Potential biochemical mechanism underlying long-term memories identified

During the holidays, we often remember the past and create new memories. But, why do some memories fade away while others last forever? Scientists at the Stowers Institute for Medical Research have identified a possible biochemical mechanism by which neurons create and maintain a long-term memory from a fleeting experience.

The research, conducted by Stowers Associate Investigator Kausik Si, Ph.D., and his team, is published in the current issue of the journal Cell. Their research builds upon previous studies by Si and Eric Kandel, M.D., of Columbia University and other scientists. These studies revealed that both short-term and long-term memories are created in synapses, the tiny junctions between neurons. A transient experience – one source of our memories – is capable of producing an enduring change in the strength of the synaptic connection, says Si.

For a memory to endure, and not fade away, the synaptic connections must be kept strong. In a previous study, Kandel and Si identified CPEB as a synaptic protein that is responsible for maintaining the strength of these connections in the sea slug, a model organism used in memory research. In subsequent research at the Stowers Institute, Si and his team identified Orb2 as the fruit fly version of the CPEB synaptic protein. In their latest study, Mohammed ‘Repon’ Khan, a predoctoral researcher in the Si Lab and first author of the Cell paper, determined that Orb2 exists in two distinct physical states, monomeric and oligomeric.

Monomeric Orb2 is a single molecule capable of binding to other molecules. Like CPEB, oligomeric Orb2 is prion-like – that is, it’s a selfcopying cluster. However, unlike disease-causing prions, oligomeric Orb2 and CPEB are not toxic.

The paper describes how monomeric Orb2 represses while oligomeric or prion-like Orb2 activates a crucial step in the complex cellular process that leads to protein synthesis. During this crucial step, messenger RNA (mRNA), which is a RNA copy of a gene’s recipe for a protein, is translated by the cell’s ribosome into the sequence of amino acids that will make up a newly synthesized protein.

“We propose that the monomeric form of Orb2 binds to the target mRNA, and the bound mRNA is kept in a repressed state,” explains Khan.

The Stowers scientists also determined that prion-like Orb2 not only activates translation but imparts its translational state to nearby monomer forms of Orb2. As a result, monomeric Orb2 is transformed into prion-like Orb2, and its role in translation switches from repression to activation. Si thinks this switch is the possible mechanism by which fleeting experiences create an enduring memory.

“Because of the self-sustaining nature of the prion-like state, this creates a local and self-sustaining translation activation of Orb2-target mRNA, which maintains the changed state of synaptic activity over time,” says Si.

The discovery that the two distinct states of Orb2 have opposing roles in the translation process provides “for the first time a biochemical mechanism of synapse-specific persistent translation and long-lasting memory,” he states.

“To our knowledge, this is the first example of a prion-based protein switch that turns a repressor into an activator,” Si adds.

“The recruitment of distinct protein complexes at the non-prion and prion-like forms to create altered activity states indicates the prion-like behaviour is in essence a protein conformation- based switch. Through this switch, a protein can lose or gain a function that can be maintained over time in the absence of the original stimuli. Although such a possibility has been anticipated prior to this study, there was no direct evidence.”



Brain receptors for hunger hormone control food intake

Activating receptors in the brain for the body’s hunger hormone increases foodrelated behaviors, such as gathering, storing and consuming food, a finding that has implications for the treatment of obesity, according to researchers at Georgia State University.

Their study suggests that stimulating brain receptors for ghrelin, a hormone that increases appetite, by injecting ghrelin into the brain is necessary and adequate to increase appetitive and consummatory behaviours in Siberian hamsters. However, activating ghrelin receptors in other parts of the body isn’t required to achieve these food-related behaviours.

The researchers also found that blocking brain receptors for grehlin neutralizes the hormone’s effect on food intake. The findings, published in The American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, have important implications for treating obesity, a major public health concern worldwide.

