colleagues designed peptoids in which each base peptoid was a long molecule with one end water-loving and the other end fat-loving. They chose chemical features that they hoped would encourage the individual molecules to pack together. They examined the resulting structures using a variety of analysis methods, including some at the Advanced Light Source and the Molecular Foundry, two DOE Office of Science User Facilities at Lawrence Berkeley National Laboratory.
The team found that after putting the lipid-like peptoids into a liquid solution, the molecules spontaneously crystallized and formed what the scientists call nanomembranes — straight-edged sheets as thin as cell membranes — floating in the beaker. These nanomembranes maintained their structure in water or alcohol, at different temperatures, in solutions with high or low pH, or high concentrations of salts, a feat that few cell membranes could accomplish.
A view from the middle
To better understand the nanomembranes, the team simulated how single peptoid molecules interacted with each other using molecular dynamics software. The simulated peptoids formed a membrane reminiscent of a lipid bilayer: The fat-loving ends lined up in the middle, and their water-loving ends pointed outward either above or below.
To test whether their synthetic membranes had the signaling ability of cell membranes, the researchers added a touch of sodium chloride salt. Salt is involved in the last step in many signaling sequences and causes real cell membranes to thicken up. And thicken up the peptoids did. The more salt the researchers added, the thicker the nanomembranes became, reaching about 125 percent of their original thickness in the range of salt concentrations they tested.
Real membranes also hold proteins that have specific functions, such as ones that let water, and only water, through. Chen’s group tested the ability of peptoids to do so by introducing a variety of side chains. Side chains are essentially small molecules of different shapes, sizes and chemical natures attached to the longer lipid-like peptoids. They tried 10 different designs. In each case, the peptoids assembled into the nanomembranes with the core structure remaining intact. The team could also build a carbohydrate into nanomembranes, showing the material can be designed to have versatile functions.
The team then tested the nanomembranes to see if they could repair themselves, a useful feature for membranes that could get scratched during use. After cutting slits in a membrane, they added more of the lipid-like peptoid. Viewed under a microscope over the course of a few hours, the scratches filled up with more peptoid and the nanomembrane became complete again. (Compare this to cuts in paper, which don’t spontaneously repair themselves even after being taped up.)
Taken together, the results showed the researchers that they are on the right path to making synthetic cell membrane-like materials. However, there are still some challenges to be addressed for applications. For example, the researchers would like to better understand how the membranes form so they can make many desirable sizes.
The next step, Chen said, is to build biomimetic membranes by incorporating natural membrane proteins or other synthetic water channels such as carbon nanotubes into these sheet matrices. The team is also looking into ways to make the peptoid membranes conductive for energy uses.
This work was supported by the Department of Energy Office of Science and PNNL.
- Haibao Jin, Fang Jiao, Michael D. Daily, Yulin Chen, Feng Yan, Yan-Huai Ding, Xin Zhang, Ellen J. Robertson, Marcel D. Baer, Chun-Long Chen.Highly stable and self-repairing membrane-mimetic 2D nanomaterials assembled from lipid-like peptoids. Nature Communications, 2016; 7: 12252 DOI: 10.1038/ncomms12252
Source: DOE/Pacific Northwest National Laboratory. “Scientists create new thin material that mimics cell membranes: Nature-inspired synthetic membranes could aid water purification, energy, and healthcare needs.” ScienceDaily. ScienceDaily, 19 July 2016. <www.sciencedaily.com/releases/2016/07/160719144728.htm>.
New research on HIV worldwide raises ‘significant challenges’ to ending the AIDS pandemic, despite progress in lowering AIDS mortality
July 19, 2016
Institute for Health Metrics and Evaluation
A new study found that 74 countries saw increases in age-standardized rates of new infections between 2005 and 2015.
AIDS deaths are falling in most countries worldwide, but the rate of new infections increased in several countries over the past decade, threatening to undermine efforts to end the AIDS epidemic by 2030, a new scientific paper shows.
The study from the Global Burden of Disease collaborative network, published today in The Lancet HIV, found that 74 countries saw increases in age-standardized rates of new infections between 2005 and 2015, including Egypt, Pakistan, Kenya, the Philippines, Cambodia, Mexico, and Russia.
The new research, released at the International AIDS Conference in Durban, South Africa, also found that while the global number of new cases continues to decline, the pace has greatly slowed. New infections of HIV fell by an average of only 0.7% per year between 2005 and 2015, compared to the 2.7% drop per year between 1997 and 2005.
The study is based on findings from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) coordinated by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington in Seattle. With more than 1,700 collaborators in 124 countries, the GBD is the largest and most comprehensive effort measuring epidemiological levels and trends worldwide.
