Different types of physical activity offer varying protection against heart disease

While it is well known that physical activity is important for heart health, neither research nor recommendations consistently differentiate between the benefits of different types of physical activity. New research, presented at the ACC Latin America Conference 2018 in Lima, Peru, found that while all physical activity is beneficial, static activities -- such as strength training -- were more strongly associated with reducing heart disease risks than dynamic activities like walking and cycling.

"Both strength training and aerobic activity appeared to be heart healthy, even in small amounts, at the population level," said Maia P. Smith, PhD, MS, statistical epidemiologist and assistant professor in the Department of Public Health and Preventive Medicine at St. George's University in St. George's, Grenada. "Clinicians should counsel patients to exercise regardless -- both activity types were beneficial. However, static activity appeared more beneficial than dynamic, and patients who did both types of physical activity fared better than patients who simply increased the level of one type of activity."
Researchers analyzed cardiovascular risk factors, such as high blood pressure, overweight, diabetes and high cholesterol, as a function of self-reported static and/or dynamic activity (strength training or walking/biking) in 4,086 American adults using data from the 2005-2006 National Health and Nutrition Examination Survey. The researchers then adjusted for age, ethnicity, gender and smoking and stratified by age: 21 to 44 years old or over 45 years old.
In total, 36 percent of younger and 25 percent of older adults engaged in static activity, and 28 percent of younger and 21 percent of older adults engaged in dynamic activity. Researchers found engaging in either type of activity was associated with 30 to 70 percent lower rates of cardiovascular disease risk factors, but associations were strongest for static activity and in youth.
"One interesting takeaway was that both static and dynamic activity were almost as popular in older people as younger," Smith said. "I believe this gives clinicians the opportunity to counsel their older patients that they will fit into the gym or the road race just fine. The important thing is to make sure they are engaging in physical activity."
Smith said future research and data collection should use definitions of physical activity that separate static from dynamic activity to further investigate independent effects.

Story Source:
Materials provided by American College of Cardiology.

Courtesy: ScienceDaily

A new approach to detecting cancer earlier from blood tests

Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined "liquid biopsy," epigenetic alterations and machine learning to develop a blood test to detect and classify cancer at its earliest stages.

The findings, published online today in Nature, describe not only a way to detect cancer, but hold promise of being able to find it earlier when it is more easily treated and long before symptoms ever appear, says Dr. De Carvalho, Senior Scientist at the cancer centre, University Health Network.
"We are very excited at this stage," says Dr. De Carvalho. "A major problem in cancer is how to detect it early. It has been a 'needle in the haystack' problem of how to find that one-in-a-billion cancer-specific mutation in the blood, especially at earlier stages, where the amount of tumour DNA in the blood is minimal."
By profiling epigenetic alterations instead of mutations, the team was able to identify thousands of modifications unique to each cancer type. Then, using a big data approach, they applied machine learning to create classifiers able to identify the presence of cancer-derived DNA within blood samples and to determine what cancer type. This basically turns the 'one needle in the haystack' problem into a more solvable 'thousands of needles in the haystack', where the computer just needs to find a few needles to define which haystack has needles.
The scientists tracked the cancer origin and type by comparing 300 patient tumour samples from seven disease sites (lung, pancreatic, colorectal, breast, leukemia, bladder and kidney) and samples from healthy donors with the analysis of cell-free DNA circulating in the blood plasma. In every sample, the "floating" plasma DNA matched the tumour DNA. The team has since expanded the research and has now profiled and successfully matched more than 700 tumour and blood samples from more cancer types.
Beyond the lab, next steps to further validate this approach include analysing data from large population health research studies already under way in several countries, where blood samples were collected months to years before cancer diagnosis. Then the approach will need to be ultimately validated in prospective studies for cancer screening.
Dr. De Carvalho is a trained immunologist (University of Sao Paulo, Brazil) with postdoctoral training in cancer epigenomics (University of Southern California, USA) whose research focuses on cancer epigenetics. He holds the Canada Research Chair in Cancer Epigenetics and Epigenetic Therapy and is an Associate Professor in Cancer Epigenetics, Department of Medical Biophysics, University of Toronto.
The research was supported by University of Toronto's McLaughlin Centre, Canadian Institutes of Health Research, Canadian Cancer Society, Ontario Institute for Cancer Research through the Province of Ontario, and The Princess Margaret Cancer Foundation.
 

Journal Reference:

1. Shu Yi Shen, Rajat Singhania, Gordon Fehringer, Ankur Chakravarthy, Michael H. A. Roehrl, Dianne Chadwick, Philip C. Zuzarte, Ayelet Borgida, Ting Ting Wang, Tiantian Li, Olena Kis, Zhen Zhao, Anna Spreafico, Tiago da Silva Medina, Yadon Wang, David Roulois, Ilias Ettayebi, Zhuo Chen, Signy Chow, Tracy Murphy, Andrea Arruda, Grainne M. O’Kane, Jessica Liu, Mark Mansour, John D. McPherson, Catherine O’Brien, Natasha Leighl, Philippe L. Bedard, Neil Fleshner, Geoffrey Liu, Mark D. Minden, Steven Gallinger, Anna Goldenberg, Trevor J. Pugh, Michael M. Hoffman, Scott V. Bratman, Rayjean J. Hung, Daniel D. De Carvalho. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature, 2018; DOI: 10.1038/s41586-018-0703-0 

Courtesy: ScienceDaily
 

Protection against Malaria: A matter of balance

A balanced production of pro and anti-inflammatory cytokines at two years of age protects against clinical malaria in early childhood, according to a study led by the Barcelona Institute for Global Health (ISGlobal), an institution supported by "la Caixa" Foundation. The results also indicated that early exposure to the parasite does not affect the risk of developing the disease, although it could affect the parasite-specific immune response later in life.

Malaria particularly affects children under five years of age, who need to develop effective immunity against the most severe forms of the disease. Certain parasite-specific antibodies are known to protect, but little is known about the protective role of mediators (cytokines) produced by cells of the immune system. Furthermore, it is not clear whether the timing of first parasite exposure during infancy affects the secretion of such cytokines.
In this study, Carlota Dobaño and her team evaluated whether the cytokines produced in the first two years after birth affect the risk of subsequent malaria. They also analysed whether the timing of parasite exposure alters the cytokine response. The study included over 300 newborns from Magrara, a village in Southern Mozambique, who received -- or not- preventive malaria treatment during their first year of life. Cytokine production by blood cells was measured at different time-points during the first two years, and the participants were followed up for clinical malaria until four years of age.
The results show that a pro-inflammatory signature (IL-1, IL-6 and TNF cytokines) followed by an anti-inflammatory (IL-10 cytokine) signature between the first and second year of life is associated with a lower risk of clinical malaria between ages 3 and 4. "This makes sense, since IL-10 suppresses excessive inflammation," explains Dobaño.
In contrast, timing of parasite exposure did not have a clinical effect: children who received preventive treatment -- and were therefore exposed later to the parasite -- had an altered cytokine profile, but this did not reduce the risk of developing malaria in the following two years. "Preventive malaria treatment during the first year after birth does not decrease the risk of malaria in early childhood, but it could be relevant later in life by influencing the development of parasite-specific immunity," adds the ISGlobal researcher.
 

Journal Reference:

1. Carlota Dobaño, Augusto J Nhabomba, Maria N Manaca, Tamara Berthoud, Ruth Aguilar, Llorenç Quintó, Arnoldo Barbosa, Mauricio H Rodríguez, Alfons Jiménez, Penny L Groves, Rebeca Santano, Quique Bassat, John J Aponte, Caterina Guinovart, Denise L Doolan, Pedro L Alonso. A balanced pro-inflammatory and regulatory cytokine signature in young African children is associated with lower risk of clinical malaria. Clinical Infectious Diseases, 2018; DOI: 10.1093/cid/ciy934 

Courtesy: ScienceDaily
 

To ward off fatty liver, breast is best for mom

Researchers at University of California San Diego School of Medicine and Kaiser Permanente have discovered that mothers who breastfed a child or children for six months or more are at lower risk for developing non-alcoholic fatty liver disease (NAFLD) years later during mid-life. With no other current prevention options aside from a healthy lifestyle, they say the finding may represent an early modifiable risk factor for a serious and chronic disease.