“We’ve shown for the first time that blocking ghrelin receptors in the brain prevents an increase in both short-term and long-term food foraging, food hoarding and food intake following an injection of ghrelin in peripheral areas of the body,” said Michael A. Thomas, lead author and a graduate student in biology at Georgia State.

Levels of ghrelin circulation in the body fluctuate in response to the time elapsed since a person’s last meal, falling immediately after food consumption. Grehlin receptors are in the brain (central area) and the vagus nerve leading to the stomach (periphery). Appetitive behaviours include driving to or shopping for food, also known as foraging, and storing food in cupboards, refrigerators, freezers and pantries, also called hoarding. Consummatory behaviours, or food intake, involve the consumption of food.

Factors such as genetics contribute to obesity, but the main cause is taking in more energy than is burned, in addition to the easy access of high-calorie, cheap food (foraging) and the ability to store these items for longer periods of time (hoarding). While research has focused on consummatory behavior, few studies have explored appetitive behaviors.

“Understanding the complex relationship between central and peripheral satiety signals is an important step in the development of clinically useful obesity treatment options,” said Vitaly Ryu, corresponding author and senior research scientist in the Department of Biology and Center for Obesity Reversal at Georgia State.

In previous work, the researchers found injecting ghrelin into the peripheral area stimulates food foraging, food hoarding and food intake in Siberian hamsters. However, it was unknown if ghrelin must stimulate receptors in the brain in order to increase these behaviors, regardless of peripheral stimulation of ghrelin receptors.

In this study, the researchers injected ghrelin into the third ventricle, or brain cavity, of Siberian hamsters and measured changes in food foraging, food hoarding and food intake. To test the effect of blocking ghrelin receptors in the brain, they used the potent antagonist JMV2959 to block the receptor in response to food deprivation and injection of ghrelin in the peripheral area. Then, they examined neuronal activation in the arcuate nucleus (Arc) and paraventricular hypothalamic nucleus (PVH) in the brain.

The antagonist successfully blocked ghrelin-induced increases in food foraging, food hoarding and food intake at all times and food deprivation-induced increases in food foraging, food hoarding and food intake up to four hours. This indicates that food-related behaviors are regulated by the ghrelin receptors in the brain.

The study also found for the first time that blocking ghrelin receptors prevented neuronal activation of the PVH, but not the Arc, suggesting that PVH activity is essential in driving both appetitive and consummatory behaviors.

Whole exome screening for cancer

A powerful new test that can reveal untapped therapies for patients with advanced cancers by scanning thousands of their genes will soon be available for patients at Weill Cornell Medicine and NewYork- Presbyterian/Weill Cornell Medical Center. The test, EXaCT-1, identifies alterations within tumours – some of which drive cancerous growth – on a magnitude up to hundreds of times greater than similar technologies designed to pinpoint the most precise ways of treating the disease.

Weill Cornell Medicine recently received approval for EXaCT-1 by the New York State Department of Health. The test was developed by the institutions’ precision medicine team. In May, the team published findings on its first 97 patients who underwent the test and found that scanning a patient’s tumour to look for any genomic mutations – rather than limiting the screen to mutations commonly associated with a given patient’s tumour type – worked. In 92% of cases in the pilot program, the precision medicine team was able to recommend new treatment options based on the test’s findings.

Now that the state has approved the test, precision medicine leaders will begin the process to implement it for large-scale clinical use for oncology patients treated at NewYork-Presbyterian/Weill Cornell. Until that time, patients with advanced cancers will be able to access EXaCT-1 through the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine, the research enterprise of the two institutions’ joint precision medicine efforts.

“Since President Obama announced his precision medicine initiative in January, there has been a huge push from institutions across the country to establish themselves as leaders in this field,” said Dr Mark Rubin, director of the Englander Institute and the Homer T. Hirst III Professor of Oncology in Pathology at Weill Cornell Medicine, vice chair for molecular and genomic pathology at NewYork-Presbyterian/ Weill Cornell, and head of the precision medicine program at both institutions. Dr Rubin was at the White House when the president announced the initiative, which dedicates $215 million from his proposed 2016 budget to expand data sharing between institutions; develop new tests, like EXaCT-1, that identify genomic drivers in cancer; and calls for more research on how to apply findings in precision medicine to more effective therapies.

