Syndicate content

Two Dopamine Receptors Are Key to Ritalin Activity

Research reported by scientists from the University of California-San Francisco (UCSF) has shown that, in a rat model, Ritalin (methylphenidate) boosts both the ability to focus on tasks and the speed of learning by increasing the activity of the neurotransmitter dopamine through mechanisms involving two distinct dopamine receptors in the amygdala region of the brain. "We found that a dopamine receptor, known as the D2 receptor, controls the ability to stay focused on a task--the well-known benefit of Ritalin," said Dr. Patricia Janak, co-senior author of the paper. "But we also discovered that another dopamine receptor, D1, underlies learning efficiency." "Since we now know that Ritalin improves behavior through two specific types of neurotransmitter receptors, the finding could help in the development of better targeted drugs, with fewer side effects, to increase focus and learning," said Dr. Antonello Bonci, the other co-senior author of the article. The research assessed the ability of rats to learn that they could get a sugar water reward when they received a signal--a flash of light and a sound. The scientists compared the behavior of animals receiving Ritalin with those that did not receive it, and found those receiving Ritalin learned much better. However, they also found that if they blocked the dopamine D1 receptors with drugs, Ritalin was unable to enhance learning. And if they blocked D2 receptors, Ritalin failed to improve focus. The experiments established the distinct role of each of the dopamine receptors in enabling Ritalin to enhance cognitive performance.

Vaccine Protects Monkeys Against Chicamanguya Virus

Chicamanguya virus (CHIKV) is an insect-borne infectious agent that can cause severe disease in humans and against which there is presently no vaccine. This alphavirus has infected millions of people in Africa, Europe, and Asia since it reemerged in Kenya in 2004. The severity of the disease and the epidemic spread of the virus present a serious public health threat in the absence of vaccines or antiviral therapies. Although seldom fatal, infection with the virus causes highly painful arthritis-like symptoms that can linger for months or even years. CHIKV is capable of adapting to spread through a mosquito species common in much of North America. The virus has been the focus of intense scientific interest ever since a 2006 outbreak on the island of La Reunion in the Indian Ocean infected approximately 266,000 people, killing 260 of them. The name “chicamanguya” comes from an East African tribal word describing the contorted postures of the virus’s pain-wracked victims. Now, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and collaborators have reported development of a virus-like particle (VLP) vaccine that protects rhesus macaques against infection by CHIKV. "This vaccine did an excellent job of protecting the macaques from chikungunya," said Dr. Stephen Higgs, one of the paper's authors.

MicroRNA Binds Protein to Help Prevent Leukemia Progression

In an international study, researchers have discovered that loss of a particular microRNA (miR-328) appears to be a key factor in causing the progression of the more treatable chronic phase of chronic myelogenous leukemia (CML) to its life-threatening phase known as the “blast crisis” stage. The study indicates that CML progresses when immature white blood cells lose miR-328, trapping the cells in their rapidly growing, immature state. The cells soon fill the bone marrow and spill into the bloodstream, a tell-tale sign that the disease has advanced to the blast crisis stage. "These findings indicate that the loss of miR-328 is probably essential for progression from the chronic phase of the disease to the blast crisis stage," said principal investigator and senior author Dr. Danilo Perrotti of Ohio State University. "Our findings also suggest that maintaining the level of this microRNA might represent a new therapeutic strategy for CML blast crisis patients who do not benefit from targeted agents such as imatinib (Gleevec) and dasatinib (Sprycel)," Dr. Perrotti continued. The study also revealed a new function for microRNAs. Researchers have known for some time that microRNAs help regulate the kinds of proteins that cells produce by base-pairing with mRNA targets. But this study shows, reportedly for the first time, that microRNAs can also attach directly to proteins and alter their function. In this case, miR-328 binds to a protein (hnRNP E2) that normally prevents immature blood cells from maturing. "We believe that it [miR-328] normally acts as a decoy molecule, tying up the protein [hnRNP E2] and enabling the white blood cells to mature as they should," Dr. Perrotti said "These findings may help unravel novel pathways responsible for the initiation and progression of leukemia generally," Dr. Perrotti asserted.

