A gene involved in brain development that can lead to severe disability and infant death has been identified by scientists.
Mutations in the gene cause profound developmental problems and seizures in young children, researchers have found.
Scientists and doctors worked with children with a range of severe problems, including seizures and abnormal brain scans, and discovered that the infants all had mutations in a gene known as PLAA. The researchers have named the condition PLAA-associated neurodevelopment disorder, or PLAAND.
By making a mouse with the same mutation as found in patients, the team – led by the University of Edinburgh – showed how this gene had to function properly for the healthy brain to develop.
PLAA is essential for signalling cells to clear build-up of damaged proteins, which is crucial for brain cell function, the researchers say.
Cells in children with PLAAND have lost this ability and damaged proteins build up, causing severe problems in brain development and at synapses – parts of brain cells that communicate with other cells.
Insights learned from the study may enable scientists to uncover new drugs to treat this rare disease. They could also shed light on conditions such as Alzheimer’s disease, in which there is also an issue with damaged protein build up.
Pinpointing mutations in this gene that lead to such severe outcomes in the affected children is an important advance.
Children affected with PLAAND die before the age of six and most heart-breaking for their families is that they fail to meet any developmental milestones. There is no treatment currently available. In identifying this gene and the processes it controls, we have made significant steps in understanding its role in healthy brain development, which will help us target drug studies in future.

University of Edinburgh
www.ed.ac.uk/news/2017/fatal-childhood-disorder-gene

This article presents data from a multicenter evaluation of the VERIS HCV assay that runs on the DxN VERIS Molecular Diagnostics System.* The study by Braun et al. was published online at the Journal of Clinical Microbiology in February 2017, and is to be published in print in the journal’s April issue. Data includes an assessment of system performance related to precision, analytical sensitivity, analytical measurement range and clinical specificity. The study featured a large number of tests performed by ten (10) participating evaluation sites based in the United Kingdom, Germany, Italy, Spain and France.

Study results demonstrated overall precision with a standard deviation (SD) of 0.22 log IU/mL or lower for each level tested. This was despite the challenges involved with the evaluation of a high number of sites. The analytical sensitivity observed among the sites was between 6.2 and 9.0 IU/mL. A broad linear range and detection of all HCV genotypes were also demonstrated.

The data is robust owing to the large numbers of tests performed. The analytical results demonstrate that the VERIS HCV assay meets the recommendations of current clinical guidelines for patient management in terms of performance and precision. The consistency of the VERIS HCV assay’s analytical performance is, in part, ascribed to the fully automated capabilities of the DxN VERIS System.

To review the full abstract please visit http://jcm.asm.org/content/early/2017/01/27/JCM.02163-16.abstract.

