News Article | May 2, 2017
The origin of life is perhaps the greatest mystery of science. It is still not adequately understood how something so complex could evolve from inanimate nature. The biochemist Markus Keller from the Medical University of Innsbruck has now made an important contribution to our understanding of how life developed on Earth. An Erwin-Schrödinger Fellowship from the FWF enabled Keller to do research abroad. In the course of his work he explored how some very old and complex processes of cellular metabolism developed. – Processes that are almost four billion years old and are also found in the human organism. "The crux here is how metabolism started in the first place", says Keller. "In some places on our planet there are very old sediments showing that life began more than 3.7 billion years ago. From these sediments we are unable, however, to conclude in exactly what form life existed and what its characteristics were. We just know that there must have been some kind of metabolic activity", notes Keller. Some metabolic pathways are identical in nearly all living organisms on the planet. One example is glycolysis, the processing of sugar. "Plants, bacteria and other living organisms use glucose in the same way we ourselves do. We may assume that the processes were the same in life-forms existing at very early stages of evolution. The question is this: how could these life-forms interconvert the intermediate products of glycolysis?" Cellular metabolism is a complicated system that depends on a number of enzymes. – These special proteins serve as catalysts, and some processes would not be possible without them. If an enzyme is missing, the entire cycle does not work. As Keller explains, it's a chicken-or-egg problem: what came first? The enzymes, which are metabolic products themselves? Or metabolism, which does not function without enzymes? Only a few years ago, the idea that several of these metabolic mechanisms might have functioned without enzymes, simply because of the prevailing environmental conditions, was disparaged as "magical thinking". But it is precisely these processes whose existence Keller was able to demonstrate. Importance of iron in the Archean Ocean His first papers dealt with glycolysis and what is called the "pentose-phosphate pathway". "At the time when life must have begun, the Archean ocean was relatively warm and contained a great deal of iron in a dissolved state", explains Keller. Under normal circumstances, iron is not water soluble in its oxidised form, i.e. rust. About four billion years ago there was, however, hardly any pure oxygen in the atmosphere or in the ocean which would have supported iron oxidation. Therefore, there existed large quantities of iron (II), or ferrous iron, which is easily dissolved in water. "We simulated the conditions prevailing in the Archean ocean and looked at how, for instance, fructose-6-phosphate, an intermediate product of cellular metabolism, would react in this environment. One of the things we found was that it converts to glucose-6-phosphate, precisely the same sequence of reaction and reaction pathways as in the living cell. In the first publications we showed that this occurs in a surprisingly efficient manner with very few side reactions. It results in exactly the right molecules." For this reason, the Archean ocean was an absolutely ideal environment for these very old metabolic reactions. And here lies the solution to this particular chicken-or-egg problem: chemical metabolic pathways were there first, and the enzymes developed later. Keller was able only recently to demonstrate a similar situation for the "citric acid cycle" (CAC), another important part of cellular metabolism. Its individual reactions can also run in the absence of enzymes. Analogous to modern cells, where glycolysis and the CAC, which is located in the cell mitochondria, run separately in different milieus, their non-enzymatic counterparts also need different chemical milieus in order to run effectively. In this way, the researcher showed that the observations made in relation to glycolysis also applied to other important metabolic pathways. Keller was able to make these observations by using mass spectrometry methods he developed during his Schrödinger Fellowship at the University of Cambridge. Mass spectrometry is an extremely sensitive method of measuring involving the breaking down of substances into their individual molecules or atoms in order to determine their mass. Keller originally examined how the components of yeast cells could be analysed by means of mass spectrometry, since it was not only highly precise but also promised additional advantages over other methods. Yeast is one of the most important model organisms of biology, and Keller's work was basic research with the aim of developing methodology for other types of research. He developed the idea of looking at the evolutionary origin of cellular metabolism together with the microbiologist Markus