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Targeting the Endocannabinoid System to Treat Human Disease
Diana Gitig
Diana Gitig is a freelance writer who has written for Science, the Proceedings of the National Academy of Sciences, and arstechnica.com, among other outlets. She earned her PhD in cell biology and genetics from the Graduate School of Medical Sciences of Cornell University in 2001.
The New York Academy of Sciences
Understanding the Endocannabinoid System
Tweaking the Endocannabinoid System to Alleviate Pain and Induce Weight Loss
Cannabis Chaos and Confusion
The Therapeutic Potential of CB2 Agonists
CB2 Agonists: Panel Discussion
People have used cannabis plants as pain relievers at least since the dawn of recorded history, some five thousand years or so ago. But the endogenous receptors mediating cannabis' multiple effects, CB1 and CB2, and their endogenous ligands weren't isolated and identified until the 1980s. Today, we know that the endocannabinoid system plays a vital role in maintaining homeostasis throughout the body; it is involved in physiological processes ranging from neurotransmission, mood, and energy balance to immune responses and wound healing. On January 27, 2021, the New York Academy of Sciences hosted a webinar on Targeting the Endocannabinoid System for Treatment of Human Diseases. Researchers described their work leveraging the endocannabinoid system to treat obesity and metabolic disorders and different types of inflammation and pain. Their ultimate goal is to promote the beneficial actions of signaling through the endocannabinoid system while eliminating the psychoactive side effects.
Symposium Highlights
Endocannabinoid receptor agonists, antagonists, and inhibitors of the enzymes that metabolize endocannabinoids are being developed to harness the endocannabinoid system's vast effects for pharmacotherapeutic purposes. >
"Cannabis" is not one thing; it contains over a hundred cannabinoids. But many health care providers, bombarded with information from the cannabis industry, lack an adequate understanding of phytocannabinoids and the various ways they can stimulate the endocannabinoid system.>
An inhibitor of MAG Lipase, the enzyme that metabolizes the endocannabinoid 2-AG, can alleviate chemotherapy induced peripheral neuropathy and is currently in Phase 2 clinical trials. >
CBD induces apoptosis in melanoma cells by inducing the Endoplasmic Reticulum stress response. >
CB1 is found primarily in the brain, while CB2 is expressed primarily on immune cells. Thus molecules that act through CB2, or those that act through CB1 but don't cross the blood-brain barrier, might provide therapeutic benefits without eliciting psychotropic side effects. >
A positive allosteric modulator of CB1, a CB2 agonist, and FAAH inhibitors all suppress pathological pain. Unlike THC and morphine, they do so without inducing tolerance, dependence, or reward. >
A CB2 agonist reduced proinflammatory mediators of gout and alleviated swelling in a rat model of the disease. >
Psychedelics for the Treatment of Depression and Psychiatric Disorders
Allyn Howlett, PhD
Wake Forest School of Medicine
George Kunos, MD, PhD
National Institute on Alcohol Abuse and Alcoholism
Kathryn Nichol, PhD
Greenwich Biosciences
Aron H. Lichtman, PhD
Kenneth Mackie, MD
Andrea Watters
NYIT College of Osteopathic Medicine
Derek Gilroy, PhD
University College of London
Andrea Hohmann, PhD
Barbara White, MD
Corbus Pharmaceuticals
Ping Zhang, MD, PhD
Cannabis and Science
New Therapeutic Strategies to Treat Metastatic Cancer
Linking Metabolism, Health, and Cancer: 2020 Dr. Paul Janssen Award Symposium
Immune-Stromal Cell Interactions in Wound Healing, Fibrosis and Cancer
Understanding Next Generation Organoids
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Biology and Pharmacology of the Endocannabinoid System
An exogenous ligand of the endocannabinoid receptors was identified before the receptors themselves were; Δ9-Tetrahydrocannabinol, popularly known as THC, was isolated from confiscated cannabis in Israel in 1965. It took twenty years for a synthetic version of THC to be granted FDA approval, first to treat nausea in cancer patients getting chemotherapy and then to treat fatal wasting syndrome in AIDS patients. At that point it and its analogs were orphan drugs. Then the two endocannabinoid receptors, CB1 and CB2, were identified; and their endogenous ligands, the lipid transmitters N-arachidonoylethanolamine (AEA, or anandamide) and 2-arachidonoylglycerol (2-AG), followed. Allyn Howlett gave an overview of what we know about the whole system today.
CB1 and CB2 are 7-transmembrane G protein coupled receptors. CB1 receptors are expressed all over the brain: in the prefrontal cortex, the seat of judgment and executive function; in the amygdala, which mediates the reward system; in the hippocampus, where memories are made; and even in the cerebellum. But they are not limited to the brain. Cells in other organs, including the liver, skeletal muscle, pancreas, GI tract, and adipose tissue, upregulate their expression of CB1 in response to a high-fat diet. CB2 receptors are found primarily in immune cells.
CB1 receptor stimulation returns a hyperactive cell to its normal state. If excessive amounts of a neurotransmitter are released from a neuron--either an excitatory neurotransmitter like glutamate or an inhibitory neurotransmitter like GABA—the postsynaptic cell makes endocannabinoids and sends them back across the synaptic cleft. When these bind and activate CB1, the CB1 receptors' G proteins dissociate into their component subunits. The 𝛂 subunit reduces cAMP production through adenylyl cyclase, which reduces protein kinase A activity and activates certain types of potassium channels. The ꞵ/γ subunit inhibits some types of calcium channels. The ultimate result is membrane hyperpolarization and a reduction of neurotransmitter release. Hydrolases at both the presynaptic and postsynaptic sites are on hand to cleave the endocannabinoids to ensure that their effects are fleeting.
Signaling through CB1 receptors.
The most straightforward way to clinically interfere with the endocannabinoid system is through selective agonists or antagonists of CB1 or CB2. But there are also drugs in the pipeline that inhibit MAG Lipase and FAAH, the enzymes that metabolize 2-AG and anandamide, respectively. Both positive and negative allosteric modulators of the receptors have also been developed. And of course there are plenty of proteins associated with CB1 and CB2 that may have regulatory functions. All of these may be appropriate targets to harness the beneficial actions of the endocannabinoid system—treatment of pain, anxiety, depression, and metabolic disorders—without eliciting the psychoactive side effects of THC.
Allyn Howlett (Wake Forest School of Medicine)
Howlett
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Regulation of Appetitive and Addictive Behavior by the Peripheral Endocannabinoid/CB1 receptor System
George Kunos and his lab hypothesized that antagonizing CB1 receptors in the periphery, but not in the brain, might be a way to treat metabolic syndrome without eliciting neuropsychiatric effects. But first, they had to show that blocking these peripheral receptors could affect appetite and addiction, behaviors that are mediated by the CNS.
To do this, his lab employed a peripherally restricted CB1 inverse agonist, JD5037. Surprisingly, they found that it reduced food intake, body weight, and insulin resistance in mice fed a high-fat diet; moreover, it did so to the same extent as its parent compound, a CB1 inverse agonist that is brain penetrant. Both compounds also dropped the highly elevated leptin levels in these obese mice back down to normal. A series of experiments amply demonstrated that that the appetite suppressive effects of peripheral CB1 blockade are in fact mediated through downregulating endogenous leptin, which in turn achieves its effects by activating anorectic POMC/CART neurons. Leptin is made peripherally in adipose cells but acts centrally. It could thus be the very link the Kunos lab set out to find connecting peripheral CB1 receptors with CNS pathways controlling appetite.
Similar results emerged from studies of a mouse model for alcoholism. The Kunos lab used two methods to model alcoholic behavior in male C57Bl6/J mice: the two-bottle free-choice paradigm and the drinking-in-the-dark paradigm. In the former, mice were free to choose to drink from a bottle containing water or one containing 15% ethanol; they preferred the ethanol. In the latter, mice were given access to 20% ethanol while they were in the dark. This is meant to be a model for binge drinking. In both cases, treatment with JD5037 reduced drinking just as much as the globally acting CB1 inverse agonist. The treatment did not alter the mice' preference for sucrose, saccharine, or quinine, so it was specific to alcohol and not to taste or calorie count.
Interplay between the endocannabinoid system and the brainstem neurocircuit comprising vagovagal reflexes
