Feelings of awe and joy can bolster your mental and physical health.

              POSITIVE EMOTIONS CAN STRENGTHEN YOUR IMMUNE SYSTEM
                                         Image Credit: Mens Health

The wonders of the world can be just as good for your health as they are for your enjoyment, suggests a UC Berkley study.

Researchers have linked positive emotions—awe, contentment, spirituality—with lower levels of pro-inflammatory cytokines, proteins that signal your immune system to work harder and bolster good health.

In two separate experiments, more than 200 young adults were asked to log the extent to which they experienced amusement, awe, compassion, joy, love, and pride on a given day. Samples of gum and cheek tissue taken that same day showed that those who experienced more of these positive emotions had the lowest levels of the cytokine Interleukin 6, a marker of inflammation that can cause autoimmune disease and depression.

“That awe, wonder and beauty promote healthier levels of cytokines suggests that the things we do to experience these emotions—a walk in nature, losing oneself in music, beholding art—has a direct influence upon health and life expectancy,” says UC Berkeley psychologist Dacher Keltner, a co-author of the study.

An added emphasis on spirituality and mindfulness may just be enough to get you through this winter happy and healthy. 

Source: Mensfitness

Summer Restoration in a Bolivian Winter

                                 El Hospital Pietro Gamba in Anzaldo, Bolivia Credit: Duke

My biggest accomplishment this summer was being able to call the mountains of Bolivia home. Far away from the lecture halls of Duke, I encountered a profound, alternative education that included everything from learning traditional dances to working in a rural hospital laboratory to raising pigs.

Of course, living in Bolivia for two months had its challenges, like a diet in which potatoes were considered vegetables, repeated food poisoning from chicha, the local alcoholic drink consisting of fermented corn, lack of a consistent water source, many near-car accidents, and most of all a deep-seated machismo, but I feel that these were all almost inextricable aspects of a culture that left such a positive impression upon me.

Of course, the inextricability of such factors posed a problem for me as an intern at El Hospital Pietro Gamba encouraging sustainable development to promote public health. Although 80% of children had head lice, a vast majority contracted repeated gastrointestinal bacterial infections, and countless had scabies, the community seemed to get along contentedly. Regardless, with support from the Foundation for Sustainable Development and DukeEngage, my sponsor organizations, I leveraged the relatively new running water system, implemented only 25 years ago, to set in motion a comprehensive lice campaign, to obtain government funding of soap in public restrooms for at least two years, and to create preventative medicine informational materials.

The majority of my education, though, occurred outside the scope of my project. Most importantly, I’ve learned to openly embrace different forms of learning, like relaxation or soccer, that energize me to wholeheartedly pursue my rigorous biophysics career, which I am so fortunate to have at one of the best universities in the world.

The idea of the Aymara New Year illustrates my mentality poignantly: on the first day of the Aymara New Year, traditional Bolivians wish for health, prosperity, and happiness, just as we do in the United States. However, they have a deeper connection with Pachamama, or Mother Nature: on New Year’s Day, they wake up early in the morning to stand on the ground barefoot, awaiting the first rays of the sun. They believe that watching these rays rise above the horizon and light the earth will bring them energy for the entire year. In this, the Aymara New Year represents both personal aspiration and attenuation with the environment.

Similarly, I now aim to maintain a balance between self and surroundings: I hope to be more attuned to the world around me rather than single-mindedly submersing myself in quantum physics, as I believe that varied experiences will infuse me with energy in whatever I pursue. Now, back at Duke for the start of my junior year, I’m excited to begin blogging again and to continue my adventures and education here on campus.

Source: Duke University

EGFR-Mediated Beclin 1 Phosphorylation in Autophagy Suppression, Tumor Progression, and Tumor Chemoresistance

EGFR negatively regulates autophagy by binding to Beclin 1.
Active EGFR phosphorylates Beclin 1 and alters its interactome.
EGFR suppression of Beclin 1 may contribute to tumor progression in lung cancer.

Lung cancer responses to EGFR inhibitors may involve activation of Beclin 1. Image Credit: Cell Press

Summary
Cell surface growth factor receptors couple environmental cues to the regulation of cytoplasmic homeostatic processes, including autophagy, and aberrant activation of such receptors is a common feature of human malignancies. Here, we defined the molecular basis by which the epidermal growth factor receptor (EGFR) tyrosine kinase regulates autophagy. Active EGFR binds the autophagy protein Beclin 1, leading to its multisite tyrosine phosphorylation, enhanced binding to inhibitors, and decreased Beclin 1-associated VPS34 kinase activity. EGFR tyrosine kinase inhibitor (TKI) therapy disrupts Beclin 1 tyrosine phosphorylation and binding to its inhibitors and restores autophagy in non-small-cell lung carcinoma (NSCLC) cells with a TKI-sensitive EGFR mutation. In NSCLC tumor xenografts, the expression of a tyrosine phosphomimetic Beclin 1 mutant leads to reduced autophagy, enhanced tumor growth, tumor dedifferentiation, and resistance to TKI therapy. Thus, oncogenic receptor tyrosine kinases directly regulate the core autophagy machinery, which may contribute to tumor progression and chemoresistance.

Introduction
Epidermal growth factor receptor (EGFR), an oncogenic receptor tyrosine kinase, links extracellular signals to cellular homeostasis. In normal cells, EGFR signaling is triggered by the binding of growth factors, such as epidermal growth factor (EGF), leading to homodimerization or heterodimerization with other EGFR family members (such as HER2/neu) and autophosphorylation of the intracellular domain (Lemmon and Schlessinger, 2010). The phosphotyrosines formed serve as a docking site for adaptor molecules, which results in the activation of signaling pathways including the Ras/MAPK pathway, the PI3K/Akt pathway, and STAT signaling pathways. In tumor cells, the tyrosine kinase activity of EGFR may be dysregulated by EGFR gene mutation, increased EGFR gene copy number, or EGFR protein overexpression, leading to aberrant EGFR signaling and increased tumor cell survival, proliferation, invasion, and metastasis ( Ciardiello and Tortora, 2008). EGFR signaling is deregulated in many human cancers, including those of the lung, head and neck, colon, pancreas, and brain.