“If this trend of stubbornly high new infections continues, there will be significant challenges in meeting the UN’s Sustainable Development Goal for the world to witness the end of AIDS in less than 15 years,” said IHME Director Dr. Christopher Murray. “Everyone in population health — researchers, policymakers, practitioners, pharmaceutical companies, advocates, and others — needs to understand that even if more people are living with HIV, we cannot end AIDS without stopping new infections.”
Professor Peter Piot, who is the director of the London School of Hygiene and Tropical Medicine and was the founding executive director of UNAIDS, also remarked on the paper’s findings.
“This study shows that the AIDS epidemic is not over by any means and that HIV/AIDS remains one of the biggest public health threats of our time,” Professor Piot said. “The continuing high rate of over 2 million new HIV infections represents a collective failure which must be addressed through intensified prevention efforts and continued investment in HIV vaccine research.”
The study examines HIV mortality, prevalence, and incidence between 1980 and 2015, and is part of the Global Burden of Disease Study 2015, which provides comprehensive population health estimates on disease, injuries, and related risk factors.
In contrast to the overall slow decline in new infections, the number of people living with HIV has significantly increased globally, largely due to the expansion of antiretroviral therapy (ART). IHME estimates there were about 39 million people globally living with HIV in 2015, as compared to 28 million in 2000.
In 2015, 41% of the people living with HIV were using ART, as compared to less than 2% in 2000.
“We’re keeping people alive longer, and these numbers should give those using antiretroviral therapies considerable hope,” said IHME Associate Professor Dr. Haidong Wang, the lead author on the study. Such improvement, however, is still far away from the ambitious 90-90-90 goals set by the global community for the year 2020. Those goals aim for 90% of people living with HIV knowing their HIV status, 90% of people diagnosed with HIV receiving antiretroviral therapy, and 90% of people receiving antiretroviral therapy experiencing viral suppression.
Interestingly, use of ART is different between men and women. On average, global ART use is 10% higher among women living with HIV, and in some sub-Saharan nations in 2015, it is 50% higher. However, in some Eastern European and South Asian nations, the percentage of men using ART is as much as 50% higher than women.
“The Global Burden of Disease HIV study provides critical health information to help shape and support national and global decision-making,” said Peter Hayward, editor of The Lancet HIV. “The estimates are also key to strengthening accountability to ensure that promises made by politicians and policymakers with regard to specific HIV targets are being delivered.”
In regard to mortality, women tend to die at younger ages from HIV than men, likely due to age-disparate relationships in which men have sex with younger women. In total, approximately 1.2 million people died from HIV in 2015, down from a peak of 1.8 million in 2005.
The results of IHME’s study underscore the need for more effective efforts to prevent new infections, as well as additional funding for these efforts. This analysis shows that development assistance for health (DAH) dedicated to HIV/AIDS grew fastest between 2000 and 2009, yet such funding has stagnated since 2010. According to Financing Global Health 2015, a report published in April by IHME, annual funding globally for HIV/AIDS peaked at US$11.2 billion in 2013, but dropped to US$10.8 billion in 2015. With slowdown in the decline of new infections and in funding for HIV/AIDS, it will be challenging to achieve the goal set by the global community to end AIDS by 2030.
- Haidong Wang et al. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2015: the Global Burden of Disease Study 2015. The Lancet HIV, 2016; DOI:10.1016/S2352-3018(16)30087-X
Source: Institute for Health Metrics and Evaluation. “Rate of new HIV infections increased in 74 countries over past decade: New research on HIV worldwide raises ‘significant challenges’ to ending the AIDS pandemic, despite progress in lowering AIDS mortality.” ScienceDaily. ScienceDaily, 19 July 2016. <www.sciencedaily.com/releases/2016/07/160719091639.htm>.
July 18, 2016
Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research
Scientists have overcome a seeming weakness of global climate models. They had previously not been able to simulate the extreme warm period of the Eocene.
Scientists from the Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research (AWI) have overcome a seeming weakness of global climate models. They had previously not been able to simulate the extreme warm period of the Eocene. One aspect of this era that particularly draws interests to climatologists: It was the only phase in recent history when greenhouse gas concentration was as high as researchers predict it to be for the future. The AWI scientists have now found that the apparent model weakness is due to a misinterpretation of the temperature indicator TEX86. These molecules, which are produced by archaea do not record the surface temperature of the ancient ocean as expected, but rather the temperature of water depths up to 500 metres. In the current issue of the journal Nature Geoscience, the scientists report on this new finding which has now made it possible to correctly simulate the temperature distribution of the Eocene in climate models.
Climate scientists often hear the same complaint: How can climate models accurately predict the future of our planet if it is not even possible to correctly reproduce the climate of the past? One of the unsolved problems was that all previous attempts to simulate the extreme temperatures of the Eocene with climate models failed.