As with their studies with obese mice, the Kunos lab wanted to find the link between peripheral CB1 receptors and the addictive behavior mediated by the CNS. But this time, it wasn't humoral, like leptin; it was neural. They found it in ghrelin signaling through receptors located on vagal afferent terminals. Ghrelin is made in the stomach mucosa, which also expresses CB1 receptors and high levels of endocannabinoids. Alcohol induces endocannabinoid expression is specifically induced by alcohol in these stomach cells but not in brain or plasma cells. Ghrelin is known to promote drinking alcohol. CB1 blockade reduces alcohol consumption by preventing the acylation of ghrelin into its active form. It does this by promoting the degradation of ghrelin's substrate, octanoic acid.
Paradoxically, there is evidence that THC—the original CB1 agonist, the one that makes people hungry—can reduce obesity. Kunos suggested that perhaps heavy THC use desensitizes CB1 receptors so that endocannabinoids can no longer signal through them, making THC act almost like these inverse agonists rather than a standard one.
George Kunos (National Institute on Alcohol Abuse and Alcoholism)
When Phytocannabinoids Meet the Endocannabinoid System
The mission of Greenwich Biosciences, a subsidiary of GW Pharmaceuticals, is to develop plant-based cannabinoid medicines for neurologic and psychiatric conditions. As their Senior Director of Medical Affairs, Kathryn Nichol oversees the translational medicine and drug development.
Nichol explained that phytocannabinoids differ from endocannabinoids in several clinically significant ways. Whereas only five endocannabinoids have been isolated to date, about 120 different chemicals have been found in Cannabis sativa. Their chemical structures are different; endocannabinoids are polyunsaturated fatty acids with a polar head group, while phytocannabinoids are terpenophenolic compounds derived from geranyl pyrophosphate. Endocannabinoids act and are degraded locally; phytocannabinoids are metabolized in the liver, and their site of action depends on how they are ingested. Both may reduce neuronal hyperexcitability. Yet research findings on endocannabinoids are often presented out of context, especially online, and presumed to apply to cannabis as well. And of course "cannabis" is not one monolithic entity; it contains hundreds of cannabinoid molecules in varying amounts, all of which exist in active and inactive forms and have active and inactive metabolites.
Phytocannabinoids have varying binding affinities and directions of action for CB1 and CB2. THC is a partial agonist of both; CBD is an inverse agonist, albeit a weak one, of both; and others have agonistic and antagonistic effects of varying levels. They can also bind to and exert their varying effects on other receptors, like TRP channels. This diversity makes drug discovery extraordinarily challenging.
Varying effects of various phytocannabinoids.
Nichol provided a few real-world examples of this challenge. In animal models of epilepsy, glaucoma, neuropathic pain, and spasticity, CBD and THC have conflicting effects. But regardless of their different and sometimes opposing activities, health care practitioners still want CBD because "it's the non-psychoactive one," and because their knowledge of cannabis and its myriad effects is generally outdated and misguided.
Findings on endocannabinoids cannot be extrapolated to phytocannabinoids, Nichol stressed, and endocannabinoid researchers "can't pretend the twenty-billion-dollar commercial cannabis industry does not exist." She said they "must be aware that marketers can and will use your basic research. But for medical utility and advancing drug development, risk/benefit analyses, preclinical molecular and animal studies, and clinical studies must be done before products are given to patients." Nichol noted that perhaps rushing opioids to market without those safeguards contributed to the current opioid crisis, and we certainly don't want to repeat that mistake with phytocannabinoids. Greenwich has thus proactively sponsored independent medical education to keep physicians updated on research into the endocannabinoid system, cannabis, and FDA regulations regarding cannabis use.
Kathryn Nichol (Greenwich Biosciences)
Kunos
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Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling
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Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis
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Targeting the Endogenous Cannabinoid System to Treat Pain
Many cancer patients undergoing chemotherapy have to contend with chemotherapy-induced peripheral neuropathy: numbness, tingling, and pain in their fingers and toes. It can be so severe that it limits the doses of chemotherapy they can handle, and can last for years after treatment. There are currently no effective treatments for it, but a number of preclinical studies in rodent models have suggested that drugs targeting the endocannabinoid system can reduce peripheral neuropathy induced by paclitaxel, a drug given to people with breast, lung, and ovarian cancers.
Overview of the endogenous cannabinoid system.
Aron Lichtman focuses on monoacylglycerol lipase (MAGL), the primary 2-AG degradative enzyme. It is expressed widely throughout the brain and periphery, in presynaptic neurons, astrocytes, microglia, and macrophages. Inhibiting MAGL increases 2-AG, decreases arachidonic acid (a breakdown product of 2-AG that has proinflammatory metabolites of its own) levels, and has antinociceptive and anti-inflammatory effects in many animal models of pain. 2-AG's stimulation of CB1 receptors exerts its antinociceptive effects, and its stimulation of CB2 receptors exerts both its anti-inflammatory and its antinociceptive effects.
Lichtman hypothesized that MAGL inhibition might alleviate paclitaxel-induced peripheral neuropathy in mice, and he was right—it did. It required both CB1 and CB2 receptors to achieve its effects. It also reduced phospho-p38 MAPK and MCP-1, two biomarkers of inflammation, in dorsal root ganglia. A high dose of the inhibitor (40mg/kg) induced tolerance by desensitizing the CB1 receptors, so it did not alleviate pain upon repeated treatments. But a lower dose (4mg/kg) was better tolerated over time. Thankfully, the inhibitor did not induce cancer cell growth or interfere with paclitaxel when assessed in a human lung cancer cell line. There is now a MAGL inhibitor in Phase 2 clinical trials to reduce cancer pain.
Chronic pain is different from chemotherapy-induced pain, and cannabinoids have already undergone clinical trials to treat chronic pain. Nabiximols, an extract of cannabis comprised of 50% THC and 50% CBD, have been approved to treat MS spasticity and cancer pain in Canada, Europe, and Australia. But Nabiximols are not FDA-approved because they lacked efficacy in three Phase 3 clinical trials when the primary endpoint was a decrease in the numeric pain scale. They were, however, effective on some secondary measures, like improving sleep and patient satisfaction. Nabiximols seemed to decrease American patients' pain more than that of patients in the rest of the world, although still not enough to achieve significance. This could be because the Americans had visceral or bone-based cancer pain, and those in the rest of the world had more neuropathic cancer pain; or because, surprisingly, patients in the rest of the world got more opiates than the US patients.
Aron H. Lichtman (Virginia Commonwealth University)
Cannabinoids for Weight Loss: A Twisted Tale
"The endocannabinoid system, like the behavior it promotes, is highly promiscuous," quipped Kenneth Mackie to start his talk. He noted that while we tend to focus on CB1 and CB2 receptors and their ligands 2-AG and anandamide, and perhaps expand slightly outward to include the enzymes that degrade them, the lipid signaling system is much broader than that and encompasses a whole host of associated molecules. He focuses on GPR119, a nutrient-sensing G protein-coupled receptor expressed in pancreatic islets and gut enteroendocrine cells (K and L cells) in intestinal villi.
It is fairly well known that activation of CB1 receptors by either THC or 2-AG makes people (and rats) eat more. This is true even for chronic cannabis users. So CB1 antagonists were pursued as a potential treatment for obesity, and they increased resting energy expenditure. CB1 blockade induced weight loss and improved measures of metabolism in over 25,000 subjects. And yet, chronic cannabis users have lower BMIs, smaller waist circumferences (a proxy for visceral fat), and are at a decreased risk of Metabolic Syndrome, insulin resistance, and Type II Diabetes than the general population—even though they consume more calories. Chronic cannabis use may therefore have paradoxically beneficial metabolic effects.
Mice being fed THC-laced sweetened condensed milk are happy to see researchers enter the animal facility.