The deregulation of EGFR in human cancers has led to the development of anticancer agents that target EGFR, including: (1) anti-EGFR antibodies that inhibit ligand binding and (2) small-molecule receptor tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, that block EGFR intracellular tyrosine kinase activity. Although the EGFR TKIs have shown limited clinical benefit in the majority of solid tumors, they are effective in non-small-cell lung carcinomas (NSCLCs) that harbor specific mutations in the tyrosine kinase domain of EGFR (most commonly, in-frame deletion in exon 19 around codons 746–750 or single-base substitution, L858R, in exon 21) (Ciardiello and Tortora, 2008, Lynch et al., 2004 and Pao and Chmielecki, 2010). Most patients with NSCLCs with EGFR mutations initially respond favorably to erlotinib or gefitinib, suggesting these mutations drive tumorigenesis. However, among tumors that initially respond to EGFR TKIs, most eventually acquire resistance, often due to the emergence of a secondary mutation, T790M, in the kinase domain of EGFR (Pao and Chmielecki, 2010).

Several studies have shown that EGFR signaling regulates autophagy, a lysosomal degradation pathway that functions in cellular homeostasis and protection against a variety of diseases, including cancer (Levine and Kroemer, 2008). The downstream targets of EGFR—PI3K, Akt, and mammalian target of rapamycin (mTOR)—are well-established negative regulators of autophagy (Botti et al., 2006). Moreover, EGFR inhibitors induce autophagy in NSCLCs (Gorzalczany et al., 2011 and Han et al., 2011) and other cancer cells (Fung et al., 2012). However, the links between EGFR signaling and autophagy remain poorly understood, particularly (1) the molecular mechanisms by which EGFR signaling suppresses autophagy, (2) the role of EGFR suppression of autophagy in lung cancer pathogenesis, and (3) the role of autophagy induction in the response to TKI therapy. EGFR inhibitor-induced autophagy in lung cancer cells has been postulated to exert either cytoprotective (Han et al., 2011) or cytotoxic (Gorzalczany et al., 2011) effects.

Conflicting results regarding the role of autophagy in the response or resistance to EGFR TKI treatment reflects broader uncertainties in the role of autophagy in cancer therapy (Rubinsztein et al., 2012). It is not understood in what contexts autophagy induction contributes to tumor progression or suppression and to tumor chemoresistance or chemosensitivity. There is a general consensus that autophagy prevents tumor initiation, as loss-of-function mutations of several different autophagy genes results in spontaneous tumorigenesis (beclin 1, Atg5, and Atg7) and/or increased chemical-induced tumorigenesis (Atg4C) in mice ( Rubinsztein et al., 2012). Despite this inhibitory role in tumor initiation, it has been proposed that autophagy may promote the growth of established tumors and contribute to chemoresistance, principally through its actions to prolong the survival of metabolically stressed neoplastic cells ( Rubinsztein et al., 2012).

To understand the relationship between oncogenic signaling, autophagy, and distinct stages of tumorigenesis, it is important to define the molecular mechanisms by which oncogenic signaling regulates autophagy. We recently showed that the oncogene Akt inhibits autophagy independently of mTOR signaling via serine phosphorylation of the essential autophagy protein, Beclin 1 (Wang et al., 2012), a haploinsufficient tumor suppressor protein frequently monoallelically deleted in human breast and ovarian cancer (Levine and Kroemer, 2008). Moreover, Akt-mediated phosphorylation of Beclin 1 contributes to Akt-dependent fibroblast transformation, supporting the concept that inactivation of Beclin 1-dependent autophagy plays a role in tumor initiation. However, it is not known whether oncogenic inactivation of Beclin 1 (or other autophagy proteins) influences progression of established tumors and/or their response to therapy.


Here, we identify the molecular basis by which EGFR tyrosine kinase activity regulates autophagy. We show that active EGFR binds to Beclin 1, leading to its tyrosine phosphorylation, alteration of its interactome, and inhibition of its autophagy function. A mutant of Beclin 1 containing phosphomimetic mutations in the EGFR-dependent tyrosine phosphorylation sites enhances autophagy suppression in EGFR-mutated NSCLC cells, resulting in enhanced tumor progression, altered tumor cell differentiation, and partial tumor resistance to EGFR TKI therapy. These findings demonstrate a heretofore unknown link between oncogenic receptor tyrosine kinases and the autophagy machinery, which may contribute to tumor progression and resistance to targeted therapy.

Source: Full Artical At - CELL PRESS

UCLA and CASIS to collaborate on International Space Station study of possible therapy for bone loss

A study of rodents on the International Space Station will allow astronauts to test the ability of a bone-forming molecule to direct stem cells to induce bone formation. Credit: Nasa

UCLA has received grant funding from the Center for the Advancement of Science in Space to lead a research mission that will send rodents to the International Space Station. The mission will allow astronauts on the space station and scientists on Earth to test a potential new therapy for accelerating bone growth in humans. 

The research will be led by Dr. Chia Soo, a UCLA professor of plastic and reconstructive surgery and orthopaedic surgery who is member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Soo also is the research director for UCLA Operation Mend, which provides medical care for wounded warriors.

The study will test the ability of a bone-forming molecule called NELL-1 to direct stem cells to induce bone formation and prevent bone degeneration. Their work will build upon previous UCLA studies that were funded by the NIH.

Other members of the UCLA research team are Dr. Kang Ting, a professor of dentistry who discovered NELL-1 and is leading efforts to translate NELL-1 therapy to humans; Dr. Ben Wu, a professor of bioengineering and dentistry who modified the NELL-1 molecule to make it useful for treating osteoporosis; and Dr. Jin Hee Kwak, an assistant professor of dentistry who will manage the study’s daily operations.