Ralser, head of the Cambridge research group of which Keller was a member. They also asked Alexandra Turchyn, an expert on Archean oceans, to join them and published the first paper on this issue. "Actually I never planned for my research to go in this direction", says Keller. "The initial study done on yeast metabolism is now also awaiting publication. But it was important that I had the freedom to look into these things. At first it was just a side-line." Keller emphasises that some of these effects have probably been measured in other studies as secondary effects but were not reported in detail. "These reactions still occur in cells today", observes Keller. He encourages groups that are active in this field to take a closer look at what they may misinterpret as being measuring errors. Explore further: Modern-day metabolism could have originated in 4-billion-year-old oceans More information: M. A. Keller et al. Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean, Molecular Systems Biology (2014). DOI: 10.1002/msb.20145228 M. A. Keller et al. Conditional iron and pH-dependent activity of a non-enzymatic glycolysis and pentose phosphate pathway, Science Advances (2016). DOI: 10.1126/sciadv.1501235 Gabriel Piedrafita et al. The Impact of Non-Enzymatic Reactions and Enzyme Promiscuity on Cellular Metabolism during (Oxidative) Stress Conditions, Biomolecules (2015). DOI: 10.3390/biom5032101 The widespread role of non-enzymatic reactions in cellular metabolism. Current Opinion in Biotechnology. dx.doi.org/10.1016/j.copbio.2014.12.020
News Article | May 3, 2017
Diabetes raises risk for many cancers, but not most common malignant brain tumor COLUMBUS, Ohio - New research further illuminates the surprising relationship between blood sugar and brain tumors and could begin to shed light on how certain cancers develop. While many cancers are more common among those with diabetes, cancerous brain tumors called gliomas are less common among those with elevated blood sugar and diabetes, a study from The Ohio State University has found. The discovery builds on previous Ohio State research showing that high blood sugar appears to reduce a person's risk of a noncancerous brain tumor called meningioma. Both studies were led by Judith Schwartzbaum, an associate professor of epidemiology and a researcher in Ohio State's Comprehensive Cancer Center. The new glioma study appears in the journal Scientific Reports. "Diabetes and elevated blood sugar increase the risk of cancer at several sites including the colon, breast and bladder. But in this case, these rare malignant brain tumors are more common among people who have normal levels of blood glucose than those with high blood sugar or diabetes," Schwartzbaum said. "Our research raises questions that, when answered, will lead to a better understanding of the mechanisms involved in glioma development," she said. Glioma is one of the most common types of cancerous tumors originating in the brain. It begins in the cells that surround nerve cells and help them function. The disease is typically diagnosed in middle age. At present, there is no treatment that ensures long-term survival, but several potential options are being studied. The Scientific Reports paper included data from two large long-term studies. One, called AMORIS, included 528,580 Swedes. The second, Me-Can, consisted of 269,365 Austrians and Swedes. In all, 812 participants developed gliomas. Schwartzbaum and her collaborators evaluated blood sugar and diabetes data and its relationship to subsequent development of brain cancer and found that those with elevated blood sugar and diabetes had a lower risk of developing glioma. "This really prompts the question, 'Why is the association between blood glucose levels and brain cancer the opposite of that for several other cancerous tumors?" she said. The researchers found that this relationship was strongest within a year of cancer diagnosis. "This may suggest that the tumor itself affects blood glucose levels or that elevated blood sugar or diabetes may paradoxically be associated with a protective factor that reduces brain tumor risk," Schwartzbaum said. "For example, insulin-like growth factor is associated with glioma recurrence and is found in lower levels in people with diabetes than those who don't have the disease." The brain accounts for only about 2 percent of body weight, but consumes about 20 percent of the body's available glucose, Schwartzbaum said. The body of research on restrictive diets and their effect on brain cancer development has shown mixed results and more work is needed to determine if there's something about the sugar/tumor relationship that can be modified in a way that's beneficial to brain cancer patients, she said. The research was supported by the National Cancer Institute. Schwartzbaum's collaborators included co-lead author Michael Edlinger of the Medical University of Innsbruck in Austria and Grzegorz Rempala of Ohio State's College of Public Health.