To unravel this quandary, Mackie's lab tried to discern whether chronic THC would make obese mice lose weight, and found that it did. The roles of CB1 or CB2 receptors in metabolism have been relatively well defined, so Mackie wondered if THC was acting through another receptor. His group found that THC (but not CBD) increased the internalization of GPR119 in HEK293 cells. GRP119's endogenous agonists are breakdown products of fat, and its activation induced glucose sensitive insulin secretion in the pancreas and incretin secretion in the gut. In rodents, activating GRP119 is metabolically beneficial. Mackie's group showed that THC is a biased agonist of GPR119; it stimulated IP1 accumulation, but not cAMP accumulation or ERK1/2 phosphorylation. THC did not elicit glucose sensitive insulin secretion since GPR119 mediates this effect through cAMP. Smoking marijuana would not give people enough THC to activate GPR119. But THC's metabolites are a different story; they accumulate at high enough concentrations in the bile to stimulate cells in the nearby small bowel. They not only stimulated the internalization of GPR119 but also increased cAMP as well as IP accumulation in HEK cells. In a more physiologically relevant cell line—GluTag cells, which are similar to the L cells in which GPR119 is expressed—THC and its metabolites stimulated the secretion of the incretin GLP-1. Mackie thinks this is the basis of its beneficial metabolic effects.
Having shown that THC helps the metabolic profile of obese mice, Mackie's lab then showed that it could prevent mice from gaining weight when fed a high-fat diet, although more so for male mice than females. This gender difference accords with anecdotal data from people.
Kenneth Mackie (Indiana University)
Lichtman
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Cannabidiol (CBD) Inhibits Cancer Survival Through Upregulating the Endoplasmic Reticulum (ER) Stress Response
CBD has been pressed into service to treat numerous cancers: glioblastomas, leukemias and lymphomas, and breast, prostate, colon, and gastric cancers. It induces the apoptosis of cancer cell lines in a time and dose dependent manner. In melanoma cells, the most sensitive cell lines Andrea Watters and her labmates assayed, CBD upregulated the expression of proteins involved in the ER stress response, especially CHOP, IRE1𝛂, and XBP1. Overexpression of CHOP in particular is known to lead to apoptosis. They found that melanoma cells were almost three times more sensitive to CBD's apoptosis inducing effects than normal skin fibroblasts, suggesting that CBD could be used clinically with minimal side effects. Watters and her colleagues think that in melanoma, CBD is acting as an agonist on TRPV1 receptors in the plasma and ER membranes to increase intracellular calcium, which leads to ER stress and induces CHOP. CHOP overexpression causes the generation of reactive oxygen species and apoptosis. They hope to confirm this proposed mechanism in mouse models of melanoma.
Andrea Watters (NYIT College of Osteopathic Medicine)
Panel Discussion One
The first panel discussion focused on and reiterated how much is still unknown about cannabis and the endocannabinoid system. Nichol was asked how CBD halts seizures and if its effects are limited to certain seizure disorders; she said "the truest answer I can give you is that we don't know," since all of the studies done thus far have been in culture or in mouse models. When asked about CB1 long term desensitization, Mackie noted that "heavy users of THC still report the munchies, so that aspect of CB1 signaling hasn't desensitized." There was some speculation that CB1 antagonists could be used to help respiratory distress, like that seen in COVID-19, since vapers who inhale synthetic CB1 agonists wound up in the hospital with respiratory distress. One question regarded THC's negative effects on psychotic disorders, bipolar disorder, and depression, which Howlett labeled "a very complex issue."
The panelists concurred that cannabis does not induce psychosis in most people, but has been shown to exacerbate anxiety. And its effects, like individuals, are wildly heterogeneous; different cannabinoids at different doses can have very different effects on different people, which makes extrapolating clinical utility from any data extremely complicated. Moreover, we don't know exactly which cannabinoids people are getting when they use cannabis to self-medicate, nor do we know their underlying physiology. Nichol summed up the state of the field by noting that "the data in the literature is so murky." The panel concluded by referencing anecdotal data about cannabis improving patients' quality of life--getting them back to work, allowing them to sleep better--even though it may not be as effective at pain relief as opioids, and collectively bemoaned that clinical trials of pain relievers don't use these secondary but perhaps more functional endpoints.
Howlett/Kunos/Nichol/Lichtman/Mackie (Wake Forest School of Medicine/National Institute on Alcohol Abuse and Alcoholism/Greenwich Biosciences/Virginia Commonwealth University/Indiana University)
Seltzer ES, Watters AK, MacKenzie D Jr, Granat LM, Zhang D.
Cannabidiol (CBD) as a Promising Anti-Cancer Drug
Cancers (Basel). 2020;12(11):3203. Published 2020 Oct 30.
New Insights into the Resolution of Acute Inflammation in Humans Provided by Lenabasum, a Synthetic Analogue of delta -8- tetrahydrocannabinol (THC)-11-oic Acid
Derek Gilroy is interested in the resolution of acute inflammation. Within minutes of an infection or injury, neutrophils migrate to the affected site, controlled by cytokines and chemokines. Once the infection has been cleared, the inflammation begins to resolve: the neutrophils die of apoptosis and are eaten by macrophages, which then release anti-inflammatory molecules. His lab would like to harness these internal pro-resolution pathways to switch off ongoing inflammation.
Lenabasum, or ajulemic acid, is a synthetic analog of the terminal metabolite of THC, so it should not have psychotropic effects. It is a selective CB2 agonist that has been shown to be anti-inflammatory in various animal models. There is even evidence that it induces pro-resolution pathways. Anti-inflammatories dampen the immune response, while a pro-resolution drug would allow the same level of acute inflammation but then clear it more quickly.
Gilroy's lab set out to determine if Lenabasum is anti-inflammatory or pro-resolution in humans. They injected UV-killed E. coli into the arms of volunteers to induce local inflammation in their skin. The skin gets red within a day, but the redness resolves two days later. When the volunteers got Lenabasum for three days before their bacterial injection, their neutrophil infiltration levels were severely diminished, as were levels of the proinflammatory cytokine IL-8 and lipid mediators of inflammation like LTB4 and PGE2. Lowering PGE2 levels is known to help neutrophils phagocytose bacteria. So Lenabasum acts as an anti-inflammatory.
UV-killed E. coli injected into the arms of volunteers to induce local inflammation in the skin.
"Inflammation will never go away or resolve until the irritant that caused it has been removed," said Gilroy. Lenabasum also reduced endotoxin levels, so it helped the immune system clear the bacteria while diminishing inflammation.
Even though it dampened molecular markers of inflammation, the higher dose of Lenabasum (20mg) seemed to draw more blood to the site and make the skin look redder. The redness was not associated with a reinfiltration of neutrophils. Gilroy thought it could be due to CO, a byproduct of heme oxygenase activity, which is elevated as inflammation is resolved. His lab found that resolution phase macrophages have increased expression of both 2-AG and its receptor CB2, revealing that the endocannabinoid system plays a role in our endogenous resolution pathway. He speculates that Lenabasum might trigger resolution by acting through CB2 to induce heme oxygenase activity. People with rheumatoid arthritis and other chronic and inflammatory diseases don't exhibit this enhanced redness; perhaps Lenabasum can help stimulate their resolution pathways if their endogenous mechanisms to do so have flagged.
Derek Gilroy (University College of London)
Medical Marijuana and the Endocannabinoid System: Therapeutic Potential for Treating Neuropathic Pain
The opioid epidemic has renewed interest in using cannabis for pain relief. But Andrea Hohmann noted that even though cannabis has been used for millennia to combat pain, the current state of the field is chaotic. Most of the studies done are small, short term, and of poor quality, without adequate blinding or appropriate placebos; disparate kinds of chronic pain and different cannabinoid-based medicines are often mixed; safety assessments are scarce; and as in other fields, only positive results tend to get published.
Her lab looks at chemotherapy-induced peripheral neuropathy using paclitaxel treated rats as their model system. The rats have pain in their extremities that manifests as hypersensitivity to cold and increased brain functional connectivity, especially in regions involved in motivational and emotional responses to chronic pain. Exposing them to vapor from cannabis that was 10.3% THC and 0.05% CBD brought their resting state brain connectivity back down to normal levels and eliminated their cold hypersensitivity. But it had the undesired side effect of reduced locomotor activity.
