Thursday, March 31, 2016

Researchers reveal Zika virus structure, a critical advance in the development of treatments

A team led by Purdue University researchers is the first to determine the structure of the Zika virus, which reveals insights critical to the development of effective antiviral treatments and vaccines.

The team also identified regions within the Zika virus structure where it differs from other flaviviruses, the family of viruses to which Zika belongs that includes dengue, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitic viruses.

A paper detailing the findings was published Thursday (March 31) in the journal Science and is available online.

Any regions within the virus structure unique to Zika have the potential to explain differences in how a virus is transmitted and how it manifests as a disease, said Richard Kuhn, director of the Purdue Institute for Inflammation, Immunology and Infectious Diseases (PI4D) who led the research team with Michael Rossmann, Purdue’s Hanley Distinguished Professor of Biological Sciences.

“The structure of the virus provides a map that shows potential regions of the virus that could be targeted by a therapeutic treatment, used to create an effective vaccine or to improve our ability to diagnose and distinguish Zika infection from that of other related viruses,” said Kuhn, who also is head of Purdue’s Department of Biological Sciences. “Determining the structure greatly advances our understanding of Zika - a virus about which little is known. It illuminates the most promising areas for further testing and research to combat infection.”

The Zika virus, a mosquito-borne disease, has recently been associated with a birth defect called microcephaly that causes brain damage and an abnormally small head in babies born to mothers infected during pregnancy. It also has been associated with the autoimmune disease Guillain-Barré syndrome, which can lead to temporary paralysis. In the majority of infected individuals symptoms are mild and include fever, skin rashes and flulike illness, according to the World Health Organization.

Zika virus transmission has been reported in 33 countries. Of the countries where Zika virus is circulating 12 have reported an increased incidence of Guillain-Barré syndrome, and Brazil and French Polynesia have reported an increase in microcephaly, according to WHO. In February WHO declared the Zika virus to be “a public health emergency of international concern.”

“This breakthrough illustrates not only the importance of basic research to the betterment of human health, but also its nimbleness in quickly addressing a pressing global concern,” said Purdue President Mitch Daniels. “This talented team of researchers solved a very difficult puzzle in a remarkably short period of time, and have provided those working on developing vaccines and treatments to stop this virus a map to guide their way.”

Rossmann and Kuhn collaborated with Theodore Pierson, chief of the viral pathogenesis section of the Laboratory of Viral Diseases at the National Institutes of Health National Institute of Allergy and Infectious Diseases. Additional research team members include Purdue graduate student Devika Sirohi and postdoctoral research associates Zhenguo Chen, Lei Sun and Thomas Klose.

The team’s paper marks the first published success of the new Purdue Institute for Inflammation, Immunology and Infectious Diseases in Purdue’s Discovery Park.

The university’s recently announced $250 million investment in the life sciences funded the purchase of advanced equipment that allowed the team to do in a couple of months what otherwise would have taken years, Rossmann said.

 “We were able to determine through cryo-electron microscopy the virus structure at a resolution that previously would only have been possible through X-ray crystallography,” he said. “Since the 1950s X-ray crystallography has been the standard method for determining the structure of viruses, but it requires a relatively large amount of virus, which isn’t always available; it can be very difficult to do, especially for viruses like Zika that have a lipid membrane and don’t organize accurately in a crystal; and it takes a long time. Now, we can do it through electron microscopy and view the virus in a more native state. This was unthinkable only a few years ago.”

The team studied a strain of Zika virus isolated from a patient infected during the French Polynesia epidemic and determined the structure to 3.8Å. At this near-atomic resolution key features of the virus structure can be seen and groups of atoms that form specific chemical entities, such as those that represent one of 20 naturally occurring amino acids, can be recognized, Rossmann said.

The team found the structure to be very similar to that of other flaviviruses with an RNA genome surrounded by a lipid, or fatty, membrane inside an icosahedral protein shell.

The strong similarity with other flaviviruses was not surprising and is perhaps reassuring in terms of vaccine development already underway, but the subtle structural differences are possibly key, Sirohi said.