At that time, 49 to 55 million years ago, the carbon dioxide content of the air was likely more than 1000 ppm (parts per million) — i.e. at least two times the current greenhouse gas concentration. The earth warmed up so strongly that the icesheets on Greenland and Antarctica disappeared. Instead of ice crystals, palm trees grew there. “Until recently, we believed that the sea surface temperature near the North Pole at the time was 23 degrees Celsius; in Antarctica, it was believed to have been more than 30 degrees Celsius,” says Dr Thomas Laepple, climate researcher at the AWI Potsdam.
These temperature estimates were based on data from the climate indicator TEX86. This abbreviation stands for a ratio of specific organic compounds produced by archaea, depending on the water temperature in which they lived. “Archaea are unicellular organisms that can in part withstand surprisingly high ambient temperatures. The molecules of the organisms that were living at that time are still preserved in the sedimentary layers of the seafloor. They are one of our most important archives for warm climate conditions, but as we have seen, we decoded them wrongly in the past,” says Thomas Laepple.
He and his AWI colleague at the time, Sze Ling Ho, first had doubts about the interpretation of the TEX86 temperature indicator during a comparison of climate data from the most recent ice age. The scientists noticed that the TEX86 temperatures were far too cold compared to other geological evidence. “The discrepancy was so obvious that we started to review the TEX86 values of around 3,000 sediment samples from different ocean basins and from different epochs of the Earth. It soon became apparent that the average temperature change inferred from TEX86 was exaggerated, always and on all time scales, by one and a half to two times. The temperature it showed for cold periods was much too cold and the one for warm periods was much too warm,” explains geochemist Sze Ling Ho.
The cause of this pattern had to be of a fundamental nature, a suspicion that was confirmed upon closer analysis. “TEX86 had previously been interpreted as an indicator of sea surface temperature, in spite the fact that the archaea that produce TEX86 rarely directly live at the sea surface. Through the comparison with other climate archives, we have been able to constrain the depth in which the TEX86 signal is produced. We now assume that TEX86 represents the water temperature at a depth of up to 500 metres,” Sze Ling Ho explains.
At this water depth, the temperature difference between the tropical oceans and the polar seas is smaller than at the surface. This has direct consequences for climate reconstruction, since the information generated from the indicator is differently translated into temperature values. “In practice, the TEX86 extreme values need to be roughly halved in the climate reconstructions. Comparing the corrected temperatures with the models shows that they now reflect the climate of the Eocene in a realistic and physically consistent way,” explains Thomas Laepple.
However, we also have to correct our temperature-conception of the Eocene. Thomas Laepple: “The era remains the warmest period of the past 65 million years. The water temperatures that we assumed for the Arctic and Antarctica, though, were overstated by at least ten degrees Celsius. Now, we know that the water in the Southern Ocean had a temperature of about 20 to 25 degrees Celsius at that time. The region was therefore still warm enough for there to be palm trees sprouting on the beach.”
The above post is reprinted from materials provided by Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research. Note: Materials may be edited for content and length.
- Sze Ling Ho, Thomas Laepple. Flat meridional temperature gradient in the early Eocene in the subsurface rather than surface ocean.Nature Geoscience, 2016; DOI: 10.1038/NGEO2763
Source: Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research. “Long-awaited breakthrough in the reconstruction of warm climate phases.” ScienceDaily. ScienceDaily, 18 July 2016. <www.sciencedaily.com/releases/2016/07/160718133009.htm>.
We Measure Our Success by the Success of Our Clients
Target Health was established as a full-service eCRO in 1993 with a culture of Our Clients First. Two of our mottos are and Better to be Smart than Sorry and The Harder We Work, the Luckier We Get.
There are 3 main stakeholders in a business, 1) customers; 2) employees and 3) shareholders. It is the opinion of Target Health and many others, that without customers there is no need for employees and without customers and employees, there is no need for shareholders. Thus are the priorities of our company. With this approach we now represent 46 companies at FDA, have over 40 products on the market and currently have 2 NDA’s under review.
Giant Thunderstorm Hits NYC on 14 July 2016
A sporadic thunderstorm quickly blew through New York City this past Thursday. As quickly as the storm arrived, it left and then the sun came out. Here is the view from the 24th floor at 261 Madison. The Empire Stet Building is on the left. The brighter buildings are the result of a lightening flash.
View From the 24th Floor During a Massive Thunderstorm. ©Target Health Inc.
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Joyce Hays, Founder and Editor in Chief of On Target
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The Endocannabinoid System
The ECS or Endocannabinoid system, is a unique and ubiquitous cell-signaling system that is just beginning to be understood. The biochemistry of EC synthesis, metabolism, and bioactivity has been difficult to study in the past. Newer techniques such as genetically modified animals, pharmacologic probes, and molecular biology promise to reveal some of these mysteries in the future. The greater promise is that with this understanding, the ECS will yield an important therapeutic target for future pharmacologic therapy.