Polar Bear Fossil Sequencing Yields Evolutionary History

In the complete sequencing of the mitochondrial genome of a rare ancient polar bear fossil, scientists have gained an understanding of the animal’s evolutionary history and its ability to adapt to changing environments. "Our results confirm that the polar bear is an evolutionarily young species that split off from brown bears some 150,000 years ago and evolved extremely rapidly during the late Pleistocene, perhaps adapting to the opening of new habitats and food sources in response to climate changes just before the last interglacial period," said Dr. Charlotte Lindqvist, research assistant professor in the Department of Biological Sciences at the University of Buffalo and co-lead author of the report. "We have found that polar bears actually survived the interglacial warming period, which was generally warmer than the current one," Dr. Lindqvist said, "but it's possible that Svalbard [the region in Norway in which the fossil was found] might have served as a refugium for bears, providing them with a habitat where they could survive. However, climate change now may be occurring at such an accelerated pace that we do not know if polar bears will be able to keep up. The polar bear may be more evolutionarily constrained because it is today very specialized; morphologically, physiologically, and behaviorally well-adapted to living on the edge of the Arctic ice, subsisting on a few species of seals." At an estimated 110,000 to 130,000 years old, "this is, by far, the oldest mammal mitochondrial genome to be sequenced," said Dr. Stephan Schuster, from Penn State's Center for Comparative Genomics and Bioinformatics and co-lead author of the report. "It's about twice the age of the oldest mammoth genome that has, to date, been sequenced."

Caddis Fly Silk May Be Useful Adhesive in Surgery

"Silk from caddis fly larvae may be useful some day as a medical bioadhesive for sticking to wet tissues," said Dr. Russell Stewart, an associate professor of bioengineering at the University of Utah and principal author of a new study of the fly silk's chemical and structural properties. "I picture it as sort of a wet Band-Aid, maybe used internally in surgery--like using a piece of tape to close an incision as opposed to sutures," he added. "Gluing things together underwater is not easy. Have you ever tried to put a Band-Aid on in the shower? This insect has been doing this for 150 million to 200 million years. There's just a fascinating diversity of these insects. Their adhesive is able to bond to a wide range of surfaces underwater: soft and hard, organic and inorganic. If we could copy this adhesive, it would be useful on a wide range of tissue types." Dr. Stewart hopes to make a synthetic version of the caddis fly silk for use as a surgical adhesive. There are thousands of caddis fly species worldwide in an order of insects named Trichoptera that is related to Lepidoptera, the order that includes moths and butterflies that spin dry silk. Because caddis flies are eaten by trout, fly fishermen often use caddis fly lures. Some species of caddis fly spend their larval stages developing underwater, and build an inch-long, tube-shaped case or shelter around themselves using sticky silk and grains of rock or sand (see photo). Some other species use silk, small sticks, and pieces of leaves. In these tube-dwelling species, each larva has a head and four legs that stick out from the tube. The larval case is often conical because it gets wider as the larva grows. A caddis fly larva eventually pupates, sealing off the tube as it develops into an adult fly, and then hatches.

Rapidly-Acting Antidepressant Shows Promise

In a recent issue of Biological Psychiatry, researchers from the NIH have reported that a medication called scopolamine appears to produce replicable rapid improvement in mood in patients with unipolar depression. Scopolamine temporarily blocks the muscarinic cholinergic receptor, thought to be overactive in people suffering from depression. Previously, the NIH team had demonstrated scopolamine’s anti-depressive effect in both unipolar and bipolar depression. The current study replicates these findings in an independent sample of unipolar depression patients. Conventional antidepressant treatments generally require three to four weeks to become effective, thus the discovery of treatments with a more rapid onset is a major goal of biological psychiatry. The authors noted that the first drug found to produce rapid improvement in mood was the synthetic NMDA glutamate receptor antagonist known as ketamine. Scopolamine is an alkaloid compound obtained from plants of the nightshade family (Solanaceae), such as henbane, jimson weed, Angel's Trumpets, corkwood, and belladonna (“deadly nightshade”). "Scopolamine was found to reduce symptoms of depression within three days of the first administration. In fact, participants reported that they experienced relief from their symptoms by the morning after the first administration of drug," explained Dr. Maura Furey, co-author of the new report. "Moreover, one half of participants experienced full symptom remission by the end of the treatment period. Finally, participants remained well during a subsequent placebo period, indicating that the antidepressant effects persist for at least two weeks in the absence of further treatment.”

Beewolves Protect Larvae with Antibiotic Cocktail from Symbionts

Digger wasps that typically hunt bees to feed their larvae are called “beewolves,” and they are known to house beneficial bacteria on their cocoons that guarantee protection against harmful microorganisms. A team of scientists from Germany has now discovered that symbiotic bacteria of the genus Streptomyces produce a cocktail of nine different antibiotics that protect the beewolf larvae from invading pathogens. Using imaging techniques based on mass spectrometry, the antibiotics could be displayed in vivo on the cocoon's exterior surface. Moreover, it was shown that the complementary actions of the nine symbiont-produced antibiotics confer a potent antimicrobial defense for the wasp larvae against a multitude of different pathogenic microorganisms. Thus, the scientists said, beewolves have, for millions of years, been taking advantage of a principle in human medicine that is known as “combination prophylaxis.” Many insects spend a part of their life underground and are exposed to the risk of fungal or bacterial infections. This is also the case for many digger wasp species that construct underground nests. Unlike bees that use pollen and nectar as food to nurture their larvae, digger wasps hunt insects to feed their offspring. Because of the warm and humid conditions, as well as the large amounts of organic material in their subterranean nests, both their food supply and their larvae are endangered by pathogens. Mold and bacterial infection are major threats and can cause larval death in many cases. Beewolves have evolved an elegant solution to the problem of fungal and bacterial infection. Earlier studies had shown that beewolves form a symbiotic relationship with bacteria of the genus Streptomyces.