The findings are published in the November 1 issue of the Journal of Hepatology.
"Breastfeeding and its benefits to the child have been widely studied for years," said Veeral Ajmera, MD, hepatologist at UC San Diego Health and an assistant professor of medicine at UC San School of Medicine. "However, this new analysis contributes to the growing body of evidence showing that breastfeeding a child also offers significant health benefits to the mother -- namely, protecting her from developing non-alcoholic fatty liver disease in middle age."
Ajmera and colleagues used data collected through the Coronary Artery Risk Development in Young Adults (CARDIA) study, a multicenter prospective cohort study of 844 black and white women who were monitored every two to five years for up to 30 years. The women were assessed for biochemical and other risk factors at enrollment in 1985 to 1986. Those who subsequently gave birth reported the duration of breastfeeding for each birth over the following 25 years. At the end of the study, participants underwent a computed tomography (CT) scan of their abdomens, which allowed researchers to look at levels of liver fat, a sign of NALFD.
"The CARDIA study's unique strength is the evaluation of cardiovascular and metabolic risk factors in young women before pregnancy and across the childbearing years," said senior author Erica P. Gunderson, PhD, MPH, a senior research scientist with the Kaiser Permanente Northern California Division of Research and investigator at the Oakland, Calif., CARDIA field site. "This design accounts for pre-pregnancy risk factors and identifies more closely the specific relation of lactation to a woman's future disease risk."
According to study findings, women in the cohort who breastfed one or more children for longer than six months had a lower risk of NAFLD compared to those who did not breastfeed or breastfed for under one month. Typical of NAFLD, women diagnosed with the disease 25 years later had a higher body mass index, larger waist circumference, higher triglycerides and lower HDL cholesterol when compared to those without NAFLD.
NAFLD remains the most common cause of chronic liver disease in the United States. It is usually asymptomatic until advanced stages of liver disease and includes a spectrum of disease severity, with nonalcoholic steatohepatitis (NASH) being the most aggressive type. Multiple genetic and environmental factors contribute to NAFLD, and certain health conditions, such as obesity and type 2 diabetes, can be predisposing factors. It is estimated that tens of millions of people globally are living with NAFLD and NASH. Weight loss and a healthier diet are the current standards of care.
Because these diseases are linked with obesity, diabetes, insulin resistance and lifestyle behaviors, Ajmera and team adjusted for these pre-pregnancy metabolic risk factors, physical activity and dietary intake. The analysis helped demonstrate that any beneficial impact of lactation duration goes beyond confounding factors of pre-pregnancy risk and lifestyle behaviors.
"Non-alcoholic fatty liver disease and all metabolic diseases have a unique relationship with socioeconomic factors," said Ajmera. "The inclusion of additional information regarding diet and exercise only further strengthen our claim that breastfeeding is beneficial in the prevention of non-alcoholic fatty liver disease."
Ajmera said more studies are needed to look at the underlying mechanisms of how lactation affects NAFLD and whether it can reduce disease severity.
Co-authors include: Norah A. Terrault and Monika Sarkar, UC San Francisco; Lisa B. VanWagner, Northwestern University; Cora E. Lewis, University of Alabama Birmingham; and John J. Carr, Vanderbilt University.
 

Reference:

Veeral H. Ajmera, Norah A. Terrault, Lisa B. VanWagner, Monika Sarkar, Cora E. Lewis, John J. Carr, Erica P. Gunderson. Longer lactation duration is associated with decreased prevalence of non-alcoholic fatty liver disease in women. Journal of Hepatology, 2018; DOI: 10.1016/j.jhep.2018.09.013 

 

Courtesy: ScienceDaily

Pessimism around youth suicide prevention approaches is unfounded

A comprehensive Australian study examining the global impact of suicide prevention approaches in young people has found that youth-specific interventions conducted in clinical, educational and community settings can be effective in reducing suicide-related behaviour in young people at risk.

The review, by researchers at Orygen, the National Centre of Excellence in Youth Mental Health, has been published this week in the UK journal E Clinical Medicine.

The comprehensive review examined 99 individual studies of which 52 were conducted in clinical settings, 31 in educational or workplace settings, and 15 in community settings, and found interventions delivered in these settings appeared to reduce self-harm and suicidal thinking in young people.

Large school-based studies showed that the interventions with the most promise for suicide prevention were integrated approaches, in particular those that combined educational workshops about suicide prevention with case detection designed to identify young people at risk.

In community settings it was also large-scale studies that combined a number of components that showed the most promise. Again, these typically included universal educational programs, training those who come into contact with at risk young people, screening for risk, and linking people to services, where appropriate.

The study's lead researcher, Dr Jo Robinson, said the study findings challenged the pessimism that often pervades discussions around suicide prevention. "At a time when we're seeing suicide rates around the world growing, this study shows us that we should feel hopeful that interventions specifically designed to reduce suicide risk in young people do work and can impact on suicide ideation and self-harm," Dr Robinson said.

"In Australia, we've seen a lot of investment in suicide prevention, but It's very important that this investment is directed in a strategic way and is being invested in evidence-based interventions.

"That's why this study is important, it will guide not just clinical services and interventions and research, but policy makers as well to ensure that we're putting funds into evidence-based suicide prevention interventions that work."

Despite the encouraging findings of the study, Dr Robinson said the research had identified some clear gaps in suicide prevention approaches.

"Many studies simply tested interventions that had previously been designed for adults as opposed to young people specifically, there was also an absence of studies that included indigenous, same sex attracted and/or gender diverse young people and those who live in low to middle income countries," Dr Robinson said.

"These findings suggest that important opportunities for youth suicide prevention are currently being missed and need to be addressed by researchers, research funders, and by policy makers, if we are to successfully address the rising rates of suicide among young people worldwide."

The research was supported by the Future Global Generations Fund, William Buckland Foundation, National Health and Medical Research Council, Auckland Medical Research Foundation, a Victorian Health and Medical Research Fellowship and the American Foundation for Suicide Prevention.

Reference:

Orygen, the National Centre of Excellence in Youth Mental Health. "Pessimism around youth suicide prevention approaches is unfounded." ScienceDaily. ScienceDaily, 2 November 2018. .

Courtesy: ScienceDaily

Grandparents: Raising their children's children, they get the job done

Millions of children are being raised solely by their grandparents, with numbers continuing to climb as the opioid crisis and other factors disrupt families. New research being presented at the American Academy of Pediatrics (AAP) 2018 National Conference & Exhibition shows that caregivers who step up to raise their grandchildren are overcoming unique challenges to manage just as well as biological and adoptive parent caregivers.

The study abstract, "Grandparents Raising Grandchildren: Are They Up to the Job?" will be presented on Monday, Nov. 5, at the Orange County Convention Center in Orlando, Fla. The study is the first to examine a nationally representative sample of children and directly compare households where children are being raised by their grandparents with those being raised by their parents.

"A large and increasing number of mothers and fathers aren't able to meet the responsibilities of parenthood, prompting their own parents to take on the primary caregiver role for their grandchildren," said senior author Andrew Adesman, MD, FAAP, Chief of Developmental and Behavioral Pediatrics for Cohen Children's Medical Center of New York. "Although these children are more likely to have endured one or more adverse childhood experiences and the grandparents themselves often face extra health and socioeconomic hurdles, our findings suggest they appear to be coping well."

The researchers analyzed and compared 2016 National Survey of Children's Health data from 44,807 parent-led households and 1,250 grandparent households. They determined that caregivers raising their grandchildren were more likely to have a greater number of physical and mental health problems, have household incomes at or below the federal poverty line, have lower levels of education, and be single.

In addition, the grandchildren they were raising were more likely to become angry/anxious with transitions, lose their temper and have other behavioral issues.

"This was not surprising, since we know that children in non-parental care are likely to have experienced more adverse childhood experiences and have an increased risk of behavioral problems as a result," said abstract co-author Sarah Keim, PhD, Principal Investigator at Nationwide Children's Hospital.

However, Keim said, grandparents and parents showed no difference when asked if the child "does things that really bother" them, is "harder to care for" than peers, or if they "felt angry with this child." In fact, grandparents and parents did not differ on most measures of parent coping, parenting stress, or caregiver-child interactions when stratified by child health and child age.

The study also found that a substantial proportion of both grandparent caregivers (31 percent) and parent caregivers (24 percent), reported that they did not have anyone "to turn to for day-to-day emotional support with parenting."