News Article | May 5, 2017
New York, NY, May 5, 2017 - An international group of experts has concluded that, for patients with schizophrenia and related psychotic disorders, antipsychotic medications do not have negative long-term effects on patients' outcomes or the brain. In addition, the benefits of these medications are much greater than their potential side effects. These findings, by Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chairman of Psychiatry at Columbia University College of Physicians and Surgeon and Director of the New York State Psychiatric Institute, and colleagues from institutions in the United States, Germany, The Netherlands, Austria, Japan, and China, were published today in the American Journal of Psychiatry. Nearly seven million Americans take antipsychotic medications for the treatment of schizophrenia and related conditions. The medications are prescribed to alleviate the symptoms of psychosis and longer-term, to prevent relapse. In recent years, however, concerns have been raised that these medications could have toxic effects and negatively impact long-term outcomes. This view, if not justified by data, has the potential mislead some patients (and their families) to refuse or discontinue antipsychotic treatment. For this reason, the researchers undertook a comprehensive examination of clinical and basic research studies that examined the effects of antipsychotic drug treatment on the clinical outcomes of patients and changes in brain structure. "The evidence from randomized clinical trials and neuroimaging studies overwhelmingly suggests that the majority of patients with schizophrenia benefit from antipsychotic treatment, both in the initial presentation of the disease and for longer-term maintenance to prevent relapse," said Dr. Lieberman. Moreover, whatever side effects that these medications might cause are greatly outweighed by their therapeutic benefits. "Anyone who doubts this conclusion should talk with people whose symptoms have been relieved by treatment and literally given back their lives," Lieberman added. The studies also revealed that delaying or withholding treatment has been associated with poorer long-term outcomes. "While a minority of patients who recover from an initial psychotic episode may maintain their remission without antipsychotic treatment, there is currently no clinical biomarker to identify them, and it is a very small number of patients who may fall into this subgroup," said Dr. Lieberman. "Consequently, withholding treatment could be detrimental for most patients with schizophrenia." And while preclinical studies in rodents suggested that antipsychotic medications can sensitize dopamine receptors, there is no evidence that antipsychotic treatment increases the risk of relapse. While antipsychotic medications can increase the risk for metabolic syndrome, which is linked to heart disease, diabetes, and stroke, the study did not include a risk-benefit analysis. "While more research is needed to address these questions, the strong evidence supporting the benefits of antipsychotic medications should be made clear to patients and their families, while at the same time they should be used judiciously" said Dr. Lieberman. The paper is entitled, "The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia." The authors are Donald Goff, MD (New York University School of Medicine, New York, NY), Peter Falkai, MD, PhD (Ludwig-Maximilians-University Munich, Germany), Wolfgang Fleischhacker, MD, (Medical University of Innsbruck, Austria), Ragy Girgis, MD (Columbia University Medical Center), Rene M. Kahn, MD, PhD (University Medical Center, Utrecht, The Netherlands;), Hiroyuki Uchida, MD, PhD (Keiyo University, Tokyo, Japan), Jingping Zhao, MD, Ph.D. (Central South University, Chengsha, China), and Jeffrey Lieberman, MD (Columbia University Medical Center and New York State Psychiatric Institute). Dr. Goff has received research support from Avanir Pharmaceuticals, the National Institute of Mental Health, and the Stanley Medical Research Institute. Dr. Fleischhacker has received research support from Boehringer-Ingelheim, Janssen, Lundbeck, and Otsuka; he has received honoraria for serving as a consultant to and/or on advisory boards for Allergan, Dainippon-Sumitomo, GedeonRichter, Janssen, Lundbeck, Otsuka, Takeda, and Teva; and he has received speaker's fees and travel support from AOP Orphan, Dainippon Sumitomo, Gedeon Richter, Janssen, Lundbeck, Pfizer, Otsuka, and Teva. Dr. Girgis receives research support from Allergan, BioAdvantex, Genentech, and Otsuka. Dr. Kahn has received consulting fees from Alkermes, Forrest, Forum, Gedeon-Richter, Janssen-Cilag, Minerva Neurosciences, and Sunovion and speaker's fees from Janssen-Cilag and Lilly. Dr. Uchida has received grants from Astellas Pharmaceutical, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Meiji-Seika Pharmaceutical, Mochida Pharmaceutical, Novartis, Otsuka Pharmaceutical, and Shionogi; speaker's honoraria from Dainippon-Sumitomo Pharma, Eli Lilly, Janssen Pharmaceutical, Meiji-Seika Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, and Yoshitomi Yakuhin; and advisory panel payments from Dainippon-Sumitomo Pharma. All other authors report no financial relationships with commercial interests. New York State Psychiatric Institute and Columbia University Department of Psychiatry (NYSPI/Columbia Psychiatry). New York State Psychiatric Institute (founded in 1896) and the Columbia University Department of Psychiatry have been closely affiliated since 1925. Their co-location in a New York State facility on the New York-Presbyterian/Columbia University Medical Center campus provides the setting for a rich and productive collaborative relationship among scientists and physicians in a variety of disciplines. NYSPI/Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. The Department and Institute are home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders and childhood psychiatric disorders. Their combined expertise provides state of the art clinical care for patients, and training for the next generation of psychiatrists and psychiatric researchers. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.