Hohmann aimed to retain THC's nociceptive effects while eliminating side effects like getting high. To start, her lab tried a positive allosteric modulator of CB1 called GAT211 that would increase the affinity and efficacy of endogenous cannabinoids or CB1 agonists. In a mouse model, GAT211 worked through CB1 to eliminate paclitaxel-induced pain. Unlike mice treated with THC, mice treated with GAT211 did not develop tolerance to it over time or experience withdrawal symptoms like paw tremors, head shakes, or scratching. It also did not seem to induce reward pathways. In contrast, mice given morphine or a MAG lipase inhibitor developed tolerance to these substances; their pain returned over time, even with treatment.
Next, Hohmann's group investigated inhibitors of Fatty Acid Amide Hydrolase (FAAH), the enzyme that metabolizes anandamide. They found that in mice, each inhibitor suppressed both the development of paclitaxel-induced neuropathic pain and also alleviated established pain. Neither inhibitor produced tolerance or physical dependence. Promisingly, both FAAH inhibitors synergized with morphine's ability to relieve pain (but not with morphine's ability to cause constipation or seek reward).
Cartoon depiction of CB2's therapeutic potential.
Lastly, they looked at CB2 activation as a means of treating pain and circumventing the side effects elicited by signaling through CB1. Like the previous agents they examined, their CB2 agonist reversed established paclitaxel neuropathy without inducing tolerance or symptoms of physical withdrawal. It did so even in CB1 knockouts, suggesting that therapeutic exploitation of CB2 receptors can be accomplished without any input from CB1 receptors. The treatment decreased mRNA levels of the proinflammatory cytokine TNF-α and the chemokine MCP1 that were elevated by paclitaxel treatment in the lumbar spinal cord of mice. This may begin to explain the mechanism by which it relieves pain. Another CB2 agonist they tried also had antinociceptive effects and was able to block the undesirable side effects of morphine like tolerance, dependence, reward seeking, and respiratory depression.
Two clinical trials of CB2 agonists for pain have already failed because of lack of efficacy, one for third molar extraction and the other for osteoarthritis pain. So although the pathway has therapeutic potential, Hohmann stressed that the proper drug must be matched to the proper indication to achieve a clinically meaningful effect.
Andrea Hohmann (Indiana University Bloomington)
Motwani MP, Bennett F, Norris PC, et al.
Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation
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Hohmann
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Targeting CB1 and CB2 for Human Therapeutics
"Without a doubt, there are therapeutic uses for CB1 agonists and cannabidiol," said Barbara White, chief medical officer and head of research at Corbus Pharmaceuticals. CB1 inverse agonists have been investigated as treatments for metabolic and fibrotic diseases and various neurologic problems. One, rimonabant, was approved for weight loss in Europe but had to be pulled because of serious side effects: anxiety and suicide. So Corbus is looking for inverse CB1 agonists that don't cross the blood-brain barrier so readily and might therefore be safer. They currently have five candidates in development that, because of size, or polarity, or lipophilicity, remain in the plasma but don't get into the brain as much. However, for some of them, the little that gets into the brain remains there for days; these may not be optimal for clinical use. But those that were tested in a mouse model of diet induced obesity precipitated weight loss and improved glucose tolerance and, they are rapidly cleared from the brain. Dr. White is hopeful that they will be safe and effective in humans.
Corbus' CB1 inverse agonists have limited penetration into the brain.
Corbus has primarily focused on CB2 agonists, which have been reported to be beneficial in cancers, fibrotic diseases, autoimmune diseases, and CNS diseases. Specifically, they are examining the synthetic selective CB2 agonist Lenabasum as a treatment for chronic inflammation and fibrotic diseases because it reduces the production of proinflammatory cytokines as well as pro-fibrotic growth factors and collagen. It also reduces myofibroblast transformation. CB2 receptors are expressed on activated immune cells and fibroblasts. While Lenabasum does have some CB1 agonist activity, it has a limited ability to cross the blood-brain barrier. White and her team tested its use in systemic sclerosis, or scleroderma. This rare, debilitating, and life-threatening autoimmune disease is characterized by inflammation and fibrosis in the skin, joints, and lungs.
CB2 knockout mice develop scleroderma-like symptoms when their innate immune system is challenged, linking the endocannabinoid system to the disorder. In a Phase 2 study of people with sclerosis, Lenabasum improved inflammation and fibrosis in skin biopsies after twelve weeks. In the RESOLVE-1 Phase 3 study, Lenabasum stabilized lung function in sclerotic patients, while those given placebos showed declining lung function over time. Similar results were found in a Phase 2 study of people with cystic fibrosis: Lenabasum lowered their rate of pulmonary exacerbations. Both studies showed a favorable safety profile, but the primary efficacy endpoint was not met in either. In the RESOLVE-1 study, this could be because many of the participants were already taking immunosuppressants.
In preliminary studies, Corbus' novel CB2 agonists also inhibited the growth of breast cancer cells in culture to varying degrees, and at least one of them inhibited Her2 phosphorylation in a breast cancer cell line and Her2+ tumor growth in a xenograft model. The agonists also inhibit the growth of non small-cell lung cancer and a glioblastoma cell line at nontoxic levels. Dr. White plans to use animal models to investigate the mechanisms responsible for this growth inhibition.
Barbara White (Corbus Pharmaceuticals)
Han JH, Shin H, Park JY, et al.
A novel peripheral cannabinoid 1 receptor antagonist, AJ5012, improves metabolic outcomes and suppresses adipose tissue inflammation in obese mice
FASEB J. 2019;33(3):4314-4326.
Lucattelli M, Fineschi S, Selvi E, et al.
Ajulemic acid exerts potent anti-fibrotic effect during the fibrogenic phase of bleomycin lung
Respir Res. 6 May 2016;17(1):49. Published 2016 May 6.
CRB-317, a Selective Cannabinoid Receptor Type 2 (CB2) Agonist, Inhibits NLRP3 Inflammasome Activation, Cytokine Production, and Has Activity in a Model of Gouty Arthritis
Ping Zhang tested another of Corbus Pharmaceuticals' novel synthetic selective CB2 agonists against gouty arthritis. Gouty arthritis is one of the most common forms of inflammatory arthritis, affecting about 4% of adults in the US. She found that the CB2 agonist inhibited activation of the inflammasomes in human macrophages known to be activated in acute gout. This inhibition manifested as a reduction in caspase-1, IL-1β, and IL-18. It also inhibited the production of a number of other proinflammatory cytokines—IL-6, IL-23, MCP-1, and TNF𝛂—in PBMCs, and attenuated knee inflammation in a rat model of arthritis in a dose dependent manner.
Ping Zhang (Corbus Pharmaceuticals)
Panel Discussion Two
This panel discussion started with Kunos asking Gilroy which disease his skin inflammation model best recapitulates. Gilroy replied, "this is something we philosophize about a lot." He went on to explain that "the model is very useful for understanding basic immune responses to infection and injury," as well as immune senescence in aging and the mechanistic basis for multimorbidities. But White warned against over interpreting any data because we so desperately want accurate models. Next, Kunos asked Hohmann if she has looked at any biased CB2 agonists—like one that worked only through G proteins—that might synergize with opiates to prevent the development of long term tolerance and respiratory depression. She said that the agonist she used was biased in that exact way-it is G protein based and does not recruit arrestins at all. But it did fail in a clinical trial for osteoarthritis pain due to lack of efficacy. She is currently trying to unravel which pathways are necessary and which are dispensable for therapeutic effects and for side effects. Howlett wondered if the agonist might be working in the brain stem, an area of the brain that incontrovertibly expresses CB2 receptors. Lastly, Kunos asked White if she'd examined the expression levels of MDR ABC transporters, given that brain tumors often express them at high levels. Do they shunt her CB2 agonist out of the tumor? White answered that they've tested some of their compounds in vitro, but not yet in tumors. They vary.
Panel Discussion 2
Kunos/Gilroy/Hohmann/White (National Institute on Alcohol Abuse and Alcoholism/University College of London/Indiana University Bloomington/Corbus Pharmaceuticals)