Prolonged space flights induce extreme changes in bone and organ systems that cannot be replicated on Earth.

The UCLA–ISS team, which will begin ground operations in early 2015, hopes that the study will provide new insights into the prevention of bone loss or osteoporosis as well as the regeneration of massive bone defects that can occur in wounded military personnel. Osteoporosis is a significant health issue commonly associated with “skeletal disuse” conditions such as immobilization, stroke, cerebral palsy, muscular dystrophy, spinal cord injury and jaw resorption after tooth loss.

“NELL-1 holds tremendous hope not only for preventing bone loss, but one day even restoring healthy bone,” Ting said. “For patients who are bed-bound and suffering from bone loss, it could be life-changing.” 

The UCLA team will oversee the ground operations of the mission in tandem with a flight operation coordinated by CASIS and NASA.  

“A group of 40 rodents will be sent to the International Space Station U.S. National Laboratory onboard the SpaceX Dragon capsule, where they will live for two months in a microgravity environment during the first ever test of NELL-1 in space,” said Dr. Julie Robinson, NASA’s chief scientist for the International Space Station program at the Johnson Space Center.

“CASIS is proud to work alongside UCLA in an effort to promote the station as a viable platform for bone loss inquiry,” said Warren Bates, director of portfolio management for CASIS. “Through investigations like this, we hope to make profound discoveries and enable the development of therapies to counteract bone loss ailments common in humans.”

“Besides testing the limits of NELL-1’s robust bone-producing effects, this mission will provide new insights about bone biology and could uncover important clues for curing diseases such as osteoporosis,” Wu said. 

“NIH has been pleased to work with NASA and CASIS to encourage the use of the International Space Station as a unique microgravity environment that can test innovative hypotheses that will benefit human health on Earth,” said Dr. Joan A. McGowan, director of the division of musculoskeletal diseases at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the NIH.

“This research has enormous translational application for astronauts in space flight and for patients on Earth who have osteoporosis or other bone-loss problems from disease, illness or trauma,” Soo said. “We very much appreciate the dedicated review staff at CASIS and the Center for Scientific Review, the portal for NIH grant applications, who made this effort possible.”

The research is supported by grants from the Center for the Advancement of Science in Space and National Institutes of Health. Additional funding and support are provided by the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, the UCLA School of Dentistry, UCLA department of orthopaedic surgery and the UCLA Orthopaedic Hospital Research Center.

Source: UCLA

Drug combo supresses growth of late-stage prostate cancer turmors

By Natalie van Hoose

Low doses of metformin, a widely used diabetes medication, and a gene inhibitor known as BI2536 can successfully halt the growth of late-stage prostate cancer tumors, a Purdue University study finds.

Prostate cancer causes the second-highest number of cancer-related deaths in men in the U.S., and methods of treating advanced prostate cancer are limited.

Xiaoqi Liu (pronounced zhow-CHEE' LEE'-oo), associate professor of biochemistry and cancer research, and fellow researchers found that the drugs metformin and BI2536 can work together to suppress the spread of prostate cancer that resists all other available treatments, potentially prolonging patients' lives.

"We've found a promising way to treat late-stage prostate cancer," Liu said. "By combining low levels of two well-tolerated drugs, the progression of this disease could be significantly delayed. Completely curing the cancer at the advanced stage is pretty much impossible, but this treatment might manage it for a while - that's exciting."

A number of treatments exist for the earlier stages of prostate cancer, which grows slowly compared with many other cancers. Because prostate cancer cells need the male sex hormone androgen to develop, one way to treat the disease is to suppress androgen - a process known as castration. If the cancer continues to spread, the patient often undergoes chemotherapy. As a last resort, drugs that block the synthesis of androgen by prostate cancer cells can be used, but these medications only extend a patient's lifespan for several months.

New approaches to treating the most persistent forms of prostate cancer are "urgently needed," Liu said.

Adding to the challenge is the fact that castration treatment can inadvertently encourage the cancer to get tougher. It can heighten oxidative stress on the prostate gland, which increases the expression of Plk1, a gene that has been linked to many cancers. Over-expression of Plk1 can also trigger the synthesis of androgen.

"The goal of castration is to block androgen synthesis," Liu said. "But cancer cells eventually become 'smart' enough to make androgen anyhow, which is why the cancer continues to grow."

Additionally, castration can disrupt the body's metabolism and lead to insulin resistance, which also can stimulate the production of androgen. The cancer will spread until both of these side effects are stopped, Liu said.

Previous studies showed that metformin - an inexpensive, antidiabetic drug that has been commonly used for more than 40 years - is particularly potent to prostate cancer tumors.

Working with fellow researchers from Purdue, the University of Wisconsin-Madison and the Indiana University School of Medicine, Liu found that a combination of low levels of metformin and BI2536, a drug that stifles the activity of Plk1, could work in tandem to slow the growth of prostate tumors too advanced for current treatments by promoting the self-destruction of cancer cells and preventing androgen synthesis.

The drugs did not impact healthy prostate cells, a "key finding," Liu said. "Ideally, cancer therapy will have minimal effects on normal cells."

Because metformin helps regulate metabolism, it may reverse some of the metabolic damage caused by castration, he said.

The researchers tested the drugs in a classical cell culture assay of prostate cancer cells and in advanced prostate tumors in mice. Low concentrations of the drugs significantly slowed the development of cancer in both trials. The mice tumors were grown from the tumor cells of a late-stage prostate cancer patient, suggesting that the treatment would prove effective in humans.

"Those results were amazing," Liu said. "These are the first data we've generated from a real patient, so I was almost jumping in the air when I saw that it worked."

Liu said that the next step in the research is to test the combination of drugs in clinical trials. Further research is also needed to understand the underlying mechanism of metformin and why it is effective at suppressing prostate cancer

Source: Purdue Univesity

Small change in blood acidity could prove detrimental to kidney disease patients

A University of Manchester scientist has discovered that very small changes in the level of acidity in blood may have a detrimental impact on the health of patients with kidney disease.