PubMed | Medical University of Innsbruck and Hospital Kufstein
Type: Case Reports | Journal: Journal of neurosurgery. Spine | Year: 2016
A 33-year-old man presented with moderate low-back pain and L-5 radiculopathy that progressed to severe paresis of L-5. On initial imaging, a corresponding spinal lesion was overlooked. Further CT and contrast-enhanced MRI demonstrated a presacral mass along the L-5 root far extraforaminally. A herniated disc was suspected, but with standard imaging a schwannoma could not be ruled out. The presacral L-5 root was explored via a microsurgical lateral extraforaminal transmuscular approach. To the best of the authors knowledge, there have been no reports of sequestered extraforaminal lumbosacral disc herniations that herniated into the presacral region.
News Article | February 15, 2017
Between 1990 and 2013, thousands of children in war-torn South Sudan and northern Uganda suddenly developed a severe and puzzling form of epilepsy. When exposed to food or cold temperatures, affected children nodded their heads uncontrollably. Over time the seizures often worsened, leaving the children severely disabled. Many died of malnutrition, accidents, or secondary infections. In some communities, roughly half of families had at least one child with the condition, called nodding syndrome; by 2013, an estimated 1600 children in Uganda were affected. But the cause of the devastation was a mystery. Now, a study finds that a parasitic worm often found in the children might trigger the body’s own defenses to attack neurons. The study doesn’t prove the worm is the culprit, but it “is the first to show that a cause-effect relationship is plausible,” says Hermann Feldmeier, a parasitologist at the Charité University Hospital in Berlin, who was not involved in the study. The rash of cases in Uganda and South Sudan triggered an intense hunt for the cause, but searches for viruses, bacteria, environmental toxins, genetic factors, and nutritional deficits all came up empty. One key clue: Areas with nodding syndrome also had high rates of onchocerciasis, an infection with the parasitic worm Onchocerca volvulus. Spread through the bites of black flies, which breed in swift-flowing streams, the worms can invade the eye, and the infection is commonly known as river blindness. The World Health Organization estimates that at least 18 million people, most in sub-Saharan Africa, are infected. Researchers had suggested as early as the 1960s that high rates of epilepsy in Tanzania, with similar nodding symptoms, might be related to onchocerciasis. Others have noted that children with nodding syndrome are more likely to be infected than their healthy peers. But there’s no evidence that the worm invades the brain or directly causes seizures. Some researchers suggested that the worm instead causes an autoimmune reaction that damages the nervous system. Searches for antibodies that might play an autoimmune role had come up empty. But neuroimmunologists Avindra Nath and Tory Johnson of the National Institutes of Health in Bethesda, Maryland, decided to use an improved protein chip to screen for antibodies to thousands of proteins at once. The new tool proved its worth. Blood from nodding syndrome patients reacted strongly to four proteins; in the case of one protein, called leiomodin-1, patient sera reacted 33,000 times more strongly than did sera from unaffected controls. The researchers then looked for the antibodies causing the reaction. As they report this week in , antibodies to leiomodin-1 turned up in 29 of 55 nodding syndrome patients but only 17 of 55 controls. Patients also carried much higher antibody levels than controls. Leiomodin-1, which likely plays a role in cell shape, is found in smooth muscle and thyroid cells. Johnson’s team showed that it is expressed in the nervous system and brain, too. They also found a clue to what might trigger an autoimmune reaction to the protein: Several O. volvulus proteins resemble it. After the immune system gears up to fight the worm, similarities between an O. volvulus protein and leiomodin-1 may cause the antibodies to mistakenly attack neurons. The study gives little hope to children already affected, Nath says. Although antiseizure drugs can help, if the immune system has attacked neurons, the damage is likely permanent. However, the work could suggest a straightforward way to eliminate the disease, says infectious disease specialist Robert Colebunders of the University of Antwerp in Belgium, because the drug ivermectin kills the worm. Existing campaigns to eliminate river blindness by giving the drug could have a collateral benefit: After the Ugandan government stepped up ivermectin treatment, new cases of nodding syndrome plunged to nearly zero, Colebunders says. “If you eliminate the onchocerciasis, the epilepsy really disappears.” Yet