A gene previously identified as critical for tumour growth in many human cancers also maintains intestinal stem cells and encourages the growth of cells that support them, according to results of a study led by Johns Hopkins researchers. The finding adds to evidence for the intimate link between stem cells and cancer, and advances prospects for regenerative medicine and cancer treatments.
Study leader Linda M. S. Resar, M.D., professor of medicine, oncology and pathology at the Institute for Cellular Engineering at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, has been studying genes in the high-mobility group (HMG) family for over two decades. Several years ago, while creating a genetically engineered mouse that expresses high levels of the mouse HMGA1 gene to investigate its role in leukaemia, Resar and her colleagues made the chance finding that the intestines of these animals were much larger and heavier than those of “wild-type” animals (or control mice that were not genetically modified). The mouse intestines were also riddled with polyps, abnormal growths projecting from the intestinal lining that can be precursors of cancer.  In fact, polyps in humans frequently progress to colon cancer, which is why they are removed during screening colonoscopies in people over 50 and others at risk for colon cancer.
To better understand how HMGA1 affected the rodents’ intestines, Resar and Lingling Xian, M.D., Ph.D., research associate at the Johns Hopkins University School of Medicine, and their colleagues examined the transgenic animals’ intestinal cells to determine which ones were expressing this gene. Several different experiments localized the active gene and its protein to stem cells buried within the crypts, or deep grooves in the intestinal lining.
After isolating these stem cells from both transgenic and wild-type mice, the researchers found that those carrying the HMGA1 transgene multiplied far more rapidly, forming identical daughter cells in a process called self-renewal, which is a defining property of all stem cells. These transgenic stem cells also readily created intestinal tissues called “organoids” in laboratory dishes. These organoids had more stem cells than those isolated from wild-type mice.
Further investigation, says Resar, showed that these unusual properties arise from the ability of HMGA1 to turn on several genes involved in the Wnt pathway, a network of proteins necessary for embryonic development and stem cell activity.
Stem cells do not function in isolation, explains Resar. They need a “niche” to survive and maintain an undifferentiated state. From the French word nicher, which means to build a nest, a niche is a nest-like compartment comprised of cells that secrete growth factors and other proteins that help stem cells survive. The niche also prevents stem cells from morphing into mature intestinal cells until new intestinal cells are needed.   Intestinal stem cells are particularly important because a new intestinal lining is generated about every 4-5 days.
Looking further into the intestinal crypts of both the transgenic and wild-type mice, the research team made what they consider a surprising finding: Not only was HMGA1 causing the stem cells themselves to self-renew or proliferate more rapidly in the transgenic animals, but it was also increasing the number of Paneth cells, a type of niche cell known to support intestinal stem cells. Additional experiments showed that the protein produced by HMGA1 activates another gene called Sox9, which is directly responsible for turning stem cells into Paneth cells.
“We suspected that HMGA1 might generate new stem cells, but we were extremely surprised that it also helps support these cells by building a niche,” Resar says. “We believe that our experiments provide the first example of a factor that both expands the intestinal stem cell compartment and builds a niche.”
Many genes that are involved in the growth and development of embryos or adult stem cells also play roles in cancer, Resar adds. After scanning the Cancer Genome Atlas, a database of genes expressed in human cancers, the research team discovered that the activity of both HMGA1 and SOX9 genes are tightly correlated in normal colon tissue, and both genes become highly overexpressed in colon cancer. “This tells us that the pathway turned on by HMGA1 in normal intestinal stem cells becomes disrupted and hyperactive in colon cancer,” Resar says.

John Hopkins Hospital
www.hopkinsmedicine.org/news/media/releases/single_gene_encourages_growth_of_intestinal_stem_cells_supporting_niche_cellsand_cancer_

Mellitus, LLC reported the publication of results from a prospective, investigator-initiated study conducted at Brigham and Women’s Hospital (BWH) demonstrating the potential clinical utility of glycated CD59 (GCD59) as a novel biomarker for the screening and diagnosis of gestational diabetes mellitus (GDM). The data from this study showed that a single blood test that measures plasma GCD59 at week 24-28 of gestation identified women with GDM with high sensitivity and specificity. The study was completed by a team of investigators at BWH led by Jose A. Halperin, M.D., in collaboration with researchers from Harvard T.H. Chan School of Public Health. Dr. Halperin, scientific Co-founder of Mellitus, is a physician and researcher at BWH and Associate Professor of Medicine at Harvard Medical School (HMS).
Gestational Diabetes Mellitus (GDM), also known as diabetes in pregnancy, is a major cause of adverse pregnancy outcomes for both babies and mothers. Babies born from mothers with GDM tend to be large for their gestational age (LGA). Delivery of LGA babies is the main cause of the many complications associated with GDM, including pre-term birth, foetal injury, perinatal mortality and required caesarean delivery. GDM also increases the mother’s risk of preeclampsia and gestational hypertension.
Because treatment of GDM mitigates the risk of complications, practice guidelines from professional organizations such as the American College of Obstetrics and Gynaecology and the American Diabetes Association recommend screening of all non-diabetic pregnant women for GDM. Approximately four million pregnant women are screened for GDM each year in the United States in accordance with these practice guidelines. Currently, the standard of care predominantly uses a two-step approach. The first step is administration of the Glucose Challenge Test (GCT); in this test, blood sugar is measured one-hour after drinking a glucose solution. If a woman has a positive GCT test, she is reflexed to having a second test, an Oral Glucose Tolerance Test (OGTT). The OGTT serves to diagnose GDM. The OGTT requires women to fast overnight prior to having a blood draw, followed by drinking a glucose solution and additional blood tests every hour for three hours. These tests are time consuming, uncomfortable for the patients and are reported to have poor reproducibility. Other tests that measure HbA1c or fructosamine are not sensitive and therefore not routinely used during prenatal care to screen and diagnose GDM. Issues associated with screening and diagnosing GDM highlight the need for an accurate, simpler and more patient-friendly test for GDM.
The protein known as CD59 is an inhibitor of the complement system that is inactivated by high glucose in diabetes to form glycated CD59 (GCD59