Chronic Kidney Disease (CKD) is common in the UK.  It is estimated that about one in five men and one in four women between the ages of 65 and 74 has some degree of CKD. The leading single cause of CKD is diabetes which is increasing so it’s expected that more patients will be diagnosed with CKD in the future.

Dr Donald Ward from the Faculty of Life Sciences has been studying the impact of kidney disease on the body. He has found that very small changes in the pH (acidity) level in the blood prevents the body from being able to accurately monitor calcium levels. This leads to too much of the hormone PTH being released which is likely to lead to a greater risk of calcium and phosphate from the bone damaging the arteries. This often proves fatal to patients with CKD. His research has been published in the Journal of the American Society of Nephrology. 

Dr Donald Ward

He says: “It was not realised before that the blood pH changes we see in patients with kidney disease can have an impact on their ability to monitor blood calcium levels. My research has demonstrated that the effect of those changes may be more significant than previously thought and thus might need to be looked at more carefully by clinicians.”

Dr Ward’s research focussed on the high level of parathyroid hormone (PTH) in patients suffering from CKD. This causes the body to release calcium and phosphate from the bones which can then damage their blood vessels. 

Dr Ward explains why this is so harmful: “The diseased kidneys prevent the body getting rid of both excess phosphate and excess acidity. So if that acidity also causes the body to release more PTH then this could compound the problem by releasing further phosphate from the bone. This vicious circle might accelerate the potentially fatal calcification of the arteries.” 

He continues: “What is so important about this research is that we have demonstrated that changes in PTH release can be prompted by very small changes in blood pH level. Before, it was assumed that only a larger change in acidity would cause problems for patients.”

The research was funded by Kidney Research UK. Elaine Davies, Director of Research Operations, from the charity says: “Donald’s work has used novel pharmacological and molecular tools in generating these new findings which increase our knowledge about the complex balance that clinicians need to consider when treating patients with CKD.”

Dr Ward is hoping to take his research to the next step, testing for therapeutic targets that could lead to better treatments for CKD.

Source: Manchester University

Stanford bioengineers develop tool for reprogramming genetic code

Stanford bioengineers have developed a new tool that allows them to preferentially activate or deactivate genes in living cells. VITSTUDIO/SHUTTERSTOCK

Biology relies upon the precise activation of specific genes to work properly. If that sequence gets out of whack, or one gene turns on only partially, the outcome can often lead to a disease.

Now, bioengineers at Stanford and other universities have developed a sort of programmable genetic code that allows them to preferentially activate or deactivate genes in living cells. The work is published in the current issue of Cell, and could help usher in a new generation of gene therapies.

The technique is an adaptation of CRISPR, itself a relatively new genetic tool that makes use of a natural defense mechanism that bacteria evolved over millions of years to slice up infectious virus DNA.

Standard CRISPR consists of two components: a short RNA that matches a particular spot in the genome, and a protein called Cas9 that snips the DNA in that location. For the purposes of gene editing, scientists can control where the protein snips the genome, insert a new gene into the cut and patch it back together.

Inserting new genetic code, however, is just one way to influence how the genome is expressed. Another involves telling the cell how much or how little to activate a particular gene, thus controlling how much protein a cell produces from that gene and altering its behavior.

It's this action that Lei Stanley Qi, an assistant professor of bioengineering and of chemical and systems biology at Stanford, and his colleagues aim to manipulate.

Influencing the genome
In the new work, the researchers describe how they have designed the CRISPR molecule to include a second piece of information on the RNA, instructing the molecule to either increase (upregulate) or decrease (downregulate) a target gene's activity, or turn it on/off entirely.

Additionally, they designed it so that it could affect two different genes at once. In a cell, the order or degree in which multiple genes are activated can produce different metabolic products.

"It's like driving a car. You control the wheel to control direction, and the engine to control the speed, and how you balance the two determines how the car moves," Qi said. "We can do the same thing in the cell by up- or downregulating genes, and produce different outcomes."

As a proof of principle, the scientists used the technique to take control of a yeast metabolic pathway, turning genes on and off in various orders to produce four different end products. They then tested it on two mammalian genes that are important in cell mobility, and were able to control the cell's direction and how fast it moved.

Future therapies
The ability to control genes is an attractive approach in designing genetic therapies for complex diseases that involve multiple genes, Qi said, and the new system may overcome several of the challenges of existing experimental therapies.

"Our technique allows us to directly control multiple specific genes and pathways in the genome without expressing new transgenes or uncontrolled behaviors, such as producing too much of a protein, or doing so in the wrong cells," Qi said. "We could eventually synthesize tens of thousands of RNA molecules to control the genome over a whole organism."

Next, Qi plans to test the technique in mice and refine the delivery method. Currently the scientists use a virus to insert the molecule into a cell, but he would eventually like to simply inject the molecules into an organism's blood.

"That is what is so exciting about working at Stanford, because the School of Medicine's immunology group is just around the corner, and working with them will help us address how to do this without triggering an immune response," said Qi, who is a member of the interdisciplinary Stanford ChEM-H institute. "I'm optimistic because everything about this system comes naturally from cells, and should be compatible with any organism."

Source: Stanford university

On the ups and downs of the seemingly idle brain

Cortical colors Inhibitory cells abound in the barrel cortex of the mouse, where three main types were labeled to fluoresce in different colors: PV (red), SOM (blue), and 5HT3aR, which includes VIP and NPY, (green). Image: Connors lab/Brown University

Even when it seems not to be doing much, the brain maintains a baseline of activity in the form of up and down states of bustle and quiet. To accomplish this seemingly simple cycle, it maintains a complex balance between the activity of many excitatory and inhibitory cells, Brown University scientists report in the Journal of Neuroscience.

PROVIDENCE, R.I. [Brown University] — Even in its quietest moments, the brain is never “off.” Instead, while under anesthesia, during slow-wave sleep, or even amid calm wakefulness, the brain’s cortex maintains a cycle of activity and quiet called “up” and “down” states. A new study by Brown University neuroscientists probed deep into this somewhat mysterious cycle in mice, to learn more about how the mammalian brain accomplishes it.