text:
Insights & Successes
News & Client Alerts
New Laws for 2016
Employment Law Reporter, Ervin Cohen & Jessup LLP
Thousands of laws are introduced each year at the state and federal level. While only a fraction of these become law, tracking the most important laws can be a daunting task. But never fear, we have taken on that task for you! Here is our list of the most important, or at least the most interesting, laws that were passed in 2015.
The Healthy Workplaces, Healthy Families Act of 2014 Clarified: Assembly Bill 304 was enacted on an emergency basis shortly after California's paid sick leave law, known as the Healthy Workplaces, Healthy Families Act of 2014, became effective on July 1, 2015. There were good reasons for the amendment: the paid sick leave law was confusing and difficult to implement. Effective immediately, AB 304 seeks to clarify some aspects of the sick leave law and provides employers with greater options regarding implementation. Specifically, AB 304 permits employers to use a sick leave accrual rate other than the one hour for every 30 hours worked rate provided in the law as originally enacted, as long as sick leave accrues regularly and the employee will accrue 24 hours by the 120th calendar day of employment. If the paid leave is not accrued at the beginning of each 12 month period, the carry over requirements apply, so that up to six days or 48 hours must carry over to the next year.
AB 304 also permits employers to continue using policies that existed prior to January 1, 2015 if at least one day or eight hours of sick leave or paid time off is earned within three months of employment, and employees are eligible to earn at least three days or 24 hours within nine months of employment. However, any modification to the accrual rate that existed prior to January 1, 2015 must meet the statutory requirements of one hour of paid leave for every 30 hours worked or the employer must provide the full amount of leave at the beginning of each year of employment, calendar year or 12 month period. In addition, if a class of employee is not covered by the existing policy, a new policy must be adopted for the class that meets the statutory rules for new policies.
AB 304 simplifies sick leave calculations, especially for employees with fluctuating pay rates or commissions, by providing that for all non-exempt employees sick leave can be calculated in one of two ways: either in the same manner as the regular rate of pay for the workweek in which the employee uses paid sick time, whether or not the employee actually works overtime in that workweek or; by dividing the employee's total wages, not including overtime pay, by the employee's total hours worked in the full pay periods of the prior 90 days of employment. AB 304 also simplifies sick pay calculation for exempt employees as well, by providing that employers may use the same rate used for other forms of paid leave.
To further assist employers, the California Department of Labor Standards Enforcement (DLSE) recently issued an opinion letter interpreting the paid sick leave law requirement that no carry-over of accrued but unused time to the next year is required if the employee is provided a minimum of three days or 24 hours at the beginning of the employment year, calendar year or 12 month period. Specifically, the DLSE determined that the employer must provide the greater of 24 hours or three days. This means that an employee regularly working six hour days would be entitled to four days of six hours each, although this is more than 3 days of leave, while an employee regularly working 10 hour days is entitled to three days of 10 hours each, or 30 hours of sick leave, although this is more than 24 hours of leave. Similarly, if an employer places a cap on accrual of six days or 48 hours, the likely interpretation would be that the cap for a 10 hour shift employee would be 60 hours, and the cap for a six hour shift employee would be 48 hours. Employers should note, however, that while DLSE opinion letters are persuasive, they are not binding on courts of law.
SB 600: Senate Bill 600 expands the protections of the Unruh Civil Rights Act, a law designed to protect consumers. The Unruh Civil Rights Act already provides that all persons within the jurisdiction of this state are entitled to full and equal accommodations in all business establishments regardless of their sex, race, color, religion, ancestry, national origin, disability, medical condition, genetic information, marital status, or sexual orientation. SB 600 extends these protections by prohibiting discrimination by businesses based on citizenship, primary language or immigration status. Although the law applies to consumers rather than employees, it is suggested that employers train employees not to discriminate against customers on the basis of any protected status. The law becomes effective on January 1, 2016.
AB 987: Effective January 1, 2016, Assembly Bill 987 prohibits an employer from retaliating or otherwise discriminating against a person for requesting accommodation of his or her disability or religious beliefs, regardless of whether the accommodation request was granted. This legislation was in response to the California Court of Appeal decision in Rope v. Auto-Chlor System of Washington, Inc., in which the court held that a request for reasonable accommodation was not a protected activity under the California Fair Employment and Housing Act, and therefore a claim of retaliation against an employer could not be made if an employer terminated an employee for requesting an accommodation. The legislature indicated that this opinion was in direct conflict with longstanding state and federal laws which do protect an employee's right to request a reasonable accommodation and sought to amend FEHA to clarify that employees are protected from retaliation and discrimination for requesting a reasonable accommodation based on a disability or religious belief, regardless of whether the request is granted.
The Fair Pay Act: It was little commented upon as it worked its way through the legislature, being just one of thousands of laws proposed each year. But make no mistake about it, Senate Bill 358, The Fair Pay Act, is an important new law for California employees and employers. Prompted by the continuing wage gap between men and women, SB 358 is designed to improve a California law that has existed since 1949. Prior to the enactment of SB 358, employees claiming that they received unequal pay based on their gender had to demonstrate that they weren't paid at the same rate as someone of the opposite sex at the same establishment for equal work. The Fair Pay Act eliminates the reference to the same establishment, so that the business enterprise as a whole will be examined, and changes the standard from equal work to substantially similar work, taking into account skill, effort and responsibility, performed under similar working conditions. If an employee can show that he or she is paid less than someone of the opposite sex doing substantially similar work, then the employer has the burden to demonstrate that the wage difference is based on a seniority system, a merit system, a system that measures earnings by quality or quantity of production, or a bona fide factor other than sex, such as education, training or experience. A bona-fide factor other than sex can only be applied if the employer demonstrates that the factor is not based on or derived from a sex-based differential in compensation, is related to the position in question, and is consistent with business necessity. "Business necessity" is defined as an overriding legitimate business purpose such that the factor relied upon effectively fulfills the business purpose it is supposed to serve. An alternative business practice that would serve the same purpose without producing the wage differential would render the defense inapplicable.
SB 358 also prohibits an employer from discriminating or retaliating against employees for discussing or disclosing their own wages, discussing the wages of others, or inquiring about the wages of others. Employees are permitted to file claims in court or with the Division of Labor Standards Enforcement to recover unpaid wages, an equal amount as liquidated damages, interest and attorneys' fees and costs. Additional relief can include reinstatement and any appropriate equitable relief. The Fair Pay Act becomes effective on January 1, 2016.
The Wage Theft Bill: Senate Bill 588, referred to as the wage theft bill, significantly expands individual liability for wage and hour violations, by authorizing the Labor Commissioner to hold a hearing to recover civil penalties for wage and hour violations against not only the employer, but also a person acting on behalf of an employer, which includes an owner, director, officer, or managing agent of the employer. These persons may now be held liable for violating or causing a violation of any provision regulating minimum wages or hours and days of work in any Wage Order or the Labor Code. SB 588 also makes it easier for the Labor Commissioner to collect unpaid wages on behalf of workers, by granting power to issue levies and liens against the employer's property and to issue stop orders requiring businesses to cease operating until payment obligations are satisfied.
The new law also includes some unusual provisions which require that any individual or business entity that contracts for services in the property services or long-term care industries to be jointly and severally liable for any unpaid wages where the individual or business entity has been provided notice, by any party, of any proceeding or investigation by the Labor Commissioner in which the employer is found liable for unpaid wages. The requirements do not impose liability on individual residences or home-based businesses. "Property services" is defined as janitorial, security guard, valet parking, landscaping or gardening services. SB 588 becomes effective on January 1, 2016.
AB 1513: Effective January 1, 2016, Assembly Bill 1513 establishes Labor Code Section 226.2, which requires that employers paying piece-rate compensation must pay employees for rest and recovery periods and other nonproductive time separately from any piece-rate compensation, and that wage statements reflect these payments. The hourly rate paid for rest and recovery periods must be the greater of the applicable minimum wage, or the employee's average hourly wage for all time worked excluding rest and recovery periods or overtime, and the rate paid for other non-productive time must be at least the applicable minimum wage. Employers are provided a limited safe harbor for certain claims filed on or after March 1, 2014 for uncompensated rest and recovery periods or other nonproductive time, provided payments are made in accordance with the new requirements by December 15, 2016.
AB 1513 also requires that employee wage statements include the total hours of paid rest and recovery periods, the rate paid for these periods and gross wages paid during the pay period, and the total of all other nonproductive time, the rate of compensation for that time, and gross wages paid for the pay period.
SB 579: Senate Bill 579 expands Labor Code section 230.8, providing additional circumstances under which employers with 25 or more employees must provide school or child care activities leave. Beginning January 1, 2016, employees may take leave of up to 40 hours per year, not to exceed eight hours per month, to find, enroll and re-enroll a child in school or with a licensed child care provider, and to handle certain child care emergencies and school emergencies that prohibit the child from attending or require that the child be picked up from school. The leave will extend to a parent, guardian, stepparent, foster parent, grandparent, and to an employee who stands in loco parentis to a child. Employers are permitted to require the employee to provide documentation from the school or the child care provider regarding the child-related activity.
SB 579 also amends Labor Code Section 233, known as the kin care law, to permit employees to use kin care for the purposes set forth in California's Healthy Workplaces, Healthy Families Act of 2014, also known as the paid sick leave law, and to give "family member" the same meaning as provided in the sick leave law.
AB 1506: Effective upon signing, Assembly Bill 1506 amends the Private Attorneys General Act of 2004, commonly known as "PAGA", in a manner that should benefit employers and employees alike and reduce lengthy litigation. Among other things, PAGA permits employees to bring civil actions for violations of California Labor Code section 226(a)(6) and (8), which require an employer to provide its employees with specified information regarding their wages, including the inclusive dates of the period for which the employee is paid and the name and address of the legal entity that is the employer.
However, under AB 1506, an employer may now cure any violation of paragraph (6) or (8) by showing that the employer has provided a fully compliant, itemized wage statement to each aggrieved employee for each pay period for the three-year period prior to the date of the written notice of the alleged violation(s). Per AB 1506, the employer must cure any violation within 33 calendar days of the notice, and may not avail himself or herself of the cure provisions more than once in a 12-month period for the same violation(s) contained in the notice, regardless of the location of the worksite.
In the event that the aggrieved employee disputes that the alleged violation has been cured, the aggrieved employee must provide written notice of the dispute to the employer and the Labor and Workforce Development Agency. Within 17 calendar days of the dispute notice, the LWDA shall review the actions of the employer to cure the alleged violation(s), and provide its decision to the aggrieved employee and the employer. The LWDA may also grant the employer three additional days to cure the alleged violation(s). If the LWDA determines that the alleged violation(s) has not been cured or if the LWDA fails to provide a timely decision, the aggrieved employee may proceed with a civil action under PAGA.
In short, this amendment enables an employer to expeditiously exit the employment litigation highway, while quickly remedying an employee's harm. Sensible, right? We hope that the California Legislature considers similar amendments in the future.
AB 622: Assembly Bill 622, which takes effect on January 1, 2016, adds section 2814 to the California Labor Code. Section 2814 prohibits employers from using E-Verify to check the employment authorization status of an existing employee or an applicant who has not been offered employment, except as required by federal law or as a condition of receiving federal funds. Furthermore, upon using the E-Verify system, if the employer receives a tentative non-confirmation issued by the Social Security Administration or the United States Department of Homeland Security which indicates the information entered into E-Verify did not match federal records, the employer shall comply with the required employee notification procedures governing the use of the E-Verify system. An employer who violates section 2814 is liable for a civil penalty up to $10,000 for each violation, in addition to other remedies available.
AB 970: By amending sections 558, 1197, and 1197.1 of the California Labor Code, Assembly Bill 970 authorizes the Labor Commissioner to investigate and, at the request of local government, enforce local laws regarding overtime hours or minimum wage provisions. The Labor Commissioner may issue citations and penalties for violations, except when local government has already issued a citation for the same violation. In addition, AB 970 amends section 2802 of the California Labor Code by authorizing the Labor Commissioner to issue citations and penalties to employers for violating the expense reimbursement requirement of section 2802. AB 970 takes effect on January 1, 2016.
AB 1509: Assembly Bill 1509 amends sections 98.6, 1102.5, and 6310 of the California Labor Code by extending certain retaliatory protections afforded to employees to their family members who work for the same employer. Under existing law, employers are prohibited from discharging an employee or taking an adverse action against an employee or applicant for employment because the employee or applicant has engaged in protected conduct, such as filing a written complaint with a government agency based on employment conditions. Effective January 1, 2016, such retaliatory protections will include the employee's or applicant's family members. AB 1509 also amends section 2810.3 of the California Labor Code, a law that prohibits the shifting of legal responsibility for certain Labor Code requirements from employers to labor contractors, to exclude client employers that are not a household goods carrier due solely to the employer's use of a third-party household goods carrier permitted by the Public Utilities Commission.
SB 501: Senate Bill 501 changes the amount of an employee's weekly earnings that would be exempt from a wage garnishment order in California. Currently the amount subject to garnishment cannot exceed the lesser of 25% of the employee's disposable earnings and the amount by which the individual's disposable earnings for the week exceed 40 times the state minimum wage in effect at the time the earnings are payable. Beginning on July 1, 2016, the maximum amount subject to garnishment will change to the lesser of 25% of the employee's disposable earnings for the week or 50% of the amount by which the employee's disposable earnings for the week exceed 40 times the state minimum hourly wage in effect at the time the earnings are payable. If the employee works in a location where the local minimum wage exceeds the state minimum wage, the local minimum wage in effect at the time the earnings are payable will be used for this calculation.
The author would like to gratefully acknowledge the assistance of Joanne Warriner and Harrison Finch, Esq.
This publication is published by the law firm of Ervin Cohen & Jessup LLP. The publication is intended to present an overview of current legal trends; no article should be construed as representing advice on specific, individual legal matters, but rather as general commentary on the subject discussed. Your questions and comments are always welcome. Articles may be reprinted with permission. Copyright ©2015. All rights reserved. ECJ is a registered service mark of Ervin Cohen & Jessup LLP. For information concerning this or other publications of the firm, or to advise us of an address change, please visit the firm's website at www.ecjlaw.com.
Kelly O. Scott
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redpajama_set_name: RedPajamaCommonCrawl