Pharmacologic 1) ___ is approved and available today world-wide. THC and cannabidiol (which together make up the drug Sativex) are active components of Cannabis sativa that bind to CB1-R and CB2-R receptors. A buccal spray is approved for use for neuropathic pain associated with multiple sclerosis in Canada only. Dronabinol (Marinol), a synthetic THC, is a CB1-R and CB2-R receptor agonist that has been approved by the FDA for use as an antiemetic for chemotherapy and an appetite stimulant for persons with acquired immunodeficiency syndrome (AIDS). Its bioavailability is 10%. Nabilone (Cesamet) is a synthetic analogue of THC; it is a CB1-R and CB2-R receptor agonist that has been FDA approved as an antiemetic in chemotherapy patients in whom all other therapy has failed. Unapproved use is employed in patients with upper motor neuron syndrome who have spasticity-related pain not controlled by conventional treatment.
CB1-R receptor antagonists:
CB1-R receptors activate the dopaminergic reward 2) ___. Commonly abused drugs, such as nicotine, opiates, THC, and alcohol, share a common pathway, the dopaminergic surge in the nucleus accumbens. Independent studies involving humans and mice, respectively, reported an increase in smoking cessation rates, decreased alcohol intake, and a reduction in cocaine-seeking behavior with CB1-R antagonism. Rimonabant (Acomplia or Zimulti) is a selective CB1-R receptor antagonist, SR141716, with an affinity to centrally acting CB1-R receptors. Rimonabant was sold in Europe for the treatment of obesity. It was not approved in the United States and later withdrawn because of psychiatric effects, especially depression. Nevertheless, the ECS is a ubiquitous regulator of cellular function in both health and diseases, which offers many potential therapeutic targets. Below is a list of ECS agonist and antagonist intervention with therapeutic potential. Potential therapeutic targets for cannabinoid pharmacologic intervention are as follows:
Neurologic diseases: Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, alcohol-induced neuroinflammation/neurodegeneration, traumatic brain injury, stroke, seizures
Autoimmune diseases: Autoimmune uveitis, systemic sclerosis, inflammatory bowel disease
Infection: HIV-1 brain infection
Psychiatric disorders: Anxiety-related disorders, impulsivity, bipolar disorder, personality disorders, attention-deficit/hyperactivity disorder, substance abuse and addictive disorders, anorexia nervosa
Gastrointestinal: Gut motility disorders, inflammatory bowel syndrome, chronic liver diseases, alcoholic liver disease
Cancer: Breast, prostate, skin, pancreatic, colon, and lymphatic, among others
Multiple human and animal studies support that endocannabinoids play a key role in memory, mood, brain reward systems, drug addiction, and metabolic processes, such as lipolysis, glucose 3) ___, and energy balance. Cannabidiol, or CBD, is a cannabinoid which has recently emerged from the looming shadow of its more famous cousin, tetrahydrocannabinol, or THC. The recent history of medical cannabis is one that is increasingly focused on CBD, as research is finding that it may have potential therapeutic use for several ailments. In addition, CBD, unlike THC, does not have psychotropic effects, meaning there is no highassociated with its consumption.
The endocannabinoid system (ECS) is a group of endogenous cannabinoid receptors located in the mammalian 4) ___ and throughout the central and peripheral nervous systems, consisting of neuromodulatory lipids and their receptors. Known as “the body’s own cannabinoid system”, the ECS is involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory, and in mediating the psychoactive effects of cannabis. Two primary endocannabinoid receptors have been identified: CB1, first cloned in 1990; and CB2, cloned in 1993. CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), Anandamide, as well as its mimetic phytocannabinoid, THC. One other main endocannabinoid is 2-Arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD. 2-AG and CBD are involved in the regulation of appetite, immune system functions and 5) ___ management.
The endocannabinoid system, broadly speaking, includes:
The endogenous arachidonate-based lipids, anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG); these are known as “endocannabinoidsand are physiological ligands for the cannabinoid receptors. Endocannabinoids are all eicosanoids.
The enzymes that synthesize and degrade the endocannabinoids, such as fatty acid amide hydrolase or monoacylglycerol lipase.
The cannabinoid receptors CB1 and CB2, two G protein-coupled receptors that are located in the central and peripheral nervous systems.
The neurons, neural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all colocalized form the endocannabinoid system.
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators for a variety of processes, including motor learning, appetite, and pain sensation, among other cognitive and physical processes. The localization of the CB1 receptor in the endocannabinoid system has a very large degree of overlap with the orexinergic projection system, which mediates many of the same functions, both physical and 6) ___. Moreover, CB1 is colocalized on orexin projection neurons in the lateral hypothalamus and many output structures of the orexin system, where the CB1 and orexin receptor 1 (OX1) receptors physically and functionally join together to form the CB1-OX1 receptor heterodimer. For more details on receptor localization, see Cannabinoid receptor type 1 (CB1) and Cannabinoid receptor type 2 (CB2).
