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Ketamine's Antidepressive Effects Tied to Opioid System in Brain; Stanford Findings Overturn Beliefs That Drug’s Antidepressive Effects Stem Solely from Impact on Glutamate System

Scientists at the Stanford University School of Medicine have discovered that ketamine works as an antidepressant, at least in part, by activating the brain's opioid system. The finding overturns previously held beliefs that the drug's antidepressant effects stemmed solely from its impact on the glutamate system. These beliefs led to the widespread use of ketamine to treat depression and spurred the development of glutamate-blocking drugs for use as antidepressants. The new finding also highlights the interaction between depression, pain, and opioid addiction and presents an opportunity for clinicians to reframe treatment approaches for three of the most important public health crises today. The research is believed to be the first to address how ketamine works in the human brain to provide relief from depression. A paper describing the work was published online on August 29, 2018 in The American Journal of Psychiatry. The article is titled “Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism.” The article is accompanied by an editorial titled “Is There Really Nothing New Under the Sun? Is Low-Dose Ketamine a Fast-Acting Antidepressant Simply Because It Is an Opioid?" "Before we did the study, I wasn't sure that ketamine really worked to treat depression. Now I know the drug works, but it doesn't work like everyone thought it was working," said Alan Schatzberg, MD, the Kenneth T. Norris Jr. Professor of Psychiatry and Behavioral Sciences, who shares senior authorship of the paper with Carolyn Rodriguez, MD, PhD, Assistant Professor of Psychiatry and Behavioral Sciences. Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery.

Progress on Identifying Aphid-Resistance Genes in Soybean Varieties

A tiny pest can cause huge losses to soybean farmers. Several top soybean-producing states in the U.S. are in the Upper Midwest. In these states, an insect (the soybean aphid) is a damaging pest. Each year, soybean aphids cause billions of dollars in crop losses. In a recent study, researchers have taken a big step toward identifying new soybean genes associated with aphid resistance. "Discovering new resistance genes will help develop soybean varieties with more robust aphid resistance," says lead author Dr. Aaron Lorenz. "There are very few commercially-available varieties of soybean with aphid resistance genes. Newly-identified genes can serve as backup sources of resistance if the ones currently used are no longer useful." Dr. Lorenz is an agronomist and plant geneticist at the University of Minnesota. Currently, insecticides are used to control aphid populations to reduce damage. But aphid populations that are resistant to widely-used insecticides have been found. Environmental issues with insecticide use can also be a concern. These issues may limit insecticide use in the future. Using soybean varieties that are naturally resistant to aphids is an alternative to using insecticides. "But the soybean aphid is a genetically diverse species. It is capable of quickly overcoming plant resistance," says Dr. Lorenz. "So, we need to identify new sources of soybean aphid resistance." To find previously unknown aphid resistance genes, researchers used already-published research. Thousands of varieties of soybean have been tested for aphid resistance. Genetic information also exists for many of these soybean varieties. Dr. Lorenz and colleagues combined data on existing aphid resistance and genetics. "Our goal was to find which parts of the soybean genome contain genes related to aphid resistance," says Dr. Lorenz.

How Cytomegalovirus, a Herpes Virus, Sustains Its Lytic Expression Cycle in Infected Cell; Results May Have Broad Implications

Human cytomegalovirus is a leading cause of birth defects and transplant failures. As it's evolved over time, this virus from the herpes family has found a way to bypass the body's defense mechanisms that usually guards against viral infections. Until now, scientists couldn't understand how it manages to do so. A team of scientists led by Leor S. Weinberger, PhD, the William and Ute Bowes Distinguished Professor and Director of the Gladstone-UCSF Center for Cell Circuitry, uncovered the mechanism that allows the virus to replicate. The team’s study, published online on August 27. 2018 in PNAS, could open new therapeutic avenues to treat not only cytomegalovirus, but other viruses as well. The article is titled “Feedback-Mediated Signal Conversion Promotes Viral Fitness." Normally, when a DNA virus enters your cell, that cell blocks the virus's DNA and prevents it from performing any actions. The virus must overcome this barrier to effectively multiply. To get around this obstacle, cytomegalovirus doesn't simply inject its own DNA into a human cell. Instead, it carries its viral DNA into the cell along with proteins called PP71. After entering the cell, the virus releases these PP71 proteins, which enables the viral DNA to replicate and the infection to spread. "The way the virus operates is pretty cool, but it also presents a problem we couldn't solve," said Noam Vardi, PhD, postdoctoral scholar in Dr. Weinberger's laboratory and first author of the new study. "The PP71 proteins are needed for the virus to replicate. But they actually die after a few hours, while it takes days to create new virus.