5 months ago benyaminj unlocked the 6 YEAR Veteran achievement!
1 year ago benyaminj unlocked the 5 YEAR Veteran achievement!
Exec: 0.16021991 © 2004-2016 VGBoxArt.com. All rights reserved. Crafted in San Francisco by Reed.


The Los Angeles Modern Design Show & Sale, formerly LA Modernism, is the American West Coast's premier shopping bash for 20th century furniture, decorative and fine arts from across the US and Europe. Now making the transoceanic trip to Japan and Ginza's Matsuya, it's set to feature dealers from both Tokyo and elsewhere in Japan, all specialised in modernist wares from the '50s all the way to the '80s. If you're looking to upgrade the décor of your home for spring (and have some extra cash to burn), this one should make for a worthy destination.


I like your article– very straight forward and have very good points!
I talked about the lack of conversation (or dialogue) on my blog just the other day. "Twitter NOT" if you're interested.
So yes, I heartily agree that social media is about engaging and not about spouting forth.


text:
Q: Live changes on site I am trying to make a php file in which I will send data from database and through them i will show 0 or 1. In my example I have a table with two user_ids and a parameter in which takes the value 0 or 1. From test.php I fill a form by giving the user_id and I submit it. When I submit it for this user the parameter in becomes 0 if it was 1 and vise versa. In next.php I use <iframe src="show.php"> and in show.php I show the user_id and in. What I want is when I submit a user_id, immediately to see the changes in show.php. What I did is to refresh the page all the time but it was too disturbing. Can you suggest something else? Here is some code.
test.php
<?php
require_once 'include_php/db.php';
global $dbcnx;
?>
<form action="" method="get">
    <input type="text" name="id"/>
    <input type="submit" name="submit"/>
</form>

<?php

if(isset($_GET['submit']))
{
    $id = $_GET['id'];
    $res = mysqli_query($dbcnx, "select * from people where uid = ".$id.";");
    $row = mysqli_fetch_array($res);

    if($row['in'] == 0) $up = mysqli_query($dbcnx, "UPDATE `people` SET `in`=1 WHERE uid=".$id.";");
    else $up = mysqli_query($dbcnx, "UPDATE `people` SET `in`=0 WHERE uid=".$id.";");
}

show.php
<?php
require_once 'include_php/db.php';
global $dbcnx;

$res = mysqli_query($dbcnx, "select * from people");

while($row = mysqli_fetch_array($res))
{
    echo $row['uid']." ".$row['in']."<br/>";
}

print "<script>window.location.replace('show.php');</script>"; //here is the disturbing refresh

next.php
<iframe src="show.php">

A: What you want is live updates without hard refreshing your page. You can achieve this by using AJAX requests, or by using websockets.
With an ajax request, you could easily set a timeout function to refresh your iframe every x-seconds/minutes.
This question gives a good description on how to give it a go.

redpajama_set_name: RedPajamaStackExchange


A fragment of a wheel thrown ceramic vessel of Roman date. The fragment has an oxidised buff orange fabric with a hard, smooth/powdery texture and is of a local (unsorced) type. Ovoid voids are present suggesting calcareous inclusions.
The fragment is 39.1mm long, 30.6mm wide, 5.6mm thick and weighs 5.6g.


On the southeast side of the Island, nestled between Surfside and Tom Nevers, is the peaceful and scenic area of Madequecham. The only access is a private road that winds through thousands of acres of beautiful conservation land, with moors, bogs, meadow land, and eventually, the beach. It is a wonderful area for bird watching, and the beach is by private access or 4-wheel drive vehicles only.
The few homes in this area enjoy the privacy of their own private acreage.


Abstract Based on binaural signals, i.e. the signals observed at the two ears, a listener can localize and recognize different sound sources and then focus on one of these. For decades, researchers have tried to invent a machine that can do the same under similar conditions. Despite all the efforts, the human auditory system is, by far, superior to any machine that has been devised. The topic of this thesis is computational techniques for the localization and separation of sources in binaural signals. In order to give an overview of different areas of research that have considered the problems of source localization and separation, we start with a review of existing techniques. This provides the background for the techniques that we propose subsequently. Binaural Localization The most important cues for localization of sound sources in binaural signals are the level and time differences between the ears. We propose a technique for the joint evaluation of these cues where noisy level difference estimates are combined with less noisy but ambiguous time difference estimates in order to provide accurate azimuth estimates. The proposed technique enables the localization of sources and the tracking of these in dynamic scenes. Head model Based on a study of the level and time differences as function of azimuth angle for different heads, we propose a generic model that is parametrized by the distance between the ears only. This enables the use of the binaural localization technique mentioned above for a listener whose head related transfer functions have not been measured. Binaural separation For the separation of sources we propose a method based on spatial windowing in the azimuth parameter space. Separation of overlapping partials Finally, we propose a technique for the separation of overlapping partials in mixtures of harmonic instruments. The technique is based on the similarity of temporal envelopes between the different partials of a harmonic note.


text:
Q: Mysql query to filter out data based on two logic This is a sample table:
  sample_id  |      timestamp       | p_id
============================================
    62054    |  2018-09-25 10:18:15 |  2652
    62054    |  2018-09-27 16:44:57 |  966
    62046    |  null                |  1809
    62046    |  2018-09-25 10:18:15 |  2097

We need to filter out unique sample_id column, but the logic is

*

*IF the timestamp column is null, then return those null column data
    62046 | null | 1809