Cannabinoid binding sites exist throughout the 7) ___ central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2receptors, which are expressed predominantly in the brain and immune system respectively. Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement. In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans. A recent analysis of cannabinoid binding in CB1 and CB2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain. Binding has been demonstrated by 2-arachidonoylglycerol (2-AG) on theTRPV1 receptor suggesting that this receptor may be a candidate for the established response. During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium. Evidence suggests that the depolarization-induced influx of 8) ___ calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). The synthesis of 2-AG is less established and warrants further research.
Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol. While arachidonic acid is a substrate for leukotriene and prostaglandinsynthesis, it is unclear whether this degradative byproduct has unique functions in the central nervous system. Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake. A neuropharmacological study demonstrated that an inhibitor of FAAH (URB597) selectively increases anandamide levels in the brain of rodents and primates. Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability.
Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms. Interestingly, some disorders seem to trigger an upregulation of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where receptors are increased in the spinal 9) ___ cord microglia, dorsal root ganglion, and thalamic neurons.
Historical records from ancient China and Greece suggest that preparations of Cannabis indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans. Due to increasing use of medical Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief. In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum. Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease. These studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function.
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB1 receptor is expressed presynaptically by motor neurons that innervate visceral organs. The endocannabinoid most researched in pain is palmitoylethanolamide. Endocannabinoids are involved in placebo induced analgesia responses. Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects. Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep. Administration of anandamide into the basal forebrain of rats has also been shown to increase levels of adenosine, which plays a role in promoting 10) ___sleep and suppressing arousal. REM sleep deprivation in rats has been demonstrated to increase CB1 receptor expression in the central nervous system. Furthermore, anandamide levels possess a circadian rhythm in the rat, with levels being higher in the light phase of the day, which is when rats are usually asleep or less active, since they are nocturnal.
Below are links to original research currently being carried out around the world into CBD’s medical potential.
Cancer: Cannabidiol as potential anticancer drug
Cancer: Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol
Epilepsy: Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders
Schizophrenia: Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
Stress: The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system
ANSWERS: 1) therapy; 2) system; 3) metabolism; 4) brain; 5) pain; 6) cognitive; 7) central; 8) calcium; 9) cord; 10) sleep
Dr. Raphael Mechoulam (1930 to Present)
Professor Raphael Mechoulam – Source: commons.wikimedia.org/w/index.php?curid=976850
Raphael Mechoulam is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel. Mechoulam is best known for his work (together with Y. Gaoni) in the isolation, structure elucidation and total synthesis of delta 9-tetrahydrocannabinol, the main active principle of cannabis and for the isolation and the identification of the endogenous cannabinoids anandamide from the brain and 2-arachidonoyl glycerol (2-AG) from peripheral organs
Raphael Mechoulam was born in Sofia, Bulgaria on November 5, 1930 to a Sephardic Jewish family. His father was a physician and head of a local hospital, while his mother who had studied in Berlin, enjoyed the life of a well-to-do Jewish family. He attended an American Grade School until his parents were forced to leave their hometown because of anti-semitic laws. His father was subsequently sent to a concentration camp, from which he survived. After the communist takeover of then pro-German Bulgaria in 1944, he studied chemical engineering, which he disliked. In 1949 his family immigrated to Israel where he later studied chemistry. He gained his first research experience in the Israeli Army working on insecticides. Mechoulam received his M.Sc. in biochemistry from the Hebrew University of Jerusalem (1952), and his Ph.D. at the Weizmann Institute, Re?ovot (1958), with a thesis on the chemistry of steroids. After postdoctoral studies at the Rockefeller Institute, New York (1959-60), he was on the scientific staff of the Weizmann Institute (1960-65), before moving to the Hebrew University of Jerusalem, where he became professor (1972) and Lionel Jacobson Professor of Medicinal Chemistry from 1975. He was rector (1979-82) and pro-rector (1983-85). In 1994 he was elected a member of the Israel Academy of Sciences. Some of his honors and awards include:
Member of the Israel Academy of Sciences and Humanities (1994)
Israel Prize in Exact Sciences – Chemistry (2000)
Honorary doctorate from Ohio State University (2001)
Honorary Member of the Israeli Society of Physiology and Pharmacology (2002)
Honorary doctorate from Complutense University (2006)
NIDA Discovery Award (2011)
EMET Prize in Exact Sciences – Chemistry (2012)
President of the International Cannabinoid Research Society (1999-2000)
Another research project initiated by him led to the isolation of the first described endocannabinoid anandamide which was isolated and characterized by two of his postdoctoral researchers, Lum?r Ondrej Hanus and William Devane. Another endogenous cannabinoid, 2-AG, was soon discovered by Shimon Ben-Shabat, one of his PhD students. He has published more than 350 scientific articles.