Goats Prefer to Interact with Images of People with Happy Facial Expressions--“Results Open New Paths to Understanding the Emotional Lives of All Domestic Animals"

Goats can differentiate between human facial expressions and prefer to interact with happy people, according to a new study led by scientists at Queen Mary University of London. The study, which provides the first evidence of how goats read human emotional expressions, implies that the ability of animals to perceive human facial cues is not limited to those with a long history of domestication as companions, such as dogs and horses. Writing in the journal Royal Society Open Science, the research team describes how 20 goats interacted with images of positive (happy) and negative (angry) human facial expressions and found that the goats preferred to look and interact with the happy faces. Dr. Alan McElligott who led the study at Queen Mary University of London and is now based at the University of Roehampton, said: "The study has important implications for how we interact with livestock and other species, because the abilities of animals to perceive human emotions might be widespread and not just limited to pets." The study, which was carried out at Buttercups Sanctuary for Goats in Kent, UK, involved the researchers showing goats pairs of unfamiliar grey-scale static human faces of the same individual showing happy and angry facial expressions. The team found that images of happy faces elicited greater interaction in the goats who looked at the images, approached them, and explored them with their snouts. This was particularly the case when the happy faces were positioned on the right of the test arena suggesting that goats use the left hemisphere of their brains to process positive emotion.

Diversity of Wild Eggplant Species in Africa May Depend on Protection of Elephant Populations

The evolutionary context of the eggplant was, until recently, very poorly known. Historical documents and genetic data have shown that the eggplant was first domesticated in Asia, but most of its wild relatives are from Africa. Researchers from the Natural History Museums of London (NHM) and Finland (University of Helsinki) have now managed to obtain the first well-supported hypothesis on the origin of the eggplant and its direct relatives. In a study published online on August 9, 2018 in the American Journal of Botany, researchers from the Natural History Museum of London (NHM) and the Finnish Museum of Natural History, University of Helsinki, have sequenced the plastomes of the eggplant and of 22 species directly related to the eggplant. (Editor’s note: Plastomes are the genome sequences of plastids, a type of organelle found in plants, in particular, the genome of the chloroplasts in photosynthetic plants.) chloroplasts.) The article is titled “Shedding New Light on the Origin and Spread of the Brinjal Eggplant (Solanum melongena L.) and Its Wild Relatives.” By comparing the plastome DNA sequences, the scientists hoped to reveal the evolutionary history of the eggplant and its wild relatives. The team obtained a well-supported hypothesis on the origin of the eggplant and its wild relatives, and showed how a single event gave rise to two lineages, one comprising an African group of species and the other the wild progenitor of the domesticated eggplant. "Nearly all species of the group of the eggplant inhabit low land savannahs and more or less arid habitats; some species are very widespread across Africa. Our results suggest that there had been a dramatic expansion of the distribution range of the group over the last two million years." says the first author of the paper, Dr. Xavier Aubriot.

Toward the Genetics of Dreams: Two Acetylcholine Receptors (Chrm1 and Chrm3) Are Found Key to Regulation of REM Sleep in Mouse Study; Double Knockout Almost Completely Abolishes REM Sleep

Rapid eye movement (REM) sleep, a mysterious stage of sleep in which animals dream, is known to play an important role in maintaining a healthy mental and physical life, but the molecular mechanisms behind this state are barely understood. Now, an international research team led by researchers at the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan has identified a pair of genes that regulate how much REM and non-REM sleep an animal experiences. Sleep is a universal and vital behavior in animals. In higher vertebrates such as mammals and birds, sleep is classified into two phases, REM sleep and non-REM sleep. During REM sleep, our brain is as active as it is during wakefulness, and this stage is believed to function in memory consolidation. Although our knowledge of the neural mechanisms underlying sleep has gradually advanced, the essential molecular factors that regulate REM sleep are still unknown. Now, however, a research team led by Dr. Hiroki Ueda at RIKEN BDR and The University of Tokyo has identified two essential genes involved in the regulation of REM sleep. The amount of REM sleep was drastically decreased down to almost undetectable levels when both genes were knocked out in a mouse model. This study was published in the August 28, 2018 issue of Cell Reports. The article is titled “Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep.” A related commentary article, titled “Life Without Dreams: Muscarinic Receptors Are Required to Regulate REM Sleep in Mice,” is published in the same issue of Cell Reports. Several past studies have suggested that acetylcholine--the first identified neurotransmitter--and its receptor(s) are important for the regulation of REM sleep. Acetylcholine is abundantly released in some parts of mammalian brain during REM sleep and wakefulness.

Combination of Immunotherapy and Synthetic CpG Oligo Shows Promise for Treatment of Advanced Melanoma

A UCLA-led study has found that a treatment that uses a bacteria-like agent in combination with an immunotherapy drug could help some people with advanced melanoma, an aggressive form of skin cancer, live longer. The research showed that using the immunotherapy drug pembrolizumab and the experimental agent SD-101, a sequence of nucleic acids that mimics a bacterial infection, altered the microenvironment around the tumor in a way that enabled the immune system to more effectively attack the cancer. The research was an early-stage study, conducted to test the side effects and best dosage of a potential new combined therapy, and the findings were published online on August 28, 2018 in Cancer Discovery. The article Is titled “SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase 1b, Multicenter Study.” Pembrolizumab, which is marketed under the brand name Keytruda, works by blocking a protein called PD-1, which interferes with immune system function. Blocking PD-1 with pembrolizumab enables the immune system cells to better attack the cancer. While pembrolizumab has been a significant advancement for treating people with a variety of advanced or metastatic cancers, a majority of metastatic melanoma tumors are still resistant to the drug. "We have found that the reason patients with metastatic melanoma do not initially respond to immunotherapy with an anti-PD-1 is that their immune system was not ready," said Antoni Ribas (photo), MD, PhD, the study's lead author, a Professor of Medicine at the David Geffen School of Medicine at UCLA and Director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program.

