Large sections of the genome that were once referred to as ‘junk’ DNA have been linked to human heart failure, according to research from Washington University School of Medicine in St. Louis.
Molecules now associated with these sections of the genome are called non-coding RNAs. They come in a variety of forms, some more widely studied than others. Of these, about 90 percent are called long non-coding RNAs, and exploration of their roles in health and disease is just beginning.
Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied non-failing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.
‘We took an unbiased approach to investigating which types of RNA might be linked to heart failure,’ said senior author Jeanne M. Nerbonne, PhD, the Alumni Endowed Professor of Molecular Biology and Pharmacology. ‘We were surprised to find that long non-coding RNAs stood out. In fact, the field is evolving so rapidly that when we did a slightly earlier, similar investigation in mice, we didn’t even think to include long non-coding RNAs in the analysis.’
Heart failure refers to a gradual loss of heart function. The left ventricle, the heart’s main pumping chamber, becomes less efficient. Blood flow diminishes, and the body no longer receives the oxygen needed to go about daily tasks. Sometimes the condition develops after an obvious trigger such as a heart attack or infection, but other times the causes are less clear.
In the new study, the investigators found that unlike other RNA molecules, expression patterns of long non-coding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.
‘We don’t know whether these changes in long non-coding RNAs are a cause or an effect of heart failure,’ Nerbonne said. ‘But it seems likely they play some role in co-ordinating the regulation of multiple genes involved in heart function.’
Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and non-failing hearts. But only expression of the long non-coding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (non-ischemic). Similarly, only long non-coding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.
Because of the difficulty in obtaining human heart tissue, the study’s sample size was relatively small, Nerbonne said. Her team analysed eight non-failing hearts, eight hearts in ischemic heart failure and eight hearts in non-ischemic heart failure. Though small, the study is unique because each of the 16 failing hearts was sampled twice, once before and once after LVAD support.
According to Nerbonne, this before-and-after sampling of heart tissue is an unusual feature of this study and one of its strengths. Cardiac surgeons first removed a sample of heart tissue while implanting the LVAD. Then, months later, transplant surgeons sampled the same failing hearts when each patient received a new donor organ. Previous studies comparing heart function before and after implanting a pump used samples taken from different patients.
This double sampling of the same organ is important for understanding what is happening on a molecular level to failing heart tissue when a pump literally takes some of the load off.
‘It’s clear that some patients experience a change in the structure and physiology of the heart tissue following pump support, and in some patients that change results in improved heart function,’ Nerbonne said. ‘One interesting question is whether these long non-coding RNAs could be a measure of whether the failing heart is getting better with an LVAD.’
Indeed, using the non-failing heart samples for comparison, about 10 percent of the long non-coding RNA expression that was disturbed in the failing hearts improved or returned to normal following LVAD support. While 10 percent may seem modest, only about 3 percent, at best, of other types of RNA expression returned to normal after pump support.
Nerbonne also is interested in exploring whether measures of long non-coding RNAs could be an early predictor of the disease, ideally before symptoms of heart failure even develop. Washington University School of Medicine in St. Louis