Sneezing Induced by Bright Light Is Subject of Study

In research published in PLoS ONE, scientists from the University of Zurich examined the curious and apparently highly prevalent phenomenon called the “photo-induced sneeze reflex” or “sun sneeze.” This reflex is characterized by the induction of a sneeze upon sudden exposure of a dark-adapted subject to intensive bright light and, according to one previous study, is seen in almost 25% of normal individuals. Although generally considered harmless, it has been hypothesized that photic sneezing is, at least in part, a causal factor in conduction deafness, mediastinorrhexis, and cerebral hemorrhage. Previous studies have pointed out that photic sneezing could be dangerous for individuals in certain professions, such as baseball outfielders, high-wire acrobats, and airplane pilots, or in commonly experienced situations such as driving out of a tunnel, which can triple the risk of sneezing. The Zurich researchers said that their results demonstrated that photic sneezers have a generally enhanced excitability of the visual cortex to standard visual stimuli, and that a stronger prickle sensation in the nose of photic sneezers was associated with both activation in the insular cortex and stronger activation in the secondary somatosensory cortex. Thus, while the results of this study do not contradict those theories that emphasize the role of reflex pathway in the brain stem of photic sneezers, they do, the researchers said, support the view that even cortical circuits, rather than just brainstem circuits, might play a pivotal role in controlling (or modulating) this extraordinary and rarely investigated behavior. The researchers said that the photic sneeze reflex is therefore not a classical reflex that occurs only at a brainstem or spinal cord level, but, in stark contrast to many theories, also involves specific cortical areas.

Personalized Warfarin Dosing Enhanced by MS-Based SNP Genotyping

The anticoagulant drug warfarin (also known under the brand name Coumadin) is commonly used to prevent blood clots and embolisms. However, the drug exhibits significant inter-individual variability in dosing requirements. This variability is partly due to single nucleotide polymorphisms (SNPs) that influence either drug action or drug metabolism. Rapid genotyping of these SNPs helps clinicians to choose appropriate initial doses to quickly achieve anticoagulation effects and to prevent complications. A group led by Dr. Haifeng Wu of Ohio State University has developed a new, rapid method to genotype SNPs that will help clinicians to choose appropriate doses of warfarin for individual patients. Using surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF MS), which can determine the elemental composition of a sample, the researchers were able to determine the genotype of three warfarin-related SNPs (CYP2C9*2, CYP2C9*3, and VKORC1 3673G>A) in under five hours with high levels of accuracy. The researchers suggested that "on-site application of this method in hospital laboratories will greatly help clinicians to determine appropriate doses of warfarin to treat patients with thromboembolic disorders." In future studies, the Ohio State scientists plan to apply the SELDI-TOF platform to genotype other medically important SNPs that influence the efficacy and safety profiles of many drug therapies and to thus ultimately promote personalized health care. This work was reported in the March issue of the Journal of Molecular Diagnostics. [Press release] [Journal of Molecular Diagnostics abstract]

Animal Model Suggests Possible Cause for ADHD

Using a mouse model they created, scientists at Rockefeller University and collaborating institutions have identified a gene (CK1 delta) that they believe merits investigation as a possible cause of attention-deficit/hyperactivity disorder (ADHD). Currently, the cause of ADHD is unknown, but there is increasing evidence that dopamine, a neurotransmitter involved in the brain’s reward-motivation system, is involved. Scientists have previously found that the levels of dopamine, and of the D2 receptor it binds to, are involved in the progression of ADHD, as are four connected regions in the frontal region of the brain, two of which are directly linked to reward and motivation. In their work, the scientists focused on an enzyme called casein kinase I (CK1), which is involved in regulating the dopamine signaling pathway. They created a line of mice genetically modified to overexpress a form of CK1 called CK1 delta, specifically in the forebrain of the mouse. Under normal conditions and in response to stimulation by drugs such as the ones used today to treat ADHD, the mice that overexpressed CK1 delta showed behavioral symptoms and responses to drugs similar to those observed in people with ADHD. “The genetically modified mice that we generated present interesting features such as hyperactivity and altered nesting capacities that might be related to attention deficit, and possibly altered impulsivity,” said Dr. Marc Flajolet, senior author of the report. Biochemical studies showed that both classes of dopamine receptors, D1R and D2R, were significantly reduced in the CK1 delta-overexpressing mice, providing further evidence that the dopaminergic system is severely affected.

Syndicate content