Most institutions offer sequencing tests that examine anywhere from 50 to 400 genes within a sample of a patient’s tumour to look for disease characteristics that physicians know can be effectively treated with particular drugs or other technologies.

Unlike these focused tests, typically called panel sequencing, the EXaCT-1 assay takes an unbiased, exploratory look at more than 21,000 genes in cells both healthy and malignant, allowing researchers to find alterations in the cancer-development process in unexpected regions of the exome, where DNA is transcribed into RNA. This type of test, known as whole exome sequencing, can be effective in advanced-stage patients for whom other treatments have failed because it uncovers mutations that the less comprehensive tests miss. In practice, this means, for example, that a patient with bladder cancer whom EXaCT-1 shows to share a mutation associated with breast cancer might benefit from a drug typically prescribed to fight the latter type of tumour.

“That’s the nice thing about sequencing the entire tumour genome – we cover genes that other tests will miss,” said Dr Olivier Elemento, head of the Englander Institute for Precision Medicine’s computational biology group, an associate professor of physiology and biophysics and head of the laboratory of cancer systems biology in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine at Weill Cornell. “This test is ideal for patients with advanced cancer because it allows us to identify mutations that may be related to the resistance of their disease, and helps us to pinpoint the best way to treat them.”

The screen requires a blood sample and a sample of the patient’s tumour. Computational biologists at the Englander Institute analyze the data and generate patient-and physician-friendly reports that summarize the key clinical and genetic findings. Once the precision medicine team has reviewed the results, it consults with the patient’s oncologist at NewYork-Presbyterian/Weill Cornell to help decide which treatment options and clinical trials may best target the patient’s disease.


Clinical workstations a reservoir for bad bugs

Clinical workstations within hospital intensive care units (ICUs) may get overlooked during routine cleanings and could therefore harbour more dangerous bacteria than regularly cleaned objects in patient areas, according to a pilot study published in the December issue of the American Journal of Infection Control, the official publication of the Association for Professionals in Infection Control and Epidemiology (APIC).

Researchers from Western Sydney University in Australia conducted a pilot study using three different sampling methods in a busy ICU in an attempt to discover if and where multidrug-resistant organisms (MDROs) might still be lurking in spite of routine environmental cleaning. Investigators traced the steps of healthcare workers (HCW) in between their workstations and patient bedsides and sampled commonly touched objects along the way for MDROs. Nine of thirteen confirmed MDROs from any area came from clinical workstations (on chairs, clipboards, keyboards, telephones, and a computer mouse).

As a secondary finding of the study, combined ATP testing on environmental surfaces was more than seven times as likely to positively identify MDROs as microbial swabbing (33.3% vs 4.3%). ATP testing is a process of rapidly measuring actively growing microorganisms through detection of adenosine triphosphate (ATP) – a marker of bio-contamination.

“In this pilot study, we found that many of the high touch objects from which MDROs were recovered were not items included in cleaning protocols,” said the study authors. “The findings of this study suggest the need to review the hygiene standards adopted in the clinical workspace, away from the immediate patient zones in busy ICUs, and indicate that ATP testing may help identify high touch objects with less than optimal cleanliness.”

• doi: 10.1016/j.ajic.2015.07.013


Eating more fruits, veggies in youth linked to healthy heart decades later

Eating more fruits and vegetables as a young adult may keep your arteries free of heart disease 20 years later, according to research in the American Heart Association journal Circulation.

Researchers found that eating more fruits and vegetables as young adults was associated with less calcified coronary artery plaque 20 years later. Coronary artery calcium can be measured by a CT scan to detect the presence and amount of atherosclerosis, a disease that hardens arteries and underlies many types of heart disease.