"Given that children being raised by their grandparents may pose greater behavioral challenges, and that nearly a third of the parenting grandparents reported they had no one to turn to for day-to-day emotional support with parenting, pediatricians and other health professionals caring for 'grandfamilies' must be mindful of these issues and be ready to refer families to counseling when needed, as well as refer them to supports groups locally and online," Dr. Adesman said.

 Reference: 

American Academy of Pediatrics. "Grandparents: Raising their children's children, they get the job done." ScienceDaily. ScienceDaily, 2 November 2018. .

Courtesy: ScienceDaily

Scientists grow human esophagus in lab

This confocal microscopic image shows a two-month-old human esophageal organoid bioengineered by scientists from pluripotent stem cells. About 700 micrometers (0.027 inches) in size, the organoid is stained to visualize key structural proteins expressed in mature esophagus, such as involucrin (green) and cornulin (blue). Researchers report in the journal Cell Stem Cell the organoids enhance the study of esophageal disorders, personalized medical and the development of regenerative tissue therapies for people.

Credit: Cincinnati Children's

Scientists working to bioengineer the entire human gastrointestinal system in a laboratory now report using pluripotent stem cells to grow human esophageal organoids.

Published in the journal Cell Stem Cell the study is the latest advancement from researchers at the Cincinnati Children's Center for Stem Cell and Organoid Medicine (CuSTOM). The center is developing new ways to study birth defects and diseases that affect millions of people with gastrointestinal disorders, such as gastric reflux, cancer, etc. The work is leading to new personalized diagnostic methods and focused in part on developing regenerative tissue therapies to treat or cure GI disorders.

The newly published research is the first time scientists have been able to grow human esophageal tissue entirely from pluripotent stem cells (PSCs), which can form any tissue type in the body, according to the authors. Cincinnati Children's scientists and their multi-institutional collaborators already have used PSCs to bioengineer human intestine, stomach, colon and liver.

"Disorders of the esophagus and trachea are prevalent enough in people that organoid models of human esophagus could be greatly beneficial," said Jim Wells, PhD, chief scientific officer at CuSTOM and study lead investigator. "In addition to being a new model to study birth defects like esophageal atresia, the organoids can be used to study diseases like eosinophilic esophagitis and Barrett's metaplasia, or to bioengineer genetically matched esophageal tissue for individual patients."

The study involves collaboration from researchers in the divisions of Developmental Biology, Oncology, Allergy and Immunology, and Endocrinology at Cincinnati Children's and the Gladstone Institutes in San Francisco. This includes study first author Stephen Trisno, a graduate student and member of the Wells laboratory.

The Food Channel

The esophagus is a muscular tube that actively passes food from the mouth to the stomach. The organ can be affected by congenital diseases, such as esophageal atresia -- a narrowing or malformation of the esophagus caused by genetic mutations.

Additionally, there are several diseases that can afflict people later in life. Some include esophageal cancer, gastroesophageal reflux disease (GERD), or a rare ailment called achalasia -- a disease affecting the muscles of the lower esophagus that prevents contraction of the organ and the passage of food.

All of the conditions need better treatments, researchers note. This requires a more precise understanding of the genetic and biochemical mechanisms behind their cause -- a need filled by the ability to generate and study robust, functional, genetically matched models of human esophageal tissue that can be grown from a person's own cells.

Tracing Nature's Path

The scientists based their new method for using human PSCs to general esophageal organoids on precisely timed, step-by-step manipulations of genetic and biochemical signals that pattern and form embryonic endoderm and foregut tissues. They focused in part on the gene Sox2 and its associated protein -- which are already known to trigger esophageal conditions when their function is disrupted. -- The scientists used mice, frogs and human tissue cultures to identify other genes and molecular pathways regulated by Sox2 during esophagus formation.

The scientists report that during critical stages of embryonic development, the Sox2 gene blocks the programming and action of genetic pathways that direct cells to become respiratory instead of esophageal. In particular, the Sox2 protein inhibits the signaling of a molecule called Wnt and promotes the formation and survival of esophageal tissues.

In another test to help confirm the importance of Sox2 expression on esophageal formation, researchers studied the complete loss of Sox2 during the development process in mice. The absence of Sox2 resulted in esophageal agenesis -- a condition in which the esophagus terminates in a pouch and does not connect to the stomach.

After successfully generating fully formed human esophageal organoids -- which grew to a length of about 300-800 micrometers in about two months -- the bioengineered tissues were compared biochemically to esophageal tissues from patient biopsies. Those tests showed the bioengineered and biopsies tissues were strikingly similar in composition, according to the authors.

The research team is continuing its studies into the bioengineering process for esophageal organoids and identifying future projects to advance the technology's eventual therapeutic potential, according to Wells. This includes using the organoids to examine the progression of specific diseases and congenital defects affecting the esophagus.

Journal Reference:

1. Stephen L. Trisno, Katherine E.D. Philo, Kyle W. McCracken, Emily M. Catá, Sonya Ruiz-Torres, Scott A. Rankin, Lu Han, Talia Nasr, Praneet Chaturvedi, Marc E. Rothenberg, Mohammad A. Mandegar, Susanne I. Wells, Aaron M. Zorn, James M. Wells. Esophageal Organoids from Human Pluripotent Stem Cells Delineate Sox2 Functions during Esophageal Specification. Cell Stem Cell, 2018; DOI: 10.1016/j.stem.2018.08.008 

Courtesy: ScienceDaily

Proof-of-concept HIV immunotherapy study passes Phase 1 safety trial

Preliminary results from a phase I clinical trial have demonstrated the safety and tolerability of a cell therapy involving the ex vivo expansion of T cells and their subsequent infusion into HIV-infected individuals previously treated with antiretroviral therapy (ART). The study appears September 21st in the journal Molecular Therapy.

"This study is focused on finding a way to re-educate the body's immune system to better fight HIV infection," says co-senior study author David Margolis of the University of North Carolina (UNC) at Chapel Hill. "We found that this approach of re-educating the immune cells and reinfusing them was safe, which was the primary goal of the study. The data from this trial will continue to help us design improved immunotherapies against HIV."

A game changer for patients living with HIV, ART has turned what was once a death sentence into a chronically managed disease. But it is not a cure, and the virus continues to persist within a latent reservoir that remains hidden from the immune system. Approaches using pharmacological HIV-latency-reversal agents to induce latent virus to express viral protein could make this reservoir vulnerable to T cells. However, the existing HIV-specific immune response in ART-treated individuals is insufficient to clear persistent infection, even in the presence of latency-reversal agents that induce HIV expression.

One safe avenue for harnessing T cell responses to fight HIV is adoptive cellular therapy. This procedure involves collecting T cells from a patient, growing them in the laboratory to increase their numbers, and then giving them back to the patient to help the immune system fight disease. Earlier adoptive-T-cell-therapy approaches for HIV had limited efficacy as a result of multiple factors. Since these earlier attempts, the adoptive-T-cell-therapy field has made significant advances, largely in the oncology field, that could help to overcome some of the pitfalls encountered with earlier T-cell-therapy approaches for HIV. T cells generated by these sophisticated methods of expansion have been safe and well tolerated, as well as highly effective.

"Before we can combine this approach with treatments meant to bring HIV out from hiding so the improved immune response can clear it from the body, we need to first establish that this immunotherapy approach is safe on its own," says co-senior study author Catherine Bollard of the Children's National Health System. "We have long-standing experience treating patients with virus-specific T cells targeting latent viruses such as Epstein-Barr virus and cytomegalovirus. Therefore, we were extremely excited to work with the UNC team to adapt this virus-specific T-cell-therapy approach to the HIV setting."

In the small proof-of-concept study, Margolis, Bollard, and their collaborators produced ex vivo expanded HIV-specific T cells (HXTCs); their long-term goal was to use HXTCs as part of a strategy to clear persistent HIV infection. The researchers administered two infusions of HXTCs over a 2 week period to six HIV-infected participants whose viral load had been reduced to an undetectable level by ART.

This treatment was well tolerated and had few adverse events. Moreover, two patients exhibited a detectable increase in T-cell-mediated antiviral activity after the two infusions, although the clinical significance of this mild-to-modest impact is unknown. When evaluating participants in aggregate, the research team found no overall enhancement of the magnitude of the HIV-specific immune response. This could be due to the low dose of the two infusions and the lack of strategies to promote the expansion of the T cells once they are in the body.