In addition to an apparent role in maintaining a baseline of brain activity, the up and down cycling serves as a model for other ways in which activity across the cortex is modulated, said Garrett Neske, graduate student and lead author. To study how the brain maintains this cycling, he found, is to learn how the brain walks a healthy line between excitement and inhibition as it strives to be idle but ready, a bit like a car at a stoplight.

Garrett Neske To study how the brain maintains up and down cycles is to learn how the brain strives to be idle but ready, a bit like a car at a stoplight. Photo: David Orenstein/Brown University

“It is very important to regulate that balance of excitation and inhibition,” said senior author Barry Connors, professor and chair of neuroscience at Brown. “Too much excitation relative to inhibition you get a seizure, too little you become comatose. So whether you are awake and active and processing information or whether you are in some kind of idling state of the brain, you need to maintain that balance.”

The cycling may seem simple, but what Neske and Connors found in their investigation, published in the Journal of Neuroscience, is that it involves a good deal of complexity. They focused on five different types of cells in a particular area of the mouse cortex and found that all five appear to contribute uniquely to the ups and downs.

Cells in a barrel

Specifically the researchers, including Saundra Patrick, neuroscience research associate and second author, looked at the activity of excitatory pyramidal cells and four kinds of inhibitory interneurons (PV, SOM, VIP and NPY) in different layers of the barrel cortex. That part of the cortex is responsible for processing sensations on the face, including the whiskers.

Neske induced up and down cycles in slices of tissue from the barrel cortex and recorded each cell type’s electrical properties and behaviors, such as its firing rate and the amounts of excitation and inhibition they received from other neurons.

The picture that emerged is that all types of interneurons were active. This included the most abundant interneuron subtype (the fast-spiking PV cell), and the various more slowly spiking subtypes (SOM, VIP, NPY). In fact, Connors said, the latter cells were active at levels similar to or higher than neighboring excitatory cells, contributing strong inhibition during the up state.

One way such findings are important is in how they complement recent ones by another research group at Yale University. In that study scientists looked at a different part of the cortex called the entorhinal cortex. There they found that only one inhibitory neuron, PV, seemed to be doing anything in the up state to balance out the excitement of the pyramidal neurons. The other inhibitory neurons stayed virtually silent. In his study, Neske replicated those results.

Taken together, the studies indicate that even though up and down cycles occur throughout the cortex, they may be regulated differently in different parts.

“It suggests that inhibition plays different roles in persistent activity in these two regions of cortex and it calls for more comparative work to be done among cortical areas,” Neske said. “You can’t just use one cortical region as the model for all inhibitory interneuron function.”

From observation to manipulation

Since observing the different behaviors of the neuron types, Neske has moved on to manipulating them to see what role each of them plays. Using the technique of optogenetics, in which the firing of different neuron types can be activated or suppressed with pulses of colored light, Neske is experimenting with squelching different interneurons to see how their enforced abstention affects the up and down cycle.

When the work is done, he should emerge with an even clearer idea of the brain’s intricate and diligent efforts to remain balanced between excitation and inhibition.

The National Institutes of Health (grants NS-050434, MH-086400, and T32NS062443) and the Defense Advanced Research Projects Agency (grant DARPA-BAA-09-27) supported the research.

Source: Brown University

Ebola: Reports from the front lines

Dr. Noah Rosenberg “Ebola was never the only killer here, and our ability to appropriately diagnose and treat these patients is woefully limited.”

Alpert Medical School professors Michael Smit and Noah Rosenberg are in Sierra Leone and Liberia respectively, treating Ebola patients. There are some signs of a slowdown in the epidemic, but the doctors emphasize that the virus must be fought “until the last case.”

PROVIDENCE, R.I. [Brown University] — In a limited sense, two Brown University medical professors who have been fighting Ebola in West Africa this winter have good news to report. They have seen some signs of slowing disease transmission. But the broader reality of what Ebola has done in Sierra Leone and Liberia is grim, according to Drs. Michael Smit and Noah Rosenberg.

Ebola shouldn’t just be contained, they note: It must be treated until all cases are resolved.

Smit, assistant professor of pediatrics and a physician at Hasbro Children’s Hospital, arrived in Sierra Leone Dec. 3, 2014, and will remain there through Jan. 18. Rosenberg, clinical assistant professor of emergency medicine and a Lifespan doctor, arrived in Liberia in mid-December and will stay until Jan. 27. They answered questions for medical science writer David Orenstein about what they are doing and seeing, and what people back in the States need to know.

Please describe a typical day.

NR: I arrive at 7 a.m. and meet with the overnight doctor and nurses to discuss our patients. My team pulls on full personal protective equipment and enters the high-risk area. We examine each patient, inquire about their current symptoms, give routine supportive medications and IV fluids if needed. We take blood to test for Ebola. We remove our equipment while being intermittently sprayed with chlorine. Rounds repeat in the afternoon and we often make an additional trip for a new admission. In the evening we meet with the night team and then rest to return in the morning.

Dr. Michael Smit “The effect of the epidemic goes far beyond those infected with Ebola virus. ... The economic impact on the country is devastating.

MS: I am the medical team leader of one of four medical teams at the Mateneh Ebola Treatment Center (ETC). Our days differ depending on which shift we are working. When working the early shift, we eat breakfast around 7 a.m. and drive to the ETC. We change into our work uniforms of scrubs and rubber boots at the ETC. At 7:30 we receive signout on the patients from the overnight team. We then assign personnel to conduct the nursing rounds, physician rounds, admissions, and discharges. During the heat of the day, we try to limit time in the high-risk area in personal protective equipment (PPE) to one hour. We deliver meals, administer medications, place intravenous catheters, and draw blood for laboratory tests. We triage admissions as they come through the ambulance bay. We also process discharges. These include survivors discharged home and deaths transferred to the morgue. At the end of the shift, we sign out the patients to the oncoming team, change back into our civilian clothes, and go back to the compound to eat. The late and overnight shifts are the same as the early shift for the most part.