History of endocannabinoid research
When Mechoulam and colleagues isolated THC in 1964, they made it possible to further understand the complex nature of the human endocannabinoid system. Other important events in endocannabinoid research are as follows:
2000-650 BCE: Cannabis (azaluu or gurgurru) mentioned in Assyrian pharmacopoeia at the library of Assurbanipal
1964: THC isolation and structure elucidation
1988: Cannabinoid-binding sites in rat brains identified
1991: Human CB1-R receptor successfully cloned
1992: Endogenous CB1-R ligand (EC), anandamide (based on Sanskrit for supreme joy), discovered in the brain
1993: CB2-R receptor found in the immune system successfully cloned
1995: Second EC, 2-AG discovered and more abundant in the brain than AEA
In the 21st century, new discoveries of other endocannabinoids, their site distributions, and roles are deepening our understanding of the endocannabinoid system.
Report of a Parent Survey of Cannabidiol-enriched Cannabis Use in Pediatric Treatment-resistant Epilepsy
Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments.
A study published in Epilepsy and Behavior (2013; 29:574-577), a parent survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child’s seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy.
Results of the survey showed that the average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child’s seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue.
The survey showed that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy, and because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. The authors concluded that objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures
Genetics of Type 2 Diabetes Revealed in Unprecedented Detail
Type 2 diabetes is a global health concern, with approximately 10% of the world’s population diagnosed with the disease or likely to develop it in their lifetime. Previous studies into the genetics of diabetes risk have identified over 80 areas in the human genome associated with type 2 diabetes. However, it remains unknown exactly how these genetic changes, known as variants, are distributed among populations and how they lead to increased risk. Functional explanations for these risk variants have been particularly elusive because most of them fall outside the coding region of genes, and are presumably involved in gene regulation.
A comprehensive investigation of the underlying genetic architecture of type 2 diabetes has unveiled the most detailed look at the genetic differences that heighten a person’s risk for disease development. The findings, published in the journal Nature (11 July 2016), reveal the complexity of the disease in more detail than previously appreciated, but also identify several promising targets for new treatments.
Using DNA sequencing in more than 120,000 people with ancestral origins in Europe, South and East Asia, the Americas and Africa, the authors evaluated the genome at a greater level of detail than had been previously attempted for type 2 diabetes. Some individuals had their entire genome sequenced while for others the authors focused on the part of the genome that codes directly for proteins, known as the exome. The authors then compared the genetic changes between affected and healthy participants.
The findings suggest that most of the genetic risk of type 2 diabetes can be attributed to common, shared genetic variants — each contributing a small amount to an individual’s risk of the disease — rather than many rare variants unique to individuals. This resolves a question about the genetics of type 2 diabetes that has puzzled researchers for decades. The authors also identified over a dozen genes in affected participants where changes in the DNA sequence altered the structure or composition of the proteins they encode, suggesting that those genes and proteins are directly involved in the development of the disease and providing important clues to the mechanism by which they confer risk. That, in turn, provides possible clues to new drug targets. Results from this study suggest that any personalized approach to treatment and prevention of type 2 diabetes will need to be tailored on the basis of an individual’s broader genetic profile, as well as environmental factors.
FDA Takes Action against Zika Virus
Zika virus was first identified in 1947 in Uganda and for decades only sporadic cases and a few outbreaks were recognized in a number of locations, including parts of Africa, Asia, and the Pacific. Since 2015, the situation has changed dramatically, with 48 countries and territories reporting a first outbreak of Zika virus as of July 2016. In the United States, cases of Zika virus disease acquired by the bite of an infected mosquito have only been reported in U.S. territories; to date, cases of Zika virus infection reported in the continental United States have involved travelers and in some instances their contacts. However, given the number of Zika cases among travelers visiting or returning to the United States and the increased mosquito activity in the summer months, FDA expects that imported cases could result in local spread of the virus in some areas of the United States. As a result, FDA is taking important steps to rapidly respond to the Zika virus outbreak. They are engaged with their partners across the U.S. Government, the private sector, and the international community – including the World Health Organization and ANVISA (the Brazilian Health Regulatory Agency) – to help minimize the impact of this outbreak.
Protecting Tissues and the Blood Supply
One of the FDA’s first actions was to take important steps to help protect the safety of the blood supply. The FDA issued guidance in February 2016 recommending the deferral of individuals from donating blood if they have been to areas with active Zika virus transmission, were potentially exposed to the virus, or have had a confirmed infection. The guidance also recommends that areas with active Zika virus transmission, like Puerto Rico, obtain whole blood and blood components from areas of the United States without active virus transmission unless a blood donor screening test for Zika virus is used. Because there were no blood donor screening tests available for Zika virus at the time, HHS arranged for and funded shipments of blood products from the continental U.S. to Puerto Rico to ensure an adequate supply of safe blood for residents until a blood donor screening test became available. The FDA worked closely with developers in a highly accelerated time frame to make available an investigational test for blood screening in March 2016. The availability of this investigational test, which has been in use in Puerto Rico since early April, has allowed blood establishments to safely collect blood in areas with active Zika virus transmission. A second investigational blood screening test was made available in June 2016. Together, these tests have also enabled blood donor screening to be put in place in areas of the United States where local virus transmission is anticipated, but not yet detected, helping to maintain the safety of the blood supply.