the link between the worm and nodding syndrome doesn’t explain why the illness suddenly appeared in a region where onchocerciasis has likely been common for centuries, or why nodding syndrome only affects children and youth. Johnson, now at Johns Hopkins University in Baltimore, Maryland, says malnutrition, exposure to other diseases, or genetic variation in how the body makes antibodies may also play a role. Other researchers have suggested that measles infection followed by malnutrition could trigger the disease. Neurologist Erich Schmutzhard of the Medical University of Innsbruck in Austria has other doubts. He says that the leiomodin-1 antibodies could be a result of epilepsy, not its cause. The protein seems to be on the inside of neurons, not the outside, he notes. Seizures kill neurons, and he speculates that dying neurons could spill the protein into the blood stream, triggering the antibodies. The onchocerciasis connection is intriguing but far from definitive, says neurologist Andrea Winkler of the Technical University of Munich in Germany. She, too, thinks the syndrome is likely caused by multiple factors, such as malnutrition, parasites, and viruses like measles. “There are still lots of links missing.”
PubMed | University of Tübingen, Medical University of Innsbruck and Innsbruck Medical University
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2016
Freeze-fracture electron microscopy has been a major technique in ultrastructural research for over 40 years. However, the lack of effective means to study the molecular composition of membranes produced a significant decline in its use. Recently, there has been a major revival in freeze-fracture electron microscopy thanks to the development of effective ways to reveal integral membrane proteins by immunogold labeling. One of these methods is known as detergent-solubilized Freeze-fracture Replica Immunolabeling (FRIL). The combination of the FRIL technique with optogenetics allows a correlated analysis of the structural and functional properties of central synapses. Using this approach it is possible to identify and characterize both pre- and postsynaptic neurons by their respective expression of a tagged channelrhodopsin and specific molecular markers. The distinctive appearance of the postsynaptic membrane specialization of glutamatergic synapses further allows, upon labeling of ionotropic glutamate receptors, to quantify and analyze the intrasynaptic distribution of these receptors. Here, we give a step-by-step description of the procedures required to prepare paired replicas and how to immunolabel them. We will also discuss the caveats and limitations of the FRIL technique, in particular those associated with potential sampling biases. The high reproducibility and versatility of the FRIL technique, when combined with optogenetics, offers a very powerful approach for the characterization of different aspects of synaptic transmission at identified neuronal microcircuits in the brain. Here, we provide an example how this approach was used to gain insights into structure-function relationships of excitatory synapses at neurons of the intercalated cell masses of the mouse amygdala. In particular, we have investigated the expression of ionotropic glutamate receptors at identified inputs originated from the thalamic posterior intralaminar and medial geniculate nuclei. These synapses were shown to relay sensory information relevant for fear learning and to undergo plastic changes upon fear conditioning.
PubMed | Innsbruck Medical University and Medical University of Innsbruck
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2017
Dendritic cells (DCs) recognize foreign structures of different pathogens, such as viruses, bacteria, and fungi, via a variety of pattern recognition receptors (PRRs) expressed on their cell surface and thereby activate and regulate immunity. The major function of DCs is the induction of adaptive immunity in the lymph nodes by presenting antigens via MHC I and MHC II molecules to nave T lymphocytes. Therefore, DCs have to migrate from the periphery to the lymph nodes after the recognition of pathogens at the sites of infection. For in vitro experiments or DC vaccination strategies, monocyte-derived DCs are routinely used. These cells show similarities in physiology, morphology, and function to conventional myeloid dendritic cells. They are generated by interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation of monocytes isolated from healthy donors. Here, we demonstrate how monocytes are isolated and stimulated from anti-coagulated human blood after peripheral blood mononuclear cell (PBMC) enrichment by density gradient centrifugation. Human monocytes are differentiated into immature DCs and are ready for experimental procedures in a non-clinical setting after 5 days of incubation.