*IF the timestamp column is not null, then return the latest timestamp column data
 62054 | 2018-09-27 16:44:57 | 966

So its great if anyone provide the sql query.
We need somethings like that,
WHERE
IF(
    NOT NULL = all row group by sample_id,
    row where cancelled_at is maximum,
    null column
)

A: This query should give you the results you want. It looks for a row with a NULL timestamp, or a row which has a non-NULL timestamp which is the maximum timestamp for that sample_id, but only if there isn't a row for that sample_id which has a NULL timestamp:
SELECT *
FROM table1 t1
WHERE timestamp IS NULL OR
      timestamp = (SELECT MAX(timestamp)
                   FROM table1 t2
                   WHERE t2.sample_id = t1.sample_id) AND
                   NOT EXISTS (SELECT *
                               FROM table1 t3
                               WHERE t3.sample_id = t1.sample_id AND
                                     t3.timestamp IS NULL)

Output:
sample_id   timestamp               p_id
62054       2018-09-27T16:44:57Z    966
62046       (null)                  1809

A: Using variables:
SELECT sample_id, timestamp, p_id
FROM (
   SELECT sample_id, timestamp, p_id,
          @seq := IF(@s_id = sample_id, @seq + 1,
                     IF(@s_id := sample_id, 1, 1)) AS seq
   FROM mytable
   CROSS JOIN (SELECT @s_id := 0, @seq := 0) AS vars
   ORDER BY
      sample_id,
      CASE
         WHEN timestamp IS NULL THEN 1
         ELSE 2
      END,
      timestamp DESC
) AS t
WHERE t.seq = 1;

Demo
Explanation:
To understand how this works you need to execute the subquery and examine the output it produces:
SELECT sample_id, timestamp, p_id,
       @seq := IF(@s_id = sample_id, @seq + 1,
                  IF(@s_id := sample_id, 1, 1)) AS seq
FROM mytable
CROSS JOIN (SELECT @s_id := 0, @seq := 0) AS vars
ORDER BY
   sample_id,
   CASE
      WHEN timestamp IS NULL THEN 1
      ELSE 2
   END,
   timestamp DESC

Output:
sample_id   timestamp           p_id    seq
-------------------------------------------
62046       NULL                1809    1
62046       25.09.2018 10:18:15 2097    2
62054       27.09.2018 16:44:57 966     1
62054       25.09.2018 10:18:15 2652    2

You can see here that calculated field seq is used to prioritize records inside each sample_id slice.
Note: If you're on MySQL 8.0 you can use window functions to implement the same logic.

A: Find out those records where time is not null and filter out
   timestamp nulls sample_id and for null timestamp
 Use union
select * from t1 where (t1.sample_id,t1.timestamp)
in (

SELECT t.sample_id,max(t.timestamp) AS time
   FROM t1 t
   WHERE t.sample_id NOT IN (select sample_id from t1 where t1.timestamp is null)
     GROUP BY t.sample_id
 )
 UNION
SELECT *
   FROM t1 t
 WHERE t.timestamp IS NULL

output
    sample_id   timestamp           p_id
    62054       2018-09-27 16:44:57 966
    62046       null                1809

A: *

*Group by on the sample_id.

*Using If() function, check if the minimum value of the timestamp for the group is null or not. If it is null, return null, else return the Max() value.

Try the following query:
SELECT sample_id,
       IF(MIN(timestamp) IS NULL,
          NULL,
          MAX(timestamp)) AS timestamp
FROM your_table
GROUP BY sample_id


New construction of a BREEAM Excellent Health Centre on the outskirts of Llangollen, constrained by the River Dee on one side and the busy A483 on the other. Effective public liaison was essential in managing this high profile project with minimal disruption.
DESIGN DEVELOPMENT - Read work with local design practices and consultancies to ensure local delivery of best value solutions. By engaging and managing the design development, the team were able to enhance the project with an additional 60m2 of photovoltaic cells, saving 3.4t carbon and £450 per annum to the client running costs.
QUALITY - Beginning with the end in mind is a quality principle Read champion to ensure built-in quality. Currently under consideration for an LABC Quality award, the design and finish of the Health Centre is exemplary with local, sustainably sourced products featuring throughout.
CONSIDERATE - By liaising closely with local residents, town council and schools, the team ensured consideration at all times. By planning effectively and communicating clearly, the interface with the adjacent housing estate, preserved steam railway and interested public groups was managed without incident and 100% positive feedback.


I was really struggling with Pinaddicts this month but as I was racking my brain wondering what I could do that wouldn't eat up too much time I received an e-mail in my inbox from a craft swap I had signed up to a few months ago. This was ideal so I went into my Pinterest account, had a good browse through my Pinaddicts folder keeping in mind what my swap partner would appreciate and love and well.
As my swap partner enjoys baking this was the perfect idea for her! I bought a case from The Works which was in the sale.
I bought some cake cases, a few extra gifts as part of the swap instructions and bought a select few toppings from my favourite local sweet shop. This included some Cornish fudge which I chopped up (perfect for a vanilla cupcake topping), some mini marshmallows, roasted and chopped hazelnuts for a chocolate and hazelnut cookie and some chocolate buttons. Yummy! I put all these in cellophane type bags to keep them fresh on their journey. Here is the finished result! Complete with some little flags for a real tea party theme!
To add a personal touch I hand made a little card with 2 mini envelopes. Inside I popped a little peice of paper, one with a recipe for a cookie mix I always use and one for a lovely fudge icing.
Pinaddicts now has a lovely new site all of its own so please head on over to check out all the other entrants here!
Thank you Kath very easy to do too!
Oh I've seen this a lot on Pinterest but I like that you've added some little extras and I would never have thought about cutting up fudge for topping - thanks for the tip!


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I'm happy to be busy. I'm happy to have a wonderful family.
@ John Williams quote of the day
John Williams Quotes (16 quotes)
"I always wrote music for my friends, but my focus was on playing piano. I didn't think I'd be quite good enough to be a soloist, but I believed that if I worked hard enough, I could work as a player, a teacher."
― John Williams ―
Good, Music, Work, Enough
"Working in Hollywood for the orchestra world is a very time consuming and laborious job."
Time, World, Hollywood, Orchestra
Family, Happy, Wonderful, Busy
"I think of myself as a film composer."
Film, Composer
"As a young pianist in Hollywood, I began orchestrating for others, and I just felt really comfortable doing that."
Young, Felt, Hollywood, Comfortable
"As a youngster, I never dreamed there could be a career actually earning a living writing music."
Music, Writing, Earning
"I, over the years, have always felt more comfortable if I could go into a projection room and look at a film and not really know what to expect. If you read the script first, you form all kinds of preconceptions about how things look, what the location's like, what the actors are like."
Felt, Film, Comfortable, If I Could
"For me, there is a strong family connection to Boston and anything connected to Boston, which includes Fenway."
Family, Strong, Connected, Boston
"I'm not a frustrated concert composer, and the concert pieces I've done have been a small part of my work. What I've sought there is instruction, variation from the demands of film and relief from its restrictions."
Work, Done, Film, Pieces
"The Olympics are a wonderful metaphor for world cooperation, the kind of international competition that's wholesome and healthy, an interplay between countries that represents the best in all of us."
Best, World, Kind, Wonderful
"There are occasionally eureka moments - off the top of my head, maybe Darth Vader's theme, you know, the imperial march."
Moments, Theme, March
"I was never that into the movies. Never. Even as a youngster. I became interested in movie music only because of the studio orchestras in Hollywood."
Music, Movies, Movie, Hollywood
"Composing music is hard work."
Music, Work, Hard, Hard Work
"Any working composer or painter or sculptor will tell you that inspiration comes at the eighth hour of labour rather than as a bolt out of the blue. We have to get our vanities and our preconceptions out of the way and do the work in the time allotted."
Time, Work, Way, Inspiration
"When you think about Boston, Harvard and M.I.T. are the brains of the city, and its soul might be Faneuil Hall or the State House or the Old Church. But I think the pulsing, pounding heart of Boston is Fenway Park."
Heart, Might, House, Church
"So much of what we do is ephemeral and quickly forgotten, even by ourselves, so it's gratifying to have something you have done linger in people's memories."
People, Done, Forgotten, Memories
Looking for more quote authors similar to John Williams?
Famous composers:
Stephen Sondheim, Nobuo Uematsu, John Zorn, Andrew Lloyd Webber, Charles Ives, Aaron Copland, Keith Jarrett, Elmer Bernstein, Alan Hovhaness, Lukas Foss
Popular American composers:
Stephen Sondheim, John Zorn, Charles Ives, Aaron Copland, Keith Jarrett, Elmer Bernstein, Alan Hovhaness, John Cage, Morton Feldman, Marvin Hamlisch
Author born: February 08, 1932
Author Profession: Composer