What do you observe and hear about the status of the epidemic where you are?

NR: The exponential growth of the epidemic is clearly over in Liberia, but sporadic outbreaks are likely to continue until every case has been eliminated from West Africa, which may take months. Most of our new admissions now test negative for Ebola; they frequently die nonetheless. This may seem counterintuitive, but Ebola was never the only killer here, and our ability to appropriately diagnose and treat these patients is woefully limited.

MS: It is difficult to assess the status of the epidemic from here. We have limited access to the Internet, so our updates of what is happening are intermittent. As for what we observe, after a slow start from our opening in mid-December, we saw a steady increase in cases in our district in Bombali. Over the last week, admissions have decreased. The reason for this is not clear. We hope that it reflects a reduction in transmission, but we cannot assume this given the complexities of case identification and transport here.

What do people in the United States most need to know, based on what you are experiencing?

NR: Before the epidemic Liberia suffered from a large disease burden and severely limited health care system. Decades of civil war, sparked by inequality and tension between descendants of indigenous West Africans and freed slaves, wrecked the infrastructure and economy. Not only was the U.S.A. responsible for the founding of Liberia, but many of the struggles here today have their origins in the slave trade. Ebola will soon fade from the news but the epidemic has only worsened an already grave condition. We have a special responsibility to Liberia and it deserves our sustained attention.

MS: People in the United States need to know that the epidemic here is far from over. Even in a situation with diminished transmission, the United States needs to send personnel and resources here to combat Ebola until the last case. The effect of the epidemic goes far beyond those infected with Ebola virus. The schools here in Sierra Leone have been closed for months. Teen pregnancy is increasing as a result. The economic impact on the country is devastating, with some estimates setting the economy back 10 years. Also, people in the United States need to know about the dedication and resilience of the local and international healthcare workers who are fighting the epidemic, often under challenging physical and emotional conditions.

Source: Brown University

HIV testing yields diagnoses in Kenya but few seek care

A sweeping effort in a rural region of Kenya to test all adults for HIV discovered 1,300 new infections, but few of the newly diagnosed people pursued treatment, a study in the journal Lancet HIV reports.
PROVIDENCE, R.I. [Brown University] — Between December 2009 and February 2011, health workers with the AMPATH Consortium sought to test and counsel every adult resident in the Bunyala subcounty of Kenya for HIV. A study in the journal Lancet HIV reports that the campaign yielded more than 1,300 new positive diagnoses, but few of those new patients sought health care.

“Home-based counseling and testing (HBCT) provided a diagnosis to nearly 40 percent of people living with HIV in this subcounty who otherwise most likely would not have gone for HIV testing,” said study lead author Becky Genberg, assistant professor (research) of health services, policy and practice in the Brown University School of Public Health. “They therefore would not have known about their HIV infection and not had the opportunity to change their behavior to protect others.”

AMPATH’s HBCT program is part of a strategy to identify all individuals living with HIV in the catchment area, start them on antiretroviral medication as soon as possible, and help them stay on their medications. Antiretroviral medication not only suppresses HIV infections for most patients but also reduces their ability to transmit the virus.

Genberg with co-author Edwin Sang “We are working on a variety of studies, all designed to understand the barriers facing the newly diagnosed, and to implement and evaluate strategies to increase their engagement and retention in HIV care over time.”

In Bunyala, home to about 66,000 people, the HBCT program tested about 32,000 adults. Among them, 3,482 had HIV. Of those, 2,122 already knew they were infected, but 1,360 did not know it yet.

A major finding of the study is that three years later only 15 percent of the newly diagnosed people had engaged in care for their infection. A likely reason why, Genberg said, is that newly diagnosed people typically don’t yet feel sick.

“That so few linked to care following HBCT is a call for innovative and creative strategies to work alongside HBCT to support the mostly healthy, asymptomatic newly diagnosed to engage with care in a way that is meaningful for them,” Genberg said.

In an editorial in the journal, Rashida Ferrand of the London School of Hygiene and Tropical Medicine said the study sounds a warning that home-based testing must be paired with effective ways to convince newly diagnosed patients to seek help.

“Unless paired with interventions targeted at hard-to-reach populations, the diagnosing of undiagnosed individuals in many settings will not be cost-effective and will have little effect on individual and population viral suppression,” she and colleagues wrote.

Genberg, who has been in Kenya this winter, said she is working with Kenyan collaborators on developing the needed interventions: “Right now we are working on a variety of studies, all designed to understand the barriers facing the newly diagnosed, and to implement and evaluate strategies to increase their engagement and retention in HIV care over time.”

In addition to Genberg the study’s authors are Joseph Hogan and Corey Duefield of Brown; Violet Naanyu, Juddy Wachira, and Samson Ndege of Moi University in Kenya; Edwin Sang, Monicah Nyambura, and Michael Odawa of AMPATH; and corresponding author Paula Braitstein of the University of Toronto.

The President’s Emergency Plan for AIDS Relief funded the study though USAID (grant AID-623-A-12-0001). Additional support came from the National Institutes of Health (K01MH099966) and the Bill and Melinda Gates Foundation.

Source: Brown University

Reducing Myc gene activity extends healthy lifespan in mice

No bones about it Young mice have good bone density whether they have two copies (top row; +/+) or one copy (bottom row; +/-) of the Myc gene. As they age, researchers found, mice with just one copy maintain better bone density and stay healthy longer. Sedivy lab/Brown University

Mice with one rather than the normal two copies of the gene Myc (also found in humans) lived 15 percent longer and had considerably healthier lives than normal mice, according to a new Brown University-led study in Cell.

PROVIDENCE, R.I. [Brown University] — A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice, the first such finding regarding this gene in a mammalian species.