Zika virus also poses a risk for transmission by human cells, tissues, and cellular and tissue-based products (HCT/Ps) such as corneas, bone, skin, heart valves, and semen used for medical, surgical, or reproductive procedures. Because of this risk, the FDA issued guidance recommending that donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had intimate relations with a partner with either of those risk factors, within the past six months.
Supporting Diagnostic Development
The ability to accurately detect and diagnose Zika virus infection is critical for a robust response to this public health threat. The FDA is actively working with manufacturers to support their diagnostic development programs, helping to ensure that their tests are properly validated before they are used to inform patient care. This collaboration has been very successful, and since the beginning of the year, we have authorized the use of five diagnostic tests for Zika virus under FDA’s Emergency Use Authorization authority – four tests to diagnose active infection and one test to assess whether individuals who may have recently been exposed to Zika were actually infected. This test is especially important for women given the link between Zika virus infection and microcephaly and other poor pregnancy outcomes in babies of mothers who were infected with Zika virus during their pregnancy.
Strategies to Suppress Mosquito Population
FDA, as well as the EPA, are reviewing the use of innovative strategies to help suppress the population of virus-carrying mosquitoes to help mitigate the threat of vector-borne epidemics, such as Zika virus, which is thought to spread to people primarily through the bite of an infected Aedes aegypti mosquito. Recently, the FDA released for public comment a draft environmental assessment (EA) submitted by Oxitec, Ltd. (Oxitec). The EA assesses the potential environmental impacts of a proposed field trial of the company’s genetically engineered (GE) Ae. aegypti mosquitoes. The FDA also released for public comment a preliminary Finding of No Significant Impact (FONSI) agreeing with the conclusion in Oxitec’s draft EA that the proposed field trial of the company’s GE mosquitoes would not result in significant impacts on the environment. The goal of the proposed field trial is to determine whether released Oxitec GE mosquitoes will mate with local wild-type Ae. aegypti and suppress their population at the release site. The FDA is reviewing the thousands of comments received during the public comment period before determining whether to finalize the EA and FONSI or prepare an environmental impact statement (EIS). Oxitec will not proceed with the field trial of the GE mosquitoes until FDA issues its final EA and FONSI or EIS. Oxitec’s GE mosquitoes are one possible approach that could be incorporated into an integrated vector control program to help mitigate the threat of vector-borne epidemics; however, it is too early to say with any certainty whether such an approach would be successful.
Facilitating Medical Product Development
There are currently no vaccines or treatments for Zika virus that have been shown to be safe and effective. Facilitating the development and availability of vaccines is one of the highest priorities for the FDA and the international community. The FDA continues to actively engage with commercial and government developers, including the NIAID and BARDA, to advance the development of investigational vaccines for Zika virus as soon as possible. We are also working with ANVISA to assist in their efforts to expedite the development of vaccines for Zika virus. As was recently reported, a commercial company announced plans to begin evaluating the first investigational Zika virus vaccine in a Phase I clinical study. Unfortunately, during outbreak situations, fraudulent products claiming to prevent, treat or cure a disease almost always appear. FDA is monitoring for fraudulent products and false product claims related to Zika virus and will take appropriate action to protect consumers when necessary.
More than 120 FDA staff from across the Agency are responding to the Zika virus outbreak, working together to address the complex range of issues that this evolving epidemic continues to present in order to protect and promote the public health, both domestically and abroad. This type of teamwork exemplifies the capacity of people at FDA to rally together to solve problems, often with little explicit credit other than the satisfaction of meeting the mission of promoting and protecting the public health. There are many fundamental scientific questions that need to be addressed with respect to Zika virus, and FDA scientists are working to help answer some of these questions in FDA’s own laboratories. FDA stands ready to use our expertise and authorities to the fullest extent to help facilitate the development and availability of products that may help mitigate the Zika virus outbreak.
Roasted Lamb with Eggplant, Almonds & Dates
This recipe was beyond delicious; it was addictive! Something about fresh tender lamb combined with the roasted eggplant, garlic, herbs and spices, that came together in perfect harmony. If you’re barbecuing these days, follow my recipe (marinade and all) and simply skewer the lamb on metal or bamboo skewers, barbecue and serve with the eggplant mixture and saffron rice. If using bamboo skewers, remember to soak them in water, before using. ©Joyce Hays, Target Health Inc.
We ate this lamb-eggplant-saffron rice, all weekend; it was so-o flavorful! ©Joyce Hays, Target Health Inc.