Have you ever wanted to have more time to do your daily tasks? Or have you ever asked time to slow down a bit so you can catch a deadline. I bet you've already done both just as I did in one time or another. These days, I long for my childhood because, back then, I cared less for time.
The book I'm reading now, The Time Keeper, is written by one of my favorite authors, Mitch Albom. I've read all his books, including the more well-know ones, Tuesdays with Morrie and The Five People You Meet in Heaven. An excellent storyteller, Albom has once again captivated my imagination while touching my inner being with the message of his story.
The Time Keeper is actually not a story about someone with an excellent collection of clocks but, rather, it's a story of Father Time and how he got to be the timekeeper of humanity. I loved how the author has woven the story of his life. And although I know that Father Time is symbolical, it's still fascinating to read about the fictional life Mitch Albom has written.
The Time Keeper also revolves around the story of two special people - Victor, who longed to slow time down; and Sarah, who wanted to make it faster. Both characters are in contrast with one another but I was able to identify with both of them. I don't want to spoil the fun and delve into details but I know that you would also learn an awful lot from their stories.
If there's one passage in this novel that struck me hard, it is this: "It is never too late or too soon. It is when it is supposed to be." Plain and simple, but full of meaning for me. It reminds me that everything happens in God's perfect time. That I should sometimes stop and smell the flowers, to enjoy precious moments with my family.
I hope you can also find time to read this book. I'd love to read about your favorite passages, too, so drop me a line in the comments box if you can!


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Home › Courses › PADI Speciality Courses › PADI Diver Propulsion Vehicle (DPV) Speciality Course
The PADI Diver Propulsion Vehicle Speciality Course will enable the participant to understand the operation, pre- and post-dive maintenance and the techniques of using a DPV. We operate Sea-Doo, Dolphin and Oceanic DPVs. The course includes basic in water skills, towing DPVs and managing a runaway DPV.
All equipment is provided.
Minimum age 12 years, parental approval is required for participants under 18 years old.
Please visit our price list page by clicking here
From Monday (18 January) there are some changes for the foreseeable future to the way the BBC will broadcast the UK Marine Weather Service – including the Shipping Forecast – owing to the impact of coronavirus (COVID-19).
On weekdays, there will be three broadcasts on LW and FM, 0048, 0520 and 1203, with one further broadcast on LW only at 1754.
At the weekends, there will be three broadcasts, all on LW and FM at 0048, 0520 and 1754.
Her Majesty's Coastguard will be broadcasting as normal via NAVTEX and MF/VHF marine radio.
Strong wind and gale warnings will still be available as and when needed.
Andrew Colenutt, Head of Hydrography and Meteorology at the Maritime and Coastguard Agency said: 'We completely understand and support the decision of the BBC which faces its own challenges. They are a key partner in bringing this vital information to mariners and are doing all they can to make sure the service continues.
'We continue to support the maritime industry at this difficult time and have taken all the measures we can to protect crew and the lifelines they are providing to the UK. Mariners should be assured that Maritime Safety Information will continue to be broadcast, still meeting the requirements of the international standard known as SOLAS (Safety of Life at Sea).'
For the latest information please visit: www.gov.uk/government/publications/maritime-safety-information-leaflet ... See MoreSee Less


Last week saw the release of another 10 lots within the Parkside release. All lots have now sold out. Don't miss out and register now for our next release or contact our New Breeze sales team on 1300 832 482.


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Celularity - Revolutionizing Cellular Medicine
The field of stem cells (Cellular Medicine) is poised to revolutionize medicine, augmenting our longevity and immunity.
This week I joined with an incredible biotech rockstar, Bob Hariri, M.D., Ph.D, to announce a new company called Celularity.
Celularity is built on 20 years of research legacy by Dr. Hariri and his team. Bob's mission has been to harness the power of the living cell to augment our biology, immunity and longevity. He is the Chairman and CEO, and I'll support his efforts as Co-Founder and Vice-Chairman.
Celularity is being born above the line of "supercredibility" with $250 million in funding from Celgene, United Therapeutics Corporation, Sorrento Therapeutics, Human Longevity, Inc., and a group of venture capitalists.
Joining the board are industry luminaries John Sculley of Apple and Pepsi-Cola, Bill Maris of Section 32 (previously founder of Google Ventures), and Andrew Von Eschenbach, the former commissioner of the US Food and Drug Administration.
Here is what Celularity is up to, and what it means to you...
Biosourcing: "Saving your child's Boot-disk"
Celularity owns and operates LifeBank, the world's only repository of donated placenta cells and biomaterials.
"At your moment of birth, you are probably at the point of biological perfection," says Dr. Bob Hariri. "Your system hasn't been exposed to all of those injurious stimuli, like electromagnetic radiation, chemicals, etc., and your biological software is uncorrupted."
Stem cell banking allows us to capture stem cells with your original, uncorrupted DNA at birth, replicate them into a large number of future dosages and then freeze those doses. Hariri discovered that in addition to cord blood (the blood found in the umbilical cord of a newborn), the placenta of a newborn is an organ very rich in stem cells.
Rather than discard the leftovers of birth, placentas, if saved, may hold the key to a longer and healthier life.
For over 20 years, new parents have trusted LifeBank to bank their children's placental stem cells.
While traditional cord blood repositories, save the newborn's hematopoietic stem cells (useful as a solution to hematopoietic cancers), banking your child's placenta stem cells will provide them with an expanded range of options aimed at enhancing their health and longevity through future developments such as organ engineering.
Currently, cord blood and placental blood transplantation are accepted as standard therapies for more than 80 diseases including leukemias, lymphomas and myelomas.
When our two boys were born 6 years ago, we banked their placental stem cells with LifeBank.
If you (or anyone you know) are planning to have a child, I strongly encourage you to considering banking their placental stem cells, not just their cord-blood.
Celularity acts as a "biorefinery," harnessing the power of the placenta to create therapies across autoimmune and degenerative disease, immuno-oncology and functional regeneration.
Using NK cells, CAR-T Cells and MSC stem cells derived from the placenta, Celularity creates transformative therapeutic options for complex medical conditions ranging from cancer to Crohn's disease.
Celularity has over a dozen pre-clinical and clinical trials and Investigational New Drug applications (IND) in progress, and an intellectual property portfolio of more than 830 issued patents and over 1,800 cases filed.
Functional Regeneration
Celularity has pioneered the use of placental biomaterials as the building blocks upon which a range of transplantable and implantable products have been created for surgical and reconstructive applications.
Celularity's BIOVANCE® and Interfyl™ products are used by physicians to facilitate a patient's regenerative process. Both products are in the market today treating a broad range of serious wounds and burns, as well as being used in reconstructive and orthopedic surgical procedures.
Celularity has also developed groundbreaking methods to produce whole organs from natural and bioprinted scaffolds populated with stem cells derived from the placenta and is today working with leading companies such as United Therapeutics to bring organogenesis to the market.
Our Vision: Augmented Longevity & Immunity
Studies have shown that as we age, the population of stem cells resident in our organs and tissues declines exponentially diminishing our body's ability to heal and repair itself. Moreover, during lifetime, our stem cells are damaged by environmental exposures, rendering them less effective and adaptable.
By replenishing our reservoir of stem cells — nature's repair kit — on an ongoing basis, we can augment our longevity.
Celularity seeks to make 100 years old the new 60, and to provide people with maximal aesthetics, mobility, and cognition as they age. We believe the 20 years of science, research, and intellectual property pioneered by Celularity is the cornerstone for the coming longevity revolution.
Celularity, through its strategic partner Sorrento Therapeutics, has acquired a powerful tool set to engineer cells for broad immunotherapeutic applications. These include proprietary antibody and Chimeric Antigen Receptor (CAR) constructs that will allow Celularity to offer the world's first immunotherapeutic suite of products against validated and novel targets for cancer and immune disease. In addition, Celularity discovered a novel Natural Killer cell from the placenta and is actively developing therapeutic uses.
Celularity is developing the world's first allogeneic off-the-shelf CAR-T cell receptor and CAR-NK products against a number of validated targets for immuno-oncology.
All of these elements together, form the basis for Celularity's vision of Augmented Immunity.
I'm excited for the potential this this company and others in the Longevity Arena can yield, speeding us towards longevity escape velocity.
2. Abundance Digital Online Community: I've also created a Digital/Online community of bold, abundance-minded entrepreneurs called Abundance-Digital. Abundance Digital is my 'on-ramp' for exponential entrepreneurs – those who want to get involved and play at a higher level. Click here to learn more.