Myc is found in the genomes of all animals, ranging from ancestral single-celled organisms to humans. It is a major topic of biomedical research and has been shown to be a central regulator of cell proliferation, growth, and death. It is of such widespread and fundamental importance that animals cannot live without it. But in humans and mice, too much expression of the protein that Myc encodes has been closely linked to cancer, making it a well-known but elusive target of drug developers.

In a new study in the journal Cell, the scientists report that when they bred laboratory mice to have only one copy of the gene, instead of the normal two, thus reducing the expression of the encoded protein, those mice lived 15 percent longer on average — 20 percent longer for females and 10 percent longer among males — than normal mice. Moreover, the experimental mice showed many signs of better health into old age.

The experimental — “heterozygous” — mice grew to be about 15 percent smaller than the normal mice (a probable disadvantage in the wild) but that was the only discernable downside found to date for lacking a second copy of the gene, said senior author John Sedivy, the Hermon C. Bumpus Professor of Biology and professor of medical science at Brown.

“The animals are definitely aging slower,” he said. “They are maintaining the function of their organs and tissues for longer periods of time.”

Physiological differences

That assessment is based on detailed studies of the physiology — down to the molecular level — of the heterozygous and normal mice. The researchers conducted these experiments to try to understand the longevity difference between the two groups.

John Sedivy “The animals are definitely aging slower [and[ they are maintaining the function of their organs and tissues for longer periods of time.”

Co-lead author Jeffrey Hoffman, a medical and doctoral student, led the studies of the health of the mice, including various bodily systems. In many cases they were just like their normal counterparts. They reproduced just as well, for example.

“These mice are incredibly normal, yet they are really long-lived,” Sedivy said. “The reason why we were struck by that is because in many other longevity models like caloric restriction or treatment with rapamycin, the animals live longer but they also have some health issues.”

Instead the Myc heterozygous mice simply experienced fewer problems of aging. They did not develop osteoporosis, they maintained a healthier balance of immune system T cells, had less cardiac fibrosis, were more active, experienced less age-related slowing of their metabolic rate, produced less cholesterol, and exhibited better coordination.

Graduate student and co-lead author Xiaoai Zhao, meanwhile, led the molecular analysis of several pathways known to be involved in regulating longevity to find out how they might be different. Sure enough, heterozygous mice exhibited changes in IGF-1 signaling and nutrient and energy-sensing pathways, but how Myc engages those mechanisms is still not clear. Of particular interest, heterozygous mice showed less protein synthesis in several tissues. Regulation of this process is known to be under direct Myc control, and its reduction by a variety of means is known to extend lifespan in diverse species from yeast to mammals.

Genome-wide patterns of gene expression showed that Myc heterozygotes had significant differences in pathways related to metabolism and the immune system. Those patterns, however, only overlapped somewhat with patterns seen in other lifespan extending interventions.

Zhao and Hoffman’s studies also argue against a role for Myc in an oft-cited paradigm of greater longevity: upregulation of a variety of stress defense mechanisms. Their experimental mice seemed to suffer from as much stress and consequences of stress as normal mice.

The different benefits of Myc reduction compared to other laboratory longevity extenders shows that just as there are many ways the body can break down with aging, Sedivy said, there may be many ways to forestall that.

“There is more than one way to become long-lived,” Sedivy said.

Help for humans?

In the long term, Sedivy said he is optimistic that the findings about Myc could prove to matter to human health.

Finding the right target for a drug in one of Myc’s key metabolic or immune system pathways may or may not extend human lifespan, he said, but it might help people stay healthier as they age — for example, if it can reduce osteoporosis in people the way it does in mice. In particular, Sedivy said, it emphasizes the importance of the process of protein synthesis as a target of interventions that are likely to have widespread benefits on many organ systems.

And the study also offers encouragement to companies seeking to develop cancer drugs that block Myc overexpression. As important as normal Myc expression is to physiology, it appears that at least in mice there were many substantial benefits in reducing it by, say, half. Thus, Sedivy said, any drug that can target Myc directly is likely to find many applications beyond cancer.

In addition to Sedivy, Hoffman, and Zhao, the paper’s other authors are Marco De Cecco, Abigail Peterson, Luca Paglilaroli, Jayameenakshi Manivannan Bin Feng, Thomas Serre, Kevin Bath, Haiyan Xu, and Nicola Neretti of Brown; Gene Hubbard, Wenbo Qi, and Holly Van Remmen of the University of Texas; Yongqing Zhang and Rafael de Cabo of the National Institute on Aging; and Richard Miller of the University of Michigan.

The National Institutes of Health (grants R37AG016694, F30AG035592), the Ellison Medical Foundation, and the Glenn Award for Research on the Biological Mechanism of Aging supported the research. Some experiments were conducted in the Brown University molecular pathology and genomics cores.

Not just a longer life, but a healthier, stronger body “Do you think she might be a Myc hypomorph?” Drawing: Emma Sedivy

Source: Brown University

Smart device delivers results for kids with asthma

Smart device

A new smart asthma inhaler with an audio-visual function has dramatically improved child and adolescent use of preventative asthma medication.

The users also experienced significant improvements to their symptoms, well-being and quality of life and needed their reliever medication less frequently.

The University of Auckland study, funded by Cure Kids and the Health Research Council, showed a significant improvement in night time awakening, coughing and wheezing.

Clinical pharmacist, Amy Chan, a doctoral student with the University of Auckland, is the lead author on the paper.  

“We know one of the key reasons for children not taking their medication is parent and patient forgetfulness.  The Smartinhaler reminder system is now clinically proven to be a real solution to the problem,” she says.

“What we’ve been able to establish for the first time with this study is that the ringtone Smartinhaler significantly improves adherence to preventative medication, which results in improved quality of life for children with asthma. It’s hugely exciting,” says Ms Chan.

Children in the study were also given a Smartinhaler tracker for their rescue or ‘blue’ inhaler to measure the amount of rescue medication they used. The device was able to objectively count date and time of rescue medication use. This provided a good indication of asthma being out of control.