There was also no decrease in the size of the latent reservoir, most likely because of the absence of therapies such as latency-reversal agents, which are designed to perturb the reservoir and induce recognizable expression of HIV proteins that trigger immune responses. In the future, a critical question will be whether HXTC therapy in combination with latency-reversal agents can deplete the HIV reservoir to an extent that is measurable by current gold-standard assays of HIV latency. A study of HXTC in combination with the latency-reversal agent vorinostat is currently undergoing evaluation in an ongoing clinical trial.

"This is a promising advancement for the field," says first author Julia Sung of UNC, although she also cautions people against over-interpreting the results. "The study did not cure HIV and should not be interpreted as doing so, but we also are very encouraged by the safety data, so it should not be considered discouraging either. This paves the way for the next step, which is to combine this immunotherapy approach with latency-reversal therapy in order to wake up the HIV out of its latent state, where it is invisible to the immune system, then clear it out with the immunotherapy."

Journal Reference:

1. Julia A. Sung, Shabnum Patel, Matthew L. Clohosey, Lauren Roesch, Tamara Tripic, JoAnn D. Kuruc, Nancie Archin, Patrick J. Hanley, C. Russell Cruz, Nilu Goonetilleke, Joseph J. Eron, Clio M. Rooney, Cynthia L. Gay, Catherine M. Bollard, David M. Margolis. HIV-Specific, Ex Vivo Expanded T Cell Therapy: Feasibility, Safety, and Efficacy in ART-Suppressed HIV-Infected Individuals. Molecular Therapy, 2018; DOI: 10.1016/j.ymthe.2018.08.015 

Courtesy: ScienceDaily

Possible molecular pathway for neurodegeneration in prion diseases

Prion diseases are a group of fatal neurological disorders that includes Creutzfeldt-Jakob disease and bovine spongiform encephalopathy ("mad cow disease"). They are caused by the spread of "prions," which are altered forms of normal cellular proteins. These abnormal molecules then interact with normal proteins to promote misfolding. While we understand that this process of converting normal to abnormal protein is what causes the symptoms of prion disease (including rapidly progressive dementia, seizures and personality changes), the exact mechanism of damage to the neuronal connections in the brain and spinal cord has been poorly understood.

Researchers from Boston University School of Medicine (BUSM) used a method they previously described for culturing nerve cells from the hippocampal region of the brain, and then exposing them to prions, to illustrate the damage to nerve cell connections usually seen in these diseases. They then added a number of different chemical compounds with known inhibitory effects on cellular responses to stressful stimuli, with the objective of identifying which pathways may be involved.

They found that inhibition of p38 MAPK? (an enzyme that typically responds to stress, such as ultraviolet radiation and heat shock) prevented injury to nerve connections and promoted recovery from the initial damage. Hippocampal nerve cells that had a mutation preventing normal function of p38 MAPK? were also protected, seeming to confirm the role the enzyme plays in this disease process.

David. A. Harris, MD, PhD, professor and chair of the Department of Biochemistry at Boston University School of Medicine and corresponding author of the study, sees these findings as a major breakthrough in trying to understand and treat these diseases. "Our results provide new insights into the pathogenesis of prion diseases, they uncover new drug targets for treating these diseases, and they allow us to compare prion diseases to other, more common neurodegenerative disorders like Alzheimer's disease."

These findings appear online in PLOS Pathogens.

Journal Reference:

1. Cheng Fang, Bei Wu, Nhat T. T. Le, Thibaut Imberdis, Robert C. C. Mercer, David A. Harris. Prions activate a p38 MAPK synaptotoxic signaling pathway. PLOS Pathogens, 2018; 14 (9): e1007283 DOI: 10.1371/journal.ppat.1007283 

Courtesy: ScienceDaily

Superbugs jumping frequently between humans and animals

The MRSA staphylococcus is an example of a pathogen, the likes of which are often called superbugs. These are resistant to most antibiotics and can cause serious infections.

"In the case of MRSA, these bacteria have also spread in hospitals almost world-wide," says Jukka Corander, professor at the University of Helsinki, who was a member of the international research team that mapped several millennia of the evolution of the staphylococcus.
In their extensive study, the researchers sequenced whole genomes of the superbugs from a large sample from different animals as well as humans, and were able to study the DNA changes that helped the bacteria to adapt to new host organisms during thousands of years.
First, there were humans
Based on genome analysis, humans were most probably the original hosts to these superbugs, and judging from DNA changes, the ability to colonise domestic animals appeared in an age when the first animals were domesticated to become livestock on farms.
In the study, published recently in Nature Ecology & Evolution, the team discovered that cows are still the source for such strains of staphylococcus that are causing MRSA infections in humans around the world.
"Our observations give emphasis to the importance of detailed epidemiological monitoring, so that strains with the potential to cause epidemics can be discovered as early as possible," Jukka Corander says.
Detailed genomic analyses reveal that, when the bacteria move from one host species to another, it hijacks new genes to help it adapt and stay alive in the long term. In some cases, these genes give the bacteria resistance towards commonly used antibiotics, eventually rendering them so-called superbugs.
The research may promote the development of strategies to minimize the risk of new strains transferring into the human population, and help slow down the occurrence and spreading of resistance to antibiotics.
 

Journal Reference:

1. Emily J. Richardson, Rodrigo Bacigalupe, Ewan M. Harrison, Lucy A. Weinert, Samantha Lycett, Manouk Vrieling, Kirsty Robb, Paul A. Hoskisson, Matthew T. G. Holden, Edward J. Feil, Gavin K. Paterson, Steven Y. C. Tong, Adebayo Shittu, Willem van Wamel, David M. Aanensen, Julian Parkhill, Sharon J. Peacock, Jukka Corander, Mark Holmes, J. Ross Fitzgerald. Gene exchange drives the ecological success of a multi-host bacterial pathogen. Nature Ecology & Evolution, 2018; 2 (9): 1468 DOI: 10.1038/s41559-018-0617-0 

Courtesy: ScienceDaily
 

Building a better brain-in-a-dish, faster and cheaper

This is a false color image of a slice of human brain organoid from a patient with autism spectrum disorder.

Credit: Alysson Muotri, UC San Diego Health

Writing in the current online issue of the journal Stem Cells and Development, researchers at University of California San Diego School of Medicine describe development of a rapid, cost-effective method to create human cortical organoids directly from primary cells.

Experimental studies of developing human brain function are limited. Research involving live embryonic subjects is constrained by ethical concerns and the fragile nature of the brain itself. Animal models only partially mimic or recapitulate human biology and cognitive function. Single cell studies do not capture the complexity of neural networks.
In recent years, the development of in vitro human organoids -- three-dimensional, miniaturized, simplified versions of an organ produced from reprogrammed stem cells -- have allowed scientists to study biological functions, diseases and treatments more realistically and in greater detail.
"And that includes the brain," said Alysson R. Muotri, PhD, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. "Cerebral organoids can form a variety of brain regions. They exhibit neurons that are functional and capable of electrical excitation. They resemble human cortical development at the gene expression levels."
Muotri is among the leaders in the field, having used the "brain-in-a-dish" approach to provide the first direct experimental proof that the Zika virus can cause severe birth defects, to repurpose existing HIV drugs on a rare, inherited neurological disorder and to create Neanderthalized "mini-brains."
But human brain organoids are difficult, time-consuming and expensive to produce, requiring sophisticated tools and know-how to first generate human induced pluripotent stem cells (iPSCs) capable of becoming almost any kind of cell from skin cells, called fibroblasts, then directing those iPSCs to differentiate into the variety of interconnected cell types that comprise an organ like the brain.
In the new paper, senior author Muotri and colleagues describe a new, rapid and cost-effective method to reprogram individual somatic cells directly into cortical organoids from hundreds of individuals simultaneously. To do so, they compressed and optimized several steps of the process so that somatic cells are reprogrammed, expanded and stimulated to form cortical cells almost simultaneously. The result is a cortical organoid that fully develops from somatic cells with only minor manipulation, Muotri said.
"What we've done is establish a proof-of-principle protocol for a systematic, automated process to generate large numbers of brain organoids," said Muotri. "The potential uses are vast, including creating large brain organoid repositories and the discovery of causal genetic variants to human neurological conditions associated with several mutations of unknown significance, such as autism spectrum disorder. If we want to understand the variability in human cognition, this is the first step."
Co-authors of the study include: Monique Schukking, Helen Miranda, Cleber A. Trujillo, and Priscilla D. Negraes, all at UC San Diego.
 