The researchers divided data from 2,506 study participants into three groups, based on their daily consumption of fruits and vegetables. Women in the top third ate an average of nearly nine servings of daily fruits and vegetables and men averaged more than seven daily servings. In the bottom third, women consumed an average 3.3 daily servings and men 2.6 daily servings. All servings were based on a 2,000-caloriea- day diet.

Researchers found that people who ate the most fruit and vegetable at the study’s start had 26% lower odds of developing calcified plaque 20 years later, compared to those who ate the least amount of fruits and vegetables.

Previous studies have shown a strong association between eating more fruits and vegetables and reduction in heart disease risk among middle-age adults. However, this is the first study to examine whether eating more fruits and vegetables as young adults could produce a measurable improvement in the health of their heart and blood vessels years later. “People shouldn’t assume that they can wait until they’re older to eat healthy – our study suggests that what you eat as a young adult may be as important as what you eat as an older adult, ” said lead author Michael D. Miedema, M.D., senior consulting cardiologist and clinical investigator at the Minneapolis Heart Institute, Minneapolis, Minnesota.

Researchers studied health information from adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a government-funded study of black and white young adults, which started in 1985. At the study’s start, participants provided a detailed diet history, information on other lifestyle variables and cardiovascular risk factors such as blood pressure, whether or not they smoked cigarettes, weight and others. Twenty years later, participants underwent a CT scan to check for buildup of calcium on the walls of the arteries of the heart, which is calculated as a coronary artery calcium score. Higher coronary calcium scores are associated with a higher risk for heart attacks and other coronary heart disease events.

“Our findings support public health initiatives aimed at increasing fruit and vegetable intake as part of a healthy dietary pattern,” Miedema said. “Further research is needed to determine what other foods impact cardiovascular health in young adults.” • doi: 10.1161/CIRCULATIONAHA. 114.012562


Study of gene therapy treatment for cystic fibrosis shows positive results

A study presented by the Laboratory for Molecular Virology and Gene Therapy at KU Leuven, Belgium, shows that an improved gene therapy treatment can cure mice with cystic fibrosis (CF). Cell cultures from CF patients, too, respond well to the treatment.

Cystic fibrosis or mucoviscidosis is a genetic disorder that makes the mucus in the body thick and sticky, which in turn causes clogging in, for instance, the airways and the gastrointestinal tract. The symptoms can be treated, but there is no cure for the disorder.

Cystic fibrosis is caused by mutations in the CFTR gene. This gene contains the production code for a protein that functions as a channel through which chloride ions and water flow out of cells. In the cells of CF patients, these chloride channels are dysfunctional or even absent, so that thick mucus starts building up.

“A few years ago, a new drug was launched that can repair dysfunctional chloride channels,” Professor Zeger Debyser explains. “Unfortunately, this medicine only works in a minority of CF patients. As for the impact of gene therapy, previous studies suggested that the treatment is safe, but largely ineffective for cystic fibrosis patients. However, as gene therapy has recently proven successful for disorders such as haemophilia and congenital blindness, we wanted to re-examine its potential for cystic fibrosis.”

That is why lead authors Dragana Vidovic and Marianne Carlon examined an improved gene therapy treatment based on inserting the genetic material for chloride channels – coded by the CFTR gene – into the genome of a recombinant AAV viral vector, which is derived from the relatively innocent AAV virus. The researchers then used this vector to ‘smuggle’ a healthy copy of the CFTR gene into the affected cells.

Both in mice with cystic fibrosis and in gut cell cultures from CF patients, this approach yielded positive results. “We administered the rAAV to the mice via their airways. Most of the CF mice recovered. In the patient-derived cell cultures, chloride and fluid transport were restored.”

There is still a long way to go before gene therapy can be used to treat cystic fibrosis patients, Debyser clarifies: “We must not give CF patients false hope. Developing a treatment based on gene therapy will take years of work. For one thing, our study did not involve actual human beings, only mice and patient-derived cell cultures. Furthermore, we still have to examine how long the therapy works. Repeated doses might be necessary. But gene therapy clearly is a promising candidate for further research towards a cure for cystic fibrosis.”