When symptoms worsened participants used their rescue reliever inhaler (blue inhaler), which is also known as a rescue medication because it provides immediate relief.  Recent studies have shown that overuse of the blue inhaler is a predictor of worsening asthma and general morbidity.

The study found that use of the rescue medication was significantly reduced in the group using the Nexus6 Smartinhaler reminder device.

Cure Kids Chair of Child Health Research and Ms Chan's supervisor on the study, Professor Ed Mitchell, says he is “absolutely staggered by the size of the effect. To see the improvement in the lives of these children is astounding.”

The participants also reported taking part in more sports and family activities. Parents reported feeling less frightened by their child’s asthma.

New Zealand has the second highest rates of asthma in the world and one in four Kiwi children experiences asthma symptoms. Despite this, regular adherence to asthma medication is poor.

New Zealand digital health company Nexus6 Ltd created the new Smartinhaler device called the SmartTrack, which was used in the study. The device has 14 different ringtones, which are cycled so users don’t get reminder fatigue. The SmartTrack reminder is only triggered when a dose is missed.

The results were published this month in The Lancet Respiratory Medical Journal.  To the researchers’ knowledge, this is the largest study in the world to investigate the effects of an inhaler device with audio-visual reminder function on asthma adherence and outcomes in children and adolescents.

It is also the first to show significant benefits in asthma outcomes and quality of life. The results are expected to gain international interest.

The controlled trial recruited 220 children between the ages of six and 15 who presented to emergency departments with asthma symptoms.

The study was randomised with half of the participants receiving a SmartTrack device for use with their preventative or ‘orange’ inhaler that had the audiovisual elements turned on, and the other half receiving the same device with the audiovisual elements turned off.

Participants were followed up every two months for six months and general asthma control was checked.

Key findings from the study were:

Medication adherence rate for the patient group given the audiovisual enabled SmartTrack inhaler were 84 percent compared to 30 percent for the control group. This equals a 180% increase in medication adherence.
The use of emergency medication or the ‘blue’ inhaler was significantly reduced. The median percentage days on which a reliever was used in the intervention group was 9.5 percent compared to 17.4 percent in the control group. This equals a 45percentreduction in rescue medication use.
Symptoms, well-being and quality of life for the children was significantly improved.

Source: Auckland University

New Zealand leads research on natural quit smoking remedy

New Zealand researchers have found that a low cost, plant-based product marketed for smoking cessation in parts of Europe for the last 40 years, is better than nicotine replacement therapy at helping smokers quit. 

Trial results show that the compound cytisine is more effective than nicotine replacement therapy (NRT) at helping smokers quit.

The trial is the first of its kind in the world and was carried out by the National Institute for Health Innovation at the University of Auckland.  The study results were published recently in the top-rated international medical journal, the New England Medical Journal.

Cytisine is a natural, plant-based compound that has been used in smoking cessation for more than 40 years in Eastern Europe and is commercially produced in Bulgaria and Poland.  The trial followed 1310 adult daily smokers who called the national Quitline in New Zealand.

 Smokers were randomly assigned to receive either cytisine for 25 days or eight weeks of NRT. Participants in both groups also received telephone-based Quitline behavioural support.

Results indicated that after using cytisine for 25 days, a smoker was more likely to have quit smoking at six months, compared to using NRT. Compared to NRT, cytisine users experienced a slight increase in side effects; the most common of which were nausea, vomiting and sleep disturbances.

 “Placebo-controlled trials showed that cytisine almost doubles the chances of still being smoke-free at six months,” says study senior author, Dr Natalie Walker, who is the Heart Foundation Douglas Senior Research Fellow (Prevention) at the University of Auckland’s National Institute for Health Innovation. “We wanted to see how effective cytisine was compared to NRT at helping smokers quit.”

 In New Zealand and many other Western countries NRT is the most common medication used to support people to quit smoking.

 Cytisine is an alkaloid which naturally occurs in the Golden Rain (Laburnum anagyroides) and other members of the Fabaceae plant family.

“To the brain cytisine looks a little like nicotine and so it works to alleviate any urges to smoke and reduces the severity of nicotine withdrawal symptoms.  Plus, if you do smoke whilst using cytisine it will be less satisfying - making quitting easier”, says Dr Walker.

Cytisine is a similar type of drug to varenicline (the most effective smoking cessation treatment available, marketed by Pfizer), but is substantially cheaper (cytisine: US$20-$30 for 25-days, NRT: US$112-$685 for 8-10 weeks, varenicline: US$474-501 for 12 weeks).

“There is a big opportunity for low and middle income countries to access a low priced quit remedy,” says Dr Walker. “It’s great for countries that cannot afford more expensive smoking cessation medicines.”

Cytisine is licensed for use as an ‘over the counter’ medication, on prescription or via the internet in a number of Central and Eastern European countries, but it is not yet available in New Zealand.  

“Internationally, very few researchers are undertaking research on the use of cytisine for smoking cessation,” says Associate Professor Chris Bullen, Director of the National Institute for Health Innovation.

“Researchers at the University of Auckland are leading the way.  For example, other researchers in the Department of Pharmacology and at the School of Pharmacy are looking at how cytisine is absorbed and metabolised by the body,” he says.

The trial is funded by the Health Research Council of New Zealand and is one of a number of studies the Institute have undertaken to find innovative options for smokers to stop smoking to achieve smoke-free New Zealand by 2025.  The last trial they completed was one involving e-cigarettes

The study, ‘Randomized comparison of cytisine versus nicotine for smoking cessation’, by Dr Natalie Walker (National Institute for Health Innovation, University of Auckland), Dr Colin Howe (NIHI), Dr Marewa Glover (Centre for Tobacco Control Research, UoA), Dr Hayden McRobbie (Queen Mary University London), Associate Professor Jo Barnes (School of Pharmacy, UoA), Dr Vili Nosa (UoA), Ms Varsha Parag (NIHI), Mr Bruce Bassett (Quit Group), Associate Professor Chris Bullen (Director, NIHI).

Source: Auckland University