Journal Reference:

1. Monique Schukking, Helen Cristina Miranda, Cleber A Trujillo, Priscilla Davidson Negraes, Alysson Renato Muotri. Direct generation of human cortical organoids from primary cells. Stem Cells and Development, 2018; DOI: 10.1089/scd.2018.0112 

Courtesy: ScienceDaily
 

Genes are key to academic success, study suggests

Child working at school (stock image).

Credit: © Nikki / Fotolia

Parents always worry about whether their children will do well in school, but their kids probably were born with much of what they will need to succeed. A new study published in npj Science of Learning by researchers from The University of Texas at Austin and King's College London explains the substantial influence genes have on academic success, from the start of elementary school to the last day of high school.

For many years, research has linked educational achievement to life trajectories, such as occupational status, health or happiness. But if performing well in school predicts better life outcomes, what predicts how well someone will do throughout school?

"Around two-thirds of individual differences in school achievement are explained by differences in children's DNA," said Margherita Malanchini, a psychology postdoctoral fellow at the Population Research Center at UT Austin. "But less is known about how these factors contribute to an individual's academic success overtime."

Malanchini and Kaili Rimfeld, a postdoctoral researcher at the Institute of Psychiatry, Psychology and Neuroscience at King's College London, analyzed test scores from primary through the end of compulsory education of more than 6,000 pairs of twins.

Researchers found educational achievement to be highly stable throughout schooling, meaning that most students who started off well in primary school continued to do well until graduation. Genetic factors explained about 70 percent of this stability, while the twins shared environment contributed to about 25 percent, and their nonshared environment, such as different friends or teachers, contributed to the remaining 5 percent.

That's not to say that an individual was simply born smart, researchers explained. Even after accounting for intelligence, genes still explained about 60 percent of the continuity of academic achievement.

"Academic achievement is driven by a range of cognitive and noncognitive traits," Malanchini said. "Previously, studies have linked it to personality, behavioral problems, motivation, health and many other factors that are partly heritable."

However, at times grades did change, such as a drop in grades between primary and secondary school. Those changes, researchers said, can be explained largely by nonshared environmental factors.

"Our findings should provide additional motivation to identify children in need of interventions as early as possible, as the problems are likely to remain throughout the school years," said Rimfeld.

Journal Reference:

1. Kaili Rimfeld, Margherita Malanchini, Eva Krapohl, Laurie J. Hannigan, Philip S. Dale, Robert Plomin. The stability of educational achievement across school years is largely explained by genetic factors. npj Science of Learning, 2018; 3 (1) DOI: 10.1038/s41539-018-0030-0 

Courtesy: ScienceDaily

8,000 new antibiotic combinations are surprisingly effective

 

"We shouldn't limit ourselves to just single drugs or two-drug combinations in our medical toolbox," said Pamela Yeh (left), with Elif Tekin.

Credit: Reed Hutchinson/UCLA

Scientists have traditionally believed that combining more than two drugs to fight harmful bacteria would yield diminishing returns. The prevailing theory is that that the incremental benefits of combining three or more drugs would be too small to matter, or that the interactions among the drugs would cause their benefits to cancel one another out.

Now, a team of UCLA biologists has discovered thousands of four- and five-drug combinations of antibiotics that are more effective at killing harmful bacteria than the prevailing views suggested. Their findings, reported today in the journal npj Systems Biology and Applications, could be a major step toward protecting public health at a time when pathogens and common infections are increasingly becoming resistant to antibiotics.

"There is a tradition of using just one drug, maybe two," said Pamela Yeh, one of the study's senior authors and a UCLA assistant professor of ecology and evolutionary biology. "We're offering an alternative that looks very promising. We shouldn't limit ourselves to just single drugs or two-drug combinations in our medical toolbox. We expect several of these combinations, or more, will work much better than existing antibiotics."

Working with eight antibiotics, the researchers analyzed how every possible four- and five-drug combination, including many with varying dosages -- a total of 18,278 combinations in all -- worked against E. coli. They expected that some of the combinations would be very effective at killing the bacteria, but they were startled by how many potent combinations they discovered.

For every combination they tested, the researchers first predicted how effective they thought it would be in stopping the growth of E. coli. Among the four-drug combinations, there were 1,676 groupings that performed better than they expected. Among the five-drug combinations, 6,443 groupings were more effective than expected.

"I was blown away by how many effective combinations there are as we increased the number of drugs," said Van Savage, the study's other senior author and a UCLA professor of ecology and evolutionary biology and of biomathematics. "People may think they know how drug combinations will interact, but they really don't."

On the other hand, 2,331 four-drug combinations and 5,199 five-drug combinations were less effective than the researchers expected they would be, said Elif Tekin, the study's lead author, who was a UCLA postdoctoral scholar during the research.

Some of the four- and five-drug combinations were effective at least partly because individual medications have different mechanisms for targeting E. coli. The eight tested by the UCLA researchers work in six unique ways.

"Some drugs attack the cell walls, others attack the DNA inside," Savage said. "It's like attacking a castle or fortress. Combining different methods of attacking may be more effective than just a single approach."

Said Yeh: "A whole can be much more, or much less, than the sum of its parts, as we often see with a baseball or basketball team." (As an example, she cited the decisive upset victory in the 2004 NBA championship of the Detroit Pistons -- a cohesive team with no superstars -- over a Los Angeles Lakers team with future Hall of Famers Kobe Bryant, Shaquille O'Neal, Karl Malone and Gary Payton.)

Yeh added that although the results are very promising, the drug combinations have been tested in only a laboratory setting and likely are at least years away from being evaluated as possible treatments for people.

"With the specter of antibiotic resistance threatening to turn back health care to the pre-antibiotic era, the ability to more judiciously use combinations of existing antibiotics that singly are losing potency is welcome," said Michael Kurilla, director of the Division of Clinical Innovation at the National Institutes of Health/National Center for Advancing Translational Sciences. "This work will accelerate the testing in humans of promising antibiotic combinations for bacterial infections that we are ill-equipped to deal with today."

The researchers are creating open-access software based on their work that they plan to make available to other scientists next year. The software will enable other researchers to analyze the different combinations of antibiotics studied by the UCLA biologists, and to input data from their own tests of drug combinations.

Using a MAGIC framework

One component of the software is a mathematical formula for analyzing how multiple factors interact, which the UCLA scientists developed as part of their research. They call the framework "mathematical analysis for general interactions of components," or MAGIC.

"We think MAGIC is a generalizable tool that can be applied to other diseases -- including cancers -- and in many other areas with three or more interacting components, to better understand how a complex system works," Tekin said.

Savage said he plans to use concepts from that framework in his ongoing research on how temperature, rain, light and other factors affect the Amazon rainforests.

He, Yeh and Mirta Galesic, a professor of human social dynamics at the Santa Fe Institute, also are using MAGIC in a study of how people's formation of ideas is influenced by their parents, friends, schools, media and other institutions -- and how those factors interact.

"It fits in perfectly with our interest in interacting components," Yeh said.

Other co-authors of the new study are Cynthia White, a UCLA graduate who was a research technician while working on the project; Tina Kang, a UCLA doctoral student; Nina Singh, a student at the University of Southern California; Mauricio Cruz-Loya, a UCLA doctoral student; and Robert Damoiseaux, professor of molecular and medical pharmacology, and director of UCLA's Molecular Screening Shared Resource, a facility with advanced robotics technology where Tekin, White, and Kang conducted much of the research.

The research team reported in 2016 that combinations of three antibiotics can often overcome bacteria's resistance to antibiotics, even when none of the three antibiotics on its own -- or even two of the three together -- is effective. The biologists reported in 2017 two combinations of drugs that are unexpectedly successful in reducing the growth of E. coli bacteria.

Journal Reference:

1. Elif Tekin, Cynthia White, Tina Manzhu Kang, Nina Singh, Mauricio Cruz-Loya, Robert Damoiseaux, Van M. Savage, Pamela J. Yeh. Prevalence and patterns of higher-order drug interactions in Escherichia coli. npj Systems Biology and Applications, 2018; 4 (1) DOI: 10.1038/s41540-018-0069-9 

Courtesy: ScienceDaily

The coming of age of gene therapy: A review of the past and path forward

A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

Credit: US National Library of Medicine

After three decades of hopes tempered by setbacks, gene therapy -- the process of treating a disease by modifying a person's DNA -- is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. The Jan. 12 issue of the journal Science provides an in-depth and timely review of the key developments that have led to several successful gene therapy treatments for patients with serious medical conditions.