“Most viruses don’t invade the nervous system or the developing fetus due to blood-brain and placental barriers, but the association with improper brain development in fetuses suggest Zika does,” Sirohi said. “It is not clear how Zika gains access to these cells and infects them, but these areas of structural difference may be involved. These unique areas may be crucial and warrant further investigation.”

The team found that all of the known flavivirus structures differ in the amino acids that surround a glycosylation site in the virus shell. The shell is made up of 180 copies of two different proteins. These, like all proteins, are long chains of amino acids folded into particular structures to create a protein molecule, Rossmann said.

The glycosylation site where Zika virus differs from other flaviviruses protrudes from the surface of the virus. A carbohydrate molecule consisting of various sugars is attached to the viral protein surface at this site.

In many other viruses it has been shown that as the virus projects a glycosylation site outward, an attachment receptor molecule on the surface of a human cell recognizes the sugars and binds to them, Kuhn said.

The virus is like a menacing stranger luring an unsuspecting victim with the offer of sweet candy. The human cell gladly reaches out for the treat and then is caught by the virus, which, once attached, may initiate infection of that cell.

The glycosylation site and surrounding residues on Zika virus may also be involved in attachment to human cells, and the differences in the amino acids between different flaviviruses could signify differences in the kinds of molecules to which the virus can attach and the different human cells it can infect, Rossmann said.

“If this site functions as it does in dengue and is involved in attachment to human cells, it could be a good spot to target an antiviral compound,” Rossmann said. “If this is the case, perhaps an inhibitor could be designed to block this function and keep the virus from attaching to and infecting human cells.”

The team plans to pursue further testing to evaluate the different regions as targets for treatment and to develop potential therapeutic molecules, Kuhn said.

Kuhn and Rossmann have studied flaviviruses, the family of viruses to which Zika belongs, for more than 14 years. They were the first to map the structure of any flavivirus when they determined the dengue virus structure in 2002. In 2003 they were first to determine the structure of West Nile virus and now they are the first to do so with the Zika virus.

Trader Joe’s to Close All Stores by 2017, Plans to Discontinue Products

Wednesday, March 09, 2016

Thirdhand smoke is real

Thirdhand smoke (THS) results when exhaled smoke gets on surfaces -- clothing, hair, homes and cars. THS has been shown, in mice, to damage the liver and lungs, complicate wound-healing and cause hyperactivity. Add to this list now type 2 diabetes, the most common form of the disease.

Research published in PLOS ONE shows, in mice, that THS exposure causes insulin resistance, a precursor to type 2 diabetes.

If confirmed in humans, our study could greatly impact how people view exposure to environmental tobacco toxins. Children and the elderly are especially vulnerable to THS and its impact on health. Because infants frequently crawl on carpets and touch objects exposed to exhaled smoke, they are at high risk for THS exposure. The elderly are at high risk simply because older organs are more susceptible to disease.

THS consists of tobacco smoke toxins that linger on surfaces and in dust after tobacco has been smoked. This includes toxins that become increasingly toxic with age and are re-emitted into the air or react with other chemicals in the environment to produce new pollutants. Some of these pollutants are carcinogenic.

To rid a house of THS, you have to strip the home of everything -- furniture, appliances, paint, clothes, ducts, ventilation -- that could have THS. It would be more effective to simply move. There are cleaners we can use, but that would mean exposure to other strong chemicals.

Little was known about the specific health implications of human exposure to THS until this study.