Fingerprinting of surface receptor will aid drug development


For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have created detailed “fingerprints” of a class of surface receptors that have proven highly useful for drug development. These detailed “fingerprints” show the surprising complexity of how these receptors activate their binding partners to produce a wide range of signalling actions.

The study, which was published recently in the journal Science Signaling, focuses on interactions of G protein-coupled receptors (GPCRs) with their signalling mediators known as G proteins. GPCRs – currently accounting for about 40% of all prescription pharmaceuticals on the market – play roles in many physiological functions because they transmit signals from outside the cell to the interior. When an outside substance binds to a GPCR, it activates a G protein inside the cell to release components and create a specific cellular response.

“Until now, it was generally believed that GPCRs are very selective, activating only a few G proteins they were designed to work with,” said TSRI Associate Professor Kirill Martemyanov, who led the study. “It turns out the reality is much more complex.” Ikuo Masuho, a senior research associate in the Martemyanov lab, added: “Our imaging technology opens a unique avenue of developing drugs that would precisely control complex GPCR-G protein coupling, maximizing therapeutic potency by activating G proteins that contribute to therapeutic efficacy while inhibiting other G proteins that cause adverse side effects.”

The study found that individual GPCRs engage multiple G proteins with varying efficacy and rates, much like a dance where the most desirable partner, the GPCR, is surrounded by 14 suitors all vying for attention. The results, as in any dance, depend on which G proteins bind to the receptor – and for how long. The same receptor changes G protein partners – and the signalling outcome – depending on the action of the signal received from outside of the cell.

This finding was made possible by novel imaging technology used by the Martemyanov lab to monitor G protein activation in live cells. Using a pair of light-emitting proteins, one attached to the G protein, the other attached to what’s known as a reporter molecule, Martemyanov and his colleagues were able to measure simultaneously both the signal and activation rates of most G proteins present in the body. “Our approach looks at 14 different types of G proteins at once – and we only have 16 in our bodies,” he said. “This is as close as it can get to what is actually happening in real time.”

In the accompanying commentary in Science Signaling, Alan Smrcka, a professor at University of Rochester Medical School and a prominent GPCR researcher, wrote: “[The findings] suggest the power of the GPCR fingerprinting approach, in that it could predict the G protein coupling specificity of a GPCR in a native system, which was previously undetected by conventional analysis. This could be very helpful for identifying previously unappreciated signalling pathways downstream of individual GPCRs that could be useful therapeutically or identified as potential side effects of GPCRs.”

• doi: 10.1126/scisignal.aad8140

Micro-map of hippocampus a great new tool for brain research


A new detailed map of the hippocampal region of the brain, compiled by researchers at the Montreal Neurological Institute and Hospital-The Neuro at McGill Uni versity, is helping the scientific community accelerate research and develop better treatments for patients suffering from epilepsy and other neurological and psychiatric disorders.

The team of researchers, led by Dr Neda Bernasconi, a neuroscientist specializing in the neuroimaging of epilepsy and co-founder of the Neuroimaging of Epilepsy Laboratory (NOEL) at The Neuro, set out to build and share a detailed model of the substructures making up one of the key centres of the brain involved in epilepsy: the hippocampus. The goal of their project, published on November 10 in Scientific Data, is to improve the tools available to researchers and clinicians working in the field around the globe.

Epilepsy is a neurological disorder characterized by a sudden, brief change in the brain, expressed as a seizure. According to Epilepsy Canada, approximately one percent of Canadians suffer from the condition and more than 30% of patients with epilepsy do not respond to anti-epileptic drugs. For these individuals, the surgical removal of the brain tissue causing seizures is the only known effective treatment for controlling the condition and improving quality of life.