Co-authored by Cynthia E. Dunbar, M.D., senior investigator at the Hematology Branch of the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health, the article also discusses emerging genome editing technologies. According to Dunbar and her colleagues, these methods, including the CRISPR/Cas9 approach, would provide ways to correct or alter an individual's genome with precision, which should translate into broader and more effective gene therapy approaches.
Gene therapy is designed to introduce genetic material into cells to compensate for or correct abnormal genes. If a mutated gene causes damage to or spurs the disappearance of a necessary protein, for example, gene therapy may be able to introduce a normal copy of the gene to restore the function of that protein.
The authors focused on the approaches that have delivered the best outcomes in gene therapy so far: 1) direct in vivo administration of viral vectors, or the use of viruses to deliver the therapeutic genes into human cells; and 2) the transfer of genetically engineered blood or bone marrow stem cells from a patient, modified in a lab, then injected back into the same patient.
Originally envisioned as a treatment solely for inherited disorders, gene therapy is now being applied to acquired conditions such as cancer. For example, the engineering of lymphocytes, white blood cells, that can be used in the targeted killing of cancer cells.
In 2017, a steady stream of encouraging clinical results showed progress in gene therapies for hemophilia, sickle-cell disease, blindness, several serious
inherited neurodegenerative disorders, an array of other genetic diseases, and multiple cancers of the bone marrow and lymph nodes.
Three gene therapies have been approved by the U.S. Food and Drug Administration in the past year, and many more are under active clinical investigation. The authors looked to the future of gene therapies, and the challenges of delivering these complex treatments to patients.
Much of this research has been funded by NIH, and key advances took place in the NIH Clinical Center.
 

Journal Reference:

1. Cynthia E. Dunbar, Katherine A. High, J. Keith Joung, Donald B. Kohn, Keiya Ozawa, Michel Sadelain. Gene Therapy Comes of Age. Science, 12 Jan 2018 DOI: 10.1126/science.aan4672 

Courtesy: ScienceDaily
 

How we judge personality from faces depends on our beliefs about how personality works

NYU researchers tested how much we believe different traits co-occur in other people's personalities--for instance, how much we think competence co-occurs with friendliness in others. They then used a method able to visualize the subjects' mental image of a personality trait, allowing them to see if subjects who believe competent people tend to also be friendly have mental images of a competent face and friendly face that are physically more resembling.

Credit: Ryan Stolier and Jonathan Freeman, New York University

We make snap judgments of others based not only on their facial appearance, but also on our pre-existing beliefs about how others' personalities work, finds a new study by a team of psychology researchers.

Its work, reported in the journal Proceedings of the National Academy of Sciences, underscores how we interpret others' facial features to form impressions of their personalities.

"People form personality impressions from others' facial appearance within only a few hundred milliseconds," observes Jonathan Freeman, the paper's senior author and an associate professor in NYU's Department of Psychology and Center for Neural Science. "Our findings suggest that face impressions are shaped not only by a face's specific features but also by our own beliefs about personality -- for instance, the cues that make a face look competent and make a face look friendly are physically more similar for those who believe competence and friendliness co-occur in other people's personalities."

"Although these impressions are highly reliable, they are often quite inaccurate," Freeman adds. "And yet they are consequential, as previous research has found face impressions to predict a range of real-world outcomes, from political elections, to hiring decisions, criminal sentencing, or dating. Initial impressions of faces can bias how we interact and make critical decisions about people, and so understanding the mechanisms behind these impressions is important for developing techniques to reduce biases based on facial features that typically operate outside of awareness."

The paper's other authors included Ryan Stolier, lead author of the paper and doctoral candidate in NYU's Department of Psychology, Eric Hehman of McGill University, and Matthias Keller and Mirella Walker of the University of Basel in Switzerland.

We have long known that people make some personality impressions of others based merely upon their facial appearance. For instance, we see those with babyish features as agreeable and harmless and those with faces that resemble anger as dishonest and unfriendly.

What's less clear is how widespread this process is and how, precisely, it transpires.

In their PNAS study, the researchers explored these questions through a series of experiments, specifically seeking to determine whether our own pre-existing beliefs about how personality works affect the way we "see" it on others' faces.

The experiments' 920 subjects indicated how much they believed different traits co-occur in other people's personalities. For example, they would indicate how much they believe competence co-occurs with friendliness in others. The subjects were each then shown dozens of faces on a computer screen and quickly judged those faces on competence and friendliness, allowing the researchers to see if subjects thought the same faces that are competent are also friendly -- or not friendly. In all, subjects were asked about several personality traits, including the following: "agreeable," "aggressive," "assertive," "caring," "competent," "conscientious," "confident," "creative," "dominant," "egotistic," "emotionally stable," "extroverted," "intelligent," "mean," "neurotic," "open to experience," "responsible," "self-disciplined," "sociable," "trustworthy," "unhappy," and "weird."

Overall, the findings confirmed what the researchers predicted. The more that subjects believed any two traits, such as competence and friendliness, co-occurs in others predicted their impressions of those two traits on faces to be more similar.

In a final experiment, the researchers measured the exact facial features used to make personality impressions using a cutting-edge method that can visualize subjects' mental image of a personality trait in their mind's eye. They found that the facial features used to judge personality indeed change based upon our beliefs. For instance, people who believe competent others tend to also be friendly have mental images of what makes a face look competent and what makes a face look friendly that are physically more resembling.

"Generally, the results suggest that beliefs about personality drive face impressions, such that people who believe any set of personality traits are related tend to see those traits similarly in faces," says Stolier. "This may explain how humans can make any set of impressions from a face."

The results lend evidence for the researchers' perspective that most traits perceived from others' faces are not unique but merely derived from one another, with a few core traits driving the process.

"For instance, while a face may not appear right away to be conscientious, it may appear to be agreeable, intelligent, and emotional -- personality traits a perceiver may believe underlie creativity, resulting in them seeing a face as conscientious," adds Stolier.

The results also provide an explanation for how people can make so many different impressions of someone just from a handful of features present on a face.

"We may only see cues in a face that directly elicit several personality impressions, such as 'submissiveness' for those who have 'baby faces,' " observes Stolier. "However, the perceptual system may take these few impressions and add them together, such that we see a face as conscientious or religious, to the extent we think the personality judgment is related to those impressions we initially make from a face -- such as agreeableness and submissiveness."

The research was supported, in part, by grants from the National Institutes of Health (F31-MH114505) and the National Science Foundation (BCS-1654731).

Journal Reference:

1. Ryan M. Stolier, Eric Hehman, Matthias D. Keller, Mirella Walker, Jonathan B. Freeman. The conceptual structure of face impressions. Proceedings of the National Academy of Sciences, 2018; 201807222 DOI: 10.1073/pnas.1807222115

 Courtesy: ScienceDaily

Key aspects of human cell aging reversed by new compounds

Key aspects of the ageing of human cells can be reversed by new compounds developed at the University of Exeter, research shows.

In a laboratory study of endothelial cells -- which line the inside of blood vessels -- researchers tested compounds designed to target mitochondria (the "power stations" of cells).
In the samples used in the study, the number of senescent cells (older cells that have deteriorated and stopped dividing) was reduced by up to 50%. The Exeter team also identified two splicing factors (a component of cells) that play a key role in when and how endothelial cells become senescent.
The findings raise the possibility of future treatments not only for blood vessels -- which become stiffer as they age, raising the risk of problems including heart attacks and strokes -- but also for other cells.
"As human bodies age, they accumulate old (senescent) cells that do not function as well as younger cells," said Professor Lorna Harries, of the University of Exeter Medical School.
"This is not just an effect of ageing -- it's a reason why we age.
"The compounds developed at Exeter have the potential to tweak the mechanisms by which this ageing of cells happens.
"We used to think age-related diseases like cancer, dementia and diabetes each had a unique cause, but they actually track back to one or two common mechanisms.
"This research focuses on one of these mechanisms, and the findings with our compounds have potentially opened up the way for new therapeutic approaches in the future.
"This may well be the basis for a new generation of anti-degenerative drugs."
Professor Harries said the goal was to help people stay healthier for longer. She added: "This is about health span and quality of life, rather than merely extending lifespan."
In a paper published last year, the team demonstrated a new way to rejuvenate old cells in the laboratory.
However, the new research looked at precisely targeting and rejuvenating mitochondria in old cells.
Each one of our genes is capable of making more than one product, and splicing factors are the genes that make the decision about which of these products are made.
In this new work, using novel chemicals, the researchers were able to very specifically target two splicing factors (SRSF2 or HNRNPD) that play a key role in determining how and why our cells change with advancing age.
"Nearly half of the aged cells we tested showed signs of rejuvenating into young cell models," said Professor Harries.
The researchers tested three different compounds, all developed at the University of Exeter, and found each produced a 40-50% drop in the number of senescent blood vessel cells.
The compounds in question -- AP39, AP123 and RT01 -- have been designed by the Exeter team to selectively deliver minute quantities of the gas hydrogen sulfide to the mitochondria in cells and help the old or damaged cells to generate the 'energy' needed for survival and to reduce senescence.
"Our compounds provide mitochondria in cells with an alternative fuel to help them function properly," said Professor Matt Whiteman, also from the University of Exeter.
"Many disease states can essentially be viewed as accelerated ageing, and keeping mitochondria healthy helps either prevent or, in many cases using animal models, reverse this.
"Our current study shows that splicing factors play a key role in determining how our compounds work."
The research was funded by Dunhill Medical Trust and the Medical Research Council.
 

Journal Reference:

1. Eva Latorre, Roberta Torregrossa, Mark E. Wood, Matthew Whiteman, Lorna W. Harries. Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2. Aging, 2018; DOI: 10.18632/aging.101500 

Courtesy: ScienceDaily
 

Mere expectation of checking work email after hours harms health of workers and families

Employer expectations of work email monitoring during nonwork hours are detrimental to the health and well-being of not only employees but their family members as well.

William Becker, a Virginia Tech associate professor of management in the Pamplin College of Business, co-authored a new study, "Killing me softly: electronic communications monitoring and employee and significant-other well-being," showing that such expectations result in anxiety, which adversely affects the health of employees and their families.
"The competing demands of work and nonwork lives present a dilemma for employees," Becker said, "which triggers feelings of anxiety and endangers work and personal lives."
Other studies have shown that the stress of increased job demands leads to strain and conflict in family relationships when the employee is unable to fulfill nonwork roles at home -- "such as when someone brings work home to finish up."
Their new study, he said, demonstrates that employees do not need to spend actual time on work in their off-hours to experience the harmful effects. The mere expectations of availability increase strain for employees and their significant others -- even when employees do not engage in actual work during nonwork time.
Unlike work-related demands that deplete employee resources, physical and psychological, by requiring time away from home, "the insidious impact of 'always on' organizational culture is often unaccounted for or disguised as a benefit -- increased convenience, for example, or higher autonomy and control over work-life boundaries," Becker said.
"Our research exposes the reality: 'flexible work boundaries' often turn into 'work without boundaries,' compromising an employee's and their family's health and well-being."
As negative health outcomes are costly to them, what can employers do to mitigate the adverse effects identified by the study? Becker said policies that reduce expectations to monitor electronic communication outside of work would be ideal.
When that is not an option, the solution may be to establish boundaries on when electronic communication is acceptable during off-hours by setting up off-hour email windows or schedules when employees are available to respond.
Additionally, he said, organizational expectations should be communicated clearly. "If the nature of a job requires email availability, such expectations should be stated formally as a part of job responsibilities." Knowing these expectations upfront may reduce anxiety in employees and increase understanding from their family members, he said.
As for employees, they could consider practicing mindfulness, which has been shown to be effective in reducing anxiety, Becker said. Mindfulness may help employees "be present" in family interactions, which could help reduce conflict and improve relationship satisfaction. And, he added, mindfulness is within the employee's control when email expectations are not.
Becker, whose research interests include work emotion, turnover, organizational neuroscience, and leadership, is based at Virginia Tech's National Capital Region campus in metro Washington, D.C.
His study, co-authored with Liuba Y. Belkin, of Lehigh University; Samantha A. Conroy, of Colorado State University; and Sarah Tuskey, a Virginia Tech Ph.D. student in executive business research, will be presented at the Academy of Management annual meeting in Chicago on August 10-14.
"Employees today must navigate more complex boundaries between work and family than ever before," said Becker. "Employer expectations during nonwork hours appear to increase this burden, as employees feel an obligation to shift roles throughout their nonwork time.
"Efforts to manage these expectations are more important than ever, given our findings that employees' families are also affected by these expectations."
 

Journal Reference:

1. William J. Becker, Liuba Belkin, Sarah Tuskey. Killing me softly: Electronic communications monitoring and employee and spouse well-being. Academy of Management Proceedings, 2018; 2018 (1): 12574 DOI: 10.5465/AMBPP.2018.121 

Courtesy: ScienceDaily
 

Scientists reverse aging-associated skin wrinkles and hair loss in a mouse model

Keshav Singh, Ph.D., and colleagues have done just that, in a mouse model developed at the University of Alabama at Birmingham. When a mutation leading to mitochondrial dysfunction is induced, the mouse develops wrinkled skin and extensive, visible hair loss in a matter of weeks. When the mitochondrial function is restored by turning off the gene responsible for mitochondrial dysfunction, the mouse returns to smooth skin and thick fur, indistinguishable from a healthy mouse of the same age.

The mouse in the center photo shows aging-associated skin wrinkles and hair loss after two months of mitochondrial DNA depletion. That same mouse, right, shows reversal of wrinkles and hair loss one month later, after mitochondrial DNA replication was resumed. The mouse on the left is a normal control, for comparison.

Credit: UAB

 

"To our knowledge, this observation is unprecedented," said Singh, a professor of genetics in the UAB School of Medicine.

Importantly, the mutation that does this is in a nuclear gene affecting mitochondrial function, the tiny organelles known as the powerhouses of the cells. Numerous mitochondria in cells produce 90 percent of the chemical energy cells need to survive.

In humans, a decline in mitochondrial function is seen during aging, and mitochondrial dysfunction can drive age-related diseases. A depletion of the DNA in mitochondria is also implicated in human mitochondrial diseases, cardiovascular disease, diabetes, age-associated neurological disorders and cancer.

"This mouse model," Singh said, "should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role."

The mutation in the mouse model is induced when the antibiotic doxycycline is added to the food or drinking water. This causes depletion of mitochondrial DNA because the enzyme to replicate the DNA becomes inactive.

In four weeks, the mice showed gray hair, reduced hair density, hair loss, slowed movements and lethargy, changes that are reminiscent of natural aging. Wrinkled skin was seen four to eight weeks after induction of the mutation, and females had more severe skin wrinkles than males.

Dramatically, this hair loss and wrinkled skin could be reversed by turning off the mutation. The photos below show the hair loss and wrinkled skin after two months of doxycycline induction, and the same mouse a month later after doxycycline was stopped, allowing restoration of the depleted mitochondrial DNA.

Little change was seen in other organs when the mutation was induced, suggesting an important role for mitochondria in skin compared to other tissues.

The wrinkled skin showed changes similar to those seen in both intrinsic and extrinsic aging -- intrinsic aging is the natural process of aging, and extrinsic aging is the effect of external factors that influence aging, such as skin wrinkles that develop from excess sun or long-term smoking.

Among the details, the skin of induced-mutation mice showed increased numbers of skin cells, abnormal thickening of the outer layer, dysfunctional hair follicles and increased inflammation that appeared to contribute to skin pathology. These are similar to extrinsic aging of the skin in humans. The mice with depleted mitochondrial DNA also showed changed expression of four aging-associated markers in cells, similar to intrinsic aging.

The skin also showed disruption in the balance between matrix metalloproteinase enzymes and their tissue-specific inhibitor -- a balance of these two is necessary to maintain the collagen fibers in the skin that prevent wrinkling.

The mitochondria of induced-mutation mice had reduced mitochondrial DNA content, altered mitochondrial gene expression, and instability of the large complexes in mitochondria that are involved in oxidative phosphorylation.

Reversal of the mutation restored mitochondrial function, as well as the skin and hair pathology. This showed that mitochondria are reversible regulators of skin aging and loss of hair, an observation that Singh calls "surprising."

"It suggests that epigenetic mechanisms underlying mitochondria-to-nucleus cross-talk must play an important role in the restoration of normal skin and hair phenotype," Singh said, who has a secondary UAB appointment as professor of pathology. "Further experiments are required to determine whether phenotypic changes in other organs can also be reversed to wildtype level by restoration of mitrochondrial DNA."