3/4 cup plain Greek yogurt (FAGE)
1 teaspoon grated lemon zest
2 ? teaspoons lemon juice
6 fat garlic cloves, finely chopped
8 Tablespoons extra virgin olive oil, more for drizzling
1 pound boneless leg of lamb, cut into 1-inch chunks
1 3/4 teaspoons kosher salt
1 1/4 teaspoons black pepper
1 pound eggplant, cut into 3/4-inch cubes
8 dates, pitted and finely chopped
2/3 cup chopped cilantro
4 Tablespoons almond slivers
1 Tablespoon fresh mint, finely chopped for marinade
1 Tablespoon fresh mint, finely chopped for garnish
Fresh lamb, wonderful spices and herbs, with dates and almonds. How could you NOT have layered flavor results. ©Joyce Hays, Target Health Inc.
Chop everything that needs chopping, at the same time.
Chopping dates, cilantro, mint and about to add garlic to cutting board. ©Joyce Hays, Target Health Inc.
Toasting almond slivers. ©Joyce Hays, Target Health Inc.
In a medium bowl, whisk together the yogurt, lemon zest, lemon juice and garlic. Whisk in 5 Tablespoons of the oil.
Season the meat with 1 teaspoon salt and 1 teaspoon black pepper and transfer to a large, glass or ceramic bowl. Pour half the yogurt mixture over the meat and toss well. Cover tightly with plastic wrap and refrigerate at least 3 hours or overnight.
Lamb pieces were marinated in this red wine (non-dairy) marinade and refrigerated overnight. Red wine marinade recipe, below** ©Joyce Hays, Target Health Inc.
Lamb pieces marinating in red wine, garlic, spices and herbs. (overnight). ©Joyce Hays, Target Health Inc.
Here is another marinade to pour over lamb pieces and refrigerate overnight. ©Joyce Hays, Target Health Inc.
Lamb marinating in garlic-yogurt (overnight). ©Joyce Hays, Target Health Inc.
Heat the oven to 425 degrees. Toss the eggplant with the remaining 3 Tablespoons oil, 3/4 teaspoon salt and 1/4 teaspoon pepper. Spread on a baking sheet and roast, tossing occasionally, until eggplant is golden brown and tender, 20 to 30 minutes. Scrape into a bowl. Whisk the dates and cilantro into the remaining yogurt mixture and toss with the warm eggplant.
Eggplant going into oven. ©Joyce Hays, Target Health Inc.
Eggplant just out of oven. ©Joyce Hays, Target Health Inc.
Here the roasted eggplant, herbs, dates, almonds are mixed together. ©Joyce Hays, Target Health Inc.
Adjust the oven to broil, with a rack 2 inches from the heat. Remove meat from marinade, wiping off any excess, and transfer to a large baking sheet. Drizzle lamb with a little oil. Broil until golden and cooked to desired doneness, about 4 minutes for medium rare. Let the meat rest for 5 minutes.
In a small skillet over medium-high heat, toast almonds, tossing occasionally, until golden brown, about 3 minutes.
This is a final re-heating of the lamb and eggplant, with saffron rice in the center, using an ever popular iron all-purpose baking dish. ©Joyce Hays, Target Health Inc.
Divide meat among serving plates and spoon eggplant next to the meat. Garnish with almonds and mint.
** Marinade for Roast Lamb
1/2 cup extra-virgin olive oil
1/2 cup red wine
1/4 cup fresh lemon juice
6 garlic cloves, minced
1 tablespoon dried oregano (preferably Greek), crumbled
2 teaspoons salt
1 teaspoon black pepper
1 butterflied boneless leg of lamb, trimmed of fat
(Special equipment: a large (2-gallon) heavy-duty sealable plastic bag; 3 or 4 (10- to 12-inch) metal skewers if you want to barbecue outside or do kebabs indoors.
Combine oil, lemon juice, garlic, oregano, salt, and pepper in sealable plastic bag. Add lamb and seal bag, pressing out air. Turn bag to coat lamb, then put bag in a shallow baking pan and marinate, chilled, turning bag over occasionally, at least 8 hours or overnight
Bring lamb to room temperature, about 1 hour, before roasting or broiling.
Pouilly Fuisse is probably not the best choice for the lamb/eggplant dish, but we’re still on a certain track, and not ready to stop. For the lamb a nice Pinot Noir would work, not to mention a robust Cab or Merlot. We have started to experiment with Rose and wine spritzers, which are especially refreshing in the summer. ©Joyce Hays, Target Health Inc.
We relaxed all weekend, watching movies at home, eating the lamb recipe (3 days, it’s finished and we still want more). Saturday, Jules beat me badly in Scrabble but Sunday I regained my self-respect. Like everyone, we’re appalled with world events and by contrast, were happy and lucky to have a lovely serene home atmosphere.
Let’s hope this next week calms down.
From Our Table to Yours !