Spouse Can Harm, Help Health

From the March 2016 issue of American Journal of Epidemiology

Low physical activity levels are a public health concern. Few studies have assessed the concordance of physical activity change among spouses. We studied this concordance during a 6-year period (baseline: 1987–1989; follow-up: 1993–1995) in 3,261 spousal pairs from the US-based Atherosclerosis Risk in Communities (ARIC) Study. Linear regression was used to examine the association between change in individuals' sport/exercise and leisure physical activity indices (ranging from 1 (low) to 5 (high)) and change in his or her spouse's indices. The association between individual and spousal changes in meeting physical activity recommendations was assessed with logistic regression. Individual changes in the sport/exercise and leisure indices were positively associated with spousal changes. For every standard deviation increase in their wives' sport/exercise index, men's exercise index increased by 0.09 (95% confidence interval: 0.05, 0.12) standard deviation; for every standard deviation increase in their wives’ leisure index, men's leisure index increased by 0.08 standard deviation. Results were similar for women. Individuals had higher odds of meeting physical activity recommendations if their spouse met recommendations at both visits or just follow-up. In conclusion, changes in an individual's physical activity are positively associated with changes in his or her spouse's physical activity. Physical activity promotion efforts should consider targeting couples.

Married couples might be an appropriate target for obesity prevention interventions. In the present study, we aimed to evaluate whether an individual's risk of obesity is associated with spousal risk of obesity and whether an individual's change in body mass index (BMI; weight in kilograms divided by height in meters squared) is associated with spousal BMI change. We analyzed data from 3,889 spouse pairs in the Atherosclerosis Risk in Communities Study cohort who were sampled at ages 45–65 years from 1986 to 1989 and followed for up to 25 years. We estimated hazard ratios for incident obesity by whether spouses remained nonobese, became obese, remained obese, or became nonobese. We estimated the association of participants' BMI changes with concurrent spousal BMI changes using linear mixed models. Analyses were stratified by sex. At baseline, 22.6% of men and 24.7% of women were obese. Nonobese participants whose spouses became obese were more likely to become obese themselves (for men, hazard ratio = 1.78, 95% confidence interval: 1.30, 2.43; for women, hazard ratio = 1.89, 95% confidence interval: 1.39, 2.57). With each 1-unit increase in spousal BMI change, women's BMI change increased by 0.15 (95% confidence interval: 0.13, 0.18) and men's BMI change increased by 0.10 (95% confidence interval: 0.09, 0.12). Having a spouse become obese nearly doubles one's risk of becoming obese. Future research should consider exploring the efficacy of obesity prevention interventions in couples.

Thursday, March 03, 2016

Metformin's Issues

Metformin-related vitamin B12 deficiency might contribute to clinically significant peripheral neuropathy in diabetes patients, new research suggests from the European Association for the Study of Diabetes Meeting.

"The consequences of vitamin B12 deficiency, like neuropathy or mental changes, may be profound. Even more, they may be difficult to diagnose, because they may be ascribed to old age or diabetes itself and may be or become irreversible. On the other hand, vitamin B12 deficiency is relatively easy to diagnose, and treatment is easy, cheap, and effective," the lead researcher commented.

Corroborating with previous research raises concern that the drug may be contributing to peripheral neuropathy separate from the effect of the diabetes itself.

Neurologists Use Mindfulness Protocols

From Practical Neurology 12/2015

Mindfulness training—mindfulness-based cognitive therapy and mindfulness-based stress reduction—is an evidence-based group program for reducing symptoms of anxiety and depression and building long-term capacity for emotion regulation, stress coping and enhancing quality of life.

It combines training of attention to moment-by-moment experience with practising a self-caring attitude and insight into self-defeating patterns of thought and behaviour.

It has been applied effectively in diverse clinical groups, including neurological patients and a variety of physical and mental health conditions.

It may be particularly relevant for people with long-term or deteriorating conditions.

It is best learned in a formal 8-week course. It is worth suggesting self-help and online formats to those who are sufficiently motivated.

Anxiety Takes Its Toll on the Heart

Anxiety has emerged as perhaps the most important risk factor for cardiovascular disease, according to a new study in Current Opinion in Psychiatry. Anxiety increases the risk of major cardiac events in coronary heart disease. There is also a need for elucidating the influence of anxiety in cardiomyopathy and hypertension.

Moreover, the researchers suggest that anxiety is an antecedent risk factor, so it influences the prognosis in patients with cardiovascular disease, and needs to be recognized and managed at every step. Anxiety drives other risk factors, such as depression, smoking, sedentary lifestyle, substance use, and overweight.