St. Jude Children’s Research Hospital scientists led a study showing that mutations in a gene responsible for amyotrophic lateral sclerosis (ALS) disrupt the RNA transport system in nerve cells.
The findings offer a new avenue for researchers to pursue in the quest for desperately needed treatments for ALS, a disorder that kills most patients within five years of diagnosis. ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 individuals nationwide each year and is associated with muscle weakness and paralysis.
The gene, TDP-43, carries instructions for making a protein of the same name. While mutations in TDP-43 were known to cause ALS and a related neurodegenerative disorder, until now the mechanism involved was a mystery. This study showed for the first time that the mutations disrupt efficient movement within nerve cells of RNA molecules. These RNA molecules direct protein assembly based on instructions carried in DNA. Correct transport of these RNAs permits proteins to be made in the right place at the right time.
Working in motor neurons derived from patients with ALS, researchers demonstrated that each of three different TDP-43 mutations impaired delivery of RNA molecules to their final destination near the junction where a nerve and its target muscle meet. Without the RNA molecules, nerves cannot make proteins necessary to function normally and respond quickly when stimulated. Motor neurons govern movement, including breathing. Their death and deterioration is a hallmark of ALS.
The results also provide insight into how problems in RNA metabolism, including disturbances in RNA regulation and functioning, lead to ALS and other neurodegenerative diseases.
‘Five years of tremendous progress in ALS genetics has revealed that RNA metabolism is a critical pathway that is impaired in this disease,’ said the study’s corresponding author J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. ‘But RNA metabolism is a complex process that involves multiple steps that are carried out in different parts of the cell. This study provides a more refined understanding of how ALS-causing mutations impair RNA metabolism so we know what needs fixing therapeutically.’
TDP-43 belongs to a family of proteins that bind to RNA and regulate its function. Normally TDP-43 is stored in the cell’s command center, the nucleus. There the protein prepares DNA for translation into the proteins that do the work of cells and shuttles the resulting RNA, called mRNA, from the nucleus to the cytoplasm, the cell’s liquid center. While clumps of TDP-43 were known to accumulate in the cytoplasm of the motor neurons of patients with ALS and other neurodegenerative diseases, the protein’s function there was unknown.
This study provides an answer. The work was done in motor neurons from the fruit fly Drosophila melanogaster, mouse brain cells and human motor neurons produced by reprogramming cells from ALS patients with three different TDP-43 mutations. Co-first author Nael Alami, Ph.D., a postdoctoral fellow in Taylor’s laboratory, developed a florescent RNA beacon that let investigators track movement of RNA molecules in living cells.
Researchers demonstrated that TDP-43 is part of a molecule called an RNA transport granule. These granules are responsible for moving mRNA efficiently to the end of the axon where the molecule is translated into a protein. For this study, scientists used Neurofilament-L (NEFL) mRNA, which is known to bind TDP-43.
In human motor neurons growing in the laboratory, investigators found that transport granules with mutant TDP-43 were more likely than granules with unaltered TDP-43 to stall en route to the nerve ending and sometimes reverse direction. The defect in the human ALS motor neurons was apparent after the first week.
Evidence from mice suggests TDP-43 mutations selectively rather than globally disrupt movement in nerve cells. The mutations did not affect movement of another cell structure, the mitochondria, along the axon where mRNA movement was impaired.
‘We know neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases, seem to share a common mechanism,’ Alami said. ‘We plan to use our finding from this study to look for similar defects in those diseases.’ St. Jude Children’s Research Hospital

Asnières sur Seine (April 14, 2014) — Leading Haemostasis specialist Stago has moved its Headquarters to a brand new building fully dedicated to its business activities.
“The rapid acceleration in our international expansion meant we needed a new Head Office, more closely reflecting the Stago image and its operations today,” said Deputy Vice President Patrick Monnot.
The sober, functional and contemporary 8,300 m² building is perfectly designed to accommodate not only the Group’s various global functions but also the activities of its French subsidiary. It will allow the company to optimise its everyday operations and to greet partners and customers in an even more welcoming environment.
Officially recognised as a low-energy, high environmental quality building, this development is part of a sustainable quality approach embodying the values that have guided Stago for nearly 70 years!
This investment is an indicator of the company’s healthy balance sheet. It was made possible by its employees’ expertise and hard work, and above all by the strong support of the Haemostasis scientific and medical community.

New address:
From 14 April 2014
Your contacts’ phone and fax numbers will remain the same
Diagnostica Stago
3 Allée Thérésa
CS 10009
92665 Asnières sur Seine Cedex
France
Ph: +33 (0) 1 46 88 20 20
Fax: +33 (0) 1 47 91 08 91 webmaster@stago.com www.stago.com

Hugo Technology, the medical technology repair and service specialist, has been appointed to support BioFire’s FilmArray System – a multi-purpose device which identifies numerous respiratory viruses and bacteria, eg: adenovirus, influenza and bordetella pertussis– a bacterium that is a cause of whooping cough.  Hugo has an ongoing contract with BioFire based in Salt Lake City, Utah, which is known for developing, manufacturing and selling the fastest, highest-quality machines in the world for DNA analysis.
Hugo will take responsibility for repairing and maintaining the equipment which will be sent to its new £700,000 (€815,000) Bromsgrove facility. This facility was designed specifically to match the needs of Hugo’s growing client base of leading original equipment manufacturers (OEMs).  Biomedical service engineers for Hugo Technology have spent two weeks in Salt Lake City being trained on the Film Array System which integrates sample preparation, amplification, detection and analysis into one process to detect emerging infectious diseases in just one hour.  The user-friendly FilmArray System is used in hospital-based, clinical laboratories across the USA and Europe.  
Hugo employs more than 50 people across the UK servicing medical devices and equipment for OEMs both at home and across Europe.  Accredited to ISO 13485 medical device quality management standard and ISO 9001:2008, Hugo’s facility and field engineer teams provide support to some of the world’s largest OEMs including: Philips, Nipro, Moog, Nutricia, Therapy Equipment, Cosmed, Nikkiso, Care Innovations-GE and Teleflex.