In order to compile this hippocampal atlas, researchers used MRI imagery from a sample of 25 healthy individuals. They then used their expertise in brain anatomy to label all the substructures composing the region, providing a model of an average, healthy hippocampus. The end result is analogous to a Google street view of this particular part of the brain. With this tool, researchers will be better able to assess the pathology of their patients by comparing their data to the atlas and will more clearly be able to locate the areas in need of surgical intervention.

“Our primary purpose was epilepsy. We wanted to be able to detect and identify different substructures in the hippocampus to enable us to be a lot more precise in our diagnosis and to pinpoint the affected region to better target treatments”, said Dr Bernasconi. “With this new submillimetric dataset, made available through open science, we are not just sharing MRI images, we are also transferring anatomical knowledge and providing a statistical map that can be used by researchers and clinicians of different levels of expertise anywhere in the world.”

These tools hold promising therapeutic implications for epilepsy, but also for other neurological and psychiatric disorders such as Alzheimer’s disease, schizophrenia and depression. Crucially, the atlas provides researchers with a non-invasive way to assess the impact of therapies targeting this region of the brain and to thus develop better treatments to improve the quality of life for their patients.

Patient mood impacts outcome of interventional procedures


Feeling high levels of distress, fear and hostility prior to undergoing an angioplasty or other interventional radiology procedure may lead to a poor outcome, according to new research presented at the annual meeting of the Radiological Society of North America (RSNA) early December.

“I was surprised by this result,” said study author Nadja Kadom, M.D., currently acting associate professor of radiology at Emory University School of Medicine and Children’s Healthcare of Atlanta. “Prior to this study, I did not believe patient mood could have an effect on outcome.”

In the study, researchers analyzed the results of 230 patients, including 120 women and 110 men (mean age 55 years) who underwent image-guided interventional radiology procedures including vascular and kidney interventions. The minimally invasive procedures involved the use of a catheter, which is inserted through a blood vessel and threaded to an area of the body, such as a blocked artery, for treatment.

Upon arriving for their procedure, patients were asked to complete a questionnaire called the Positive Affect Negative Affect Schedule (PANAS) to assess their mood. Using a five-point rating scale, the patients reported to what extent they felt strong, alert, determined and other positive feeling states and to what degree they were experiencing negative feelings, such as guilt, nervousness or irritability.

Dr Kadom and fellow researchers Elvira V. Lang, M.D., Ph.D., and Gheorghe Doros, Ph.D., grouped the patients based on high and low scores for positive affect and high and low scores for negative affect. Those groups were then correlated with the occurrence of adverse events during the procedures, such as a prolonged lack of oxygen, low or high blood pressure, post-operative bleeding or an abnormally slow heart rate. A statistical analysis of the data revealed that patients with a high negative affect experienced significantly more adverse events than patients with low negative affect. Of the 104 patients with high negative affect, 23 (22%) had an adverse event, compared to 15 (12%) of the 126 patients with low negative affect. The degree of positive affect did not make a significant difference in the incidence of adverse events.

“Our study shows that mood matters,” noted Dr Lang, an interventional radiologist in Boston. “You don’t need to have a chipper, cheery attitude prior to your procedure. You just have to overcome negative emotions and get to a neutral level.”

Unlike surgical procedures in which patients are not conscious, interventional radiology procedures are often performed on patients who are sedated but awake and able to talk with the physician and healthcare team. “This is a real issue,” Dr Lang said. “The procedure room is a two-way street in which the patient can affect the healthcare professional and vice versa. Any time the team must manage an adverse event, it takes attention away from the procedure.”

Dr Kadom said that although the tendency in radiology is to focus on improving equipment and techniques to minimize adverse outcomes, there is a growing awareness of what patients bring to the table. Dr Lang suggested that healthcare teams should be trained in resilience and techniques to create their own positive emotional states, as well as coping strategies to help patients modify negative emotions and reframe their mindset prior to undergoing a procedure.

“We need to help staff show patients how to manage their own emotions to help create an environment for a better outcome,” she said.


                                  
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