Journal Reference:

1. Bhupendra Singh, Trenton R. Schoeb, Prachi Bajpai, Andrzej Slominski, Keshav K. Singh. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death & Disease, 2018; 9 (7) DOI: 10.1038/s41419-018-0765-9 

Courtesy: ScienceDaily

Mobile phone radiation may affect memory performance in adolescents, study finds

Radiofrequency electromagnetic fields may have adverse effects on the development of memory performance of specific brain regions exposed during mobile phone use. These are the findings of a study involving nearly 700 adolescents in Switzerland. The investigation, led by the Swiss Tropical and Public Health Institute (Swiss TPH), will be published on Monday, 23 July 2018 in the peer-reviewed journal Environmental Health Perspectives.

The rapid evolution of information and communication technologies (ICT) goes along with an increase in exposure to radiofrequency electromagnetic fields (RF-EMF) in our daily life. The most relevant exposure source to the brain is the use of a mobile phone close to the head. Several studies have been conducted to identify potential health effects related to RF-EMF, though results have remained inconclusive.
The research conducted by scientists at the Swiss Tropical and Public Health Institute (Swiss TPH) looked at the relationship between exposure to RF-EMF from wireless communication devices and memory performance in adolescents. The study follows up a report published in the scientific journal Environment International in 2015 with twice the sample size and more recent information on the absorption of RF-EMF in adolescent brains during different types of wireless communication device use. These are the world's first epidemiological studies to estimate cumulative RF-EMF brain dose in adolescents.
Media usage and brain exposure in young adults
The study to be published on 23 July 2018 found that cumulative RF-EMF brain exposure from mobile phone use over one year may have a negative effect on the development of figural memory performance in adolescents, confirming prior results published in 2015. Figural memory is mainly located in the right brain hemisphere and association with RF-EMF was more pronounced in adolescents using the mobile phone on the right side of the head. "This may suggest that indeed RF-EMF absorbed by the brain is responsible for the observed associations." said Martin Röösli, Head of Environmental Exposures and Health at Swiss TPH.
The rapid evolution of information and communication technologies (ICT) goes along with an increase in exposure to radiofrequency electromagnetic fields (RF-EMF) in our daily life. The most relevant exposure source to the brain is the use of a mobile phone close to the head. Several studies have been conducted to identify potential health effects related to RF-EMF, though results have remained inconclusive.
The research conducted by scientists at the Swiss Tropical and Public Health Institute (Swiss TPH) looked at the relationship between exposure to RF-EMF from wireless communication devices and memory performance in adolescents. The study follows up a report published in the scientific journal Environment International in 2015 with twice the sample size and more recent information on the absorption of RF-EMF in adolescent brains during different types of wireless communication device use. These are the world's first epidemiological studies to estimate cumulative RF-EMF brain dose in adolescents.
Media usage and brain exposure in young adults
The study to be published on 23 July 2018 found that cumulative RF-EMF brain exposure from mobile phone use over one year may have a negative effect on the development of figural memory performance in adolescents, confirming prior results published in 2015. Figural memory is mainly located in the right brain hemisphere and association with RF-EMF was more pronounced in adolescents using the mobile phone on the right side of the head. "This may suggest that indeed RF-EMF absorbed by the brain is responsible for the observed associations." said Martin Röösli, Head of Environmental Exposures and Health at Swiss TPH.
Other aspects of wireless communication use, such as sending text messages, playing games or browsing the Internet cause only marginal RF-EMF exposure to the brain and were not associated with the development of memory performance. "A unique feature of this study is the use of objectively collected mobile phone user data from mobile phone operators." said Röösli. He emphasised that further research is needed to rule out the influence of other factors. "For instance, the study results could have been affected by puberty, which affects both mobile phone use and the participant's cognitive and behavioural state."
The data gathered from the Health Effects Related to Mobile phone usE in adolescentS (HERMES) cohort looked at the relationship between exposure to RF-EMF and development of memory performance of almost 700 adolescents over the course of one year. Participants, aged 12 to 17 years, were recruited from 7th to 9th public school grades in urban and rural areas of Swiss-German speaking Switzerland.
Minimising the risk of RF-EMF exposure
The potential effect of RF-EMF exposure to the brain is a relatively new field of scientific inquiry. "It is not yet clear how RF-EMF could potentially affect brain processes or how relevant our findings are in the long-term." said Röösli. "Potential risks to the brain can be minimised by using headphones or the loud speaker while calling, in particular when network quality is low and the mobile phone is functioning at maximum power."
About the publication
The study was conducted by Swiss TPH in collaboration with the European Union project GERoNiMO, which aims to improve the knowledge of whether and to what extent RF-EMF affects health. The work on dose calculations was conducted in collaboration with Belgian scientists. The project was funded by the European Community's Seventh Framework Programme and the Swiss National Science Foundation (SNSF).
 

Journal References:

1. Foerster M., Thielens A., Joseph W., Eeftens M., Röösli M. A prospective cohort study of adolescents' memory performance and individual brain dose of microwave radiation from wireless communication. Environmental Health Perspectives, 2018 DOI: 10.1289/EHP2427
2. Anna Schoeni, Katharina Roser, Martin Röösli. Memory performance, wireless communication and exposure to radiofrequency electromagnetic fields: A prospective cohort study in adolescents. Environment International, 2015; 85: 343 DOI: 10.1016/j.envint.2015.09.025

 Courtesy: ScienceDaily

Marriage may protect against heart disease/stroke and associated risk of death

The single, divorced, and widowed at heightened risk, pooled data analysis suggests

Marriage may protect against the development of heart disease/stroke as well as influencing who is more likely to die of it, suggests a pooled analysis of the available data, published online in the journal Heart.

The findings prompt the researchers to suggest that marital status should be included as a risk factor for heart disease/stroke and likely survival in its own right.
Most (80%) cardiovascular disease can be attributed to well known risk factors: age; sex; high blood pressure; high cholesterol; smoking; and diabetes. But it's not clear what influences the remaining 20 per cent.
The findings of previous research on the impact of marital status have been somewhat mixed, so in a bid to clarify the issues, the authors trawled research databases for relevant published studies.
They drew on 34 out of a total of 225, all of which had been published between 1963 and 2015, and involved more than 2 million people aged between 42 and 77 from Europe, Scandinavia, North America, the Middle East, and Asia.
Pooled analysis of the data revealed that, compared with people who were married, those who weren't (never married, divorced, widowed) were at heightened risk of developing cardiovascular disease (42%) and coronary artery heart disease (16%).
Not being married was also associated with a heightened risk of dying from both coronary heart disease (42%) and stroke (55%).
When the data were broken down further, the analysis showed that divorce was associated with a 35 per cent higher risk of developing heart disease for both men and women, while widowers of both sexes were 16 per cent more likely to have a stroke.
While there was no difference in the risk of death following a stroke between the married and the unmarried, this was not the case after a heart attack, the risk of which was significantly higher (42%) among those who had never married.
The authors caution that the methods used and adjustments made for potentially influential factors varied considerably across all the studies, which may have affected the results of their analysis.
Similarly, there was no information on same sex partnerships or the quality of marriage, and the potential role of living with someone, as opposed to being married to them, was not explored.
But this is the largest study to date, with the age and ethnicity of the participants strengthening the wider applicability of the findings, the authors point out.
And there are various theories as to why marriage may be protective. These include earlier recognition of, and response to, health problems; better adherence to medication; better financial security; enhanced wellbeing; and better friendship networks.
"Future research should focus around whether marital status is a surrogate marker for other adverse health behaviour or cardiovascular risk profiles that underlies our reported findings or whether marital status should be considered as a risk factor by itself," the authors conclude.

Journal References:

1. Chun Wai Wong, Chun Shing Kwok, Aditya Narain, Martha Gulati, Anastasia S Mihalidou, Pensee Wu, Mirvat Alasnag, Phyo Kyaw Myint, Mamas A Mamas. Marital status and risk of cardiovascular diseases: a systematic review and meta-analysis. Heart, 2018; heartjnl-2018-313005 DOI: 10.1136/heartjnl-2018-313005
2. Valeria Raparelli, Marco Proietti, Stefania Basili. Explanatory power of gender relations in cardiovascular outcomes: the missing piece of the puzzle. Heart, 2018; heartjnl-2018-313469 DOI: 10.1136/heartjnl-2018-313469 

Courtesy: ScienceDaily