3D Liver Tissue Implants Made from Human Stem Cells Support Liver Function in Mice

Stem cells transformed into 3D human liver tissue by scientists from the Medical Research Council (MRC) Centre for Regenerative Medicine at the University of Edinburgh in Scotland show promising support of liver function when implanted into mice with a liver disease. The scientists say that, in addition to being early-stage progress towards developing human liver tissue implants, it could also reduce the need for animals in research by providing a better platform to study human liver disease and test drugs in the lab. In this study, published in Archives of Toxicology, the scientists took human embryonic stem cells and induced pluripotent stem cells (adult cells that have been induced to turn back into stem cells) and carefully stimulated them to develop the characteristics of liver cells, called hepatocytes. The researchers grew these cells as small spheres in a dish for over a year. Professor David Hay from the MRC Centre for Regenerative Medicine at the University of Edinburgh, who led the research, said: "This is the first time anyone has kept stem cell-derived liver tissue alive for more than a year in the lab. Keeping the cells alive and stable as liver cells for a long time is a very difficult step, but crucial if we hope to use this technology in people." The scientists then collaborated with materials chemists and engineers to identify suitable polymers already approved for use in humans in order to develop them into 3D scaffolds. The best material was a biodegradable polyester, polycaprolactone, which was spun into microscopic fibers. The fiber mesh formed a scaffold one centimeter square and a few millimeters thick. Liver cells derived from embryonic stem cells, which had been grown in culture for 20 days, were loaded onto the scaffolds and implanted under the skin of mice.

New Kind of Human Brain Cell (Rosehip Neuron) Identified

One of the most intriguing questions about the human brain is also one of the most difficult for neuroscientists to answer: What sets our brains apart from those of other animals? "We really don't understand what makes the human brain special," said Ed Lein, PhD, Investigator at the Allen Institute for Brain Science. "Studying the differences at the level of cells and circuits is a good place to start, and now we have new tools to do just that." In a new study published online on August 27, 2018 in Nature Neuroscience, Dr. Lein and his colleagues reveal one possible answer to that difficult question. The article is titled “Transcriptomic and Morphophysiological Evidence for a Specialized Human Cortical Gabaergic Cell Type.” The research team, co-led by Dr. Lein and Gábor Tamás, PhD, a neuroscientist at the University of Szeged in Szeged, Hungary, has uncovered a new type of human brain cell that has never been seen in mice or other well-studied laboratory animals. Dr. Tamás and University of Szeged doctoral student Eszter Boldog called these new cells "rosehip neurons" – because, to them, the dense bundle each brain cell's axon forms around the cell's center looks just like a rose after it has shed its petals, he said. The newly discovered cells belong to a class of neurons known as inhibitory neurons, which put the brakes on the activity of other neurons in the brain. The study hasn't proven that this special brain cell is unique to humans. But the fact that the special neuron doesn't exist in rodents is intriguing, adding these cells to a very short list of specialized neurons that may exist only in humans or only in primate brains.

Research Reveals FKBP5 Gene Variant Affects Chronic Pain After Traumatic Injury Because It Alters Ability of the Gene to Be Regulated by a MicroRNA

The gene FKBP5 is a critical regulator of the stress response and affects how we respond to environmental stimuli. Previous studies have shown that certain variants of this gene play a role in the development of neuropsychiatric disorders such as posttraumatic stress disorder, depression, suicide risk, and aggressive behavior. But in 2013, University of North Carolina (UNC) School of Medicine researchers were first to show an association between genetic variants in FKBP5 and posttraumatic chronic pain. In particular, the study found that people with a variant or minor/risk allele on chromosome 6 known as rs3800373 are likely to experience more pain after exposure to trauma (such as sexual assault or motor vehicle collision) compared to people who don't have this variant. Now, a new study by the same research group, published in the Journal of Neuroscience, has confirmed this association in a cohort of more than 1,500 people of both European American and African American descent who experienced motor vehicle collision trauma. Sarah Linnstaedt (photo), PhD, Assistant Professor of Anesthesiology and an investigator in the Institute for Trauma Recovery, is the study's lead author. The article is titled “A Functional riboSNitch in the 3′UTR of FKBP5 Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Posttraumatic Pain.” "In our current study, we showed that the reason this variant affects chronic pain outcomes is because it alters the ability of FKBP5 to be regulated by a microRNA called miR-320a," Dr, Linnstaedt said. MicroRNAs play an important role in the regulation of gene expression, primarily by degrading or repressing the translation of messenger RNA (mRNA). "In individuals with the minor/risk allele, the microRNA does not bind well to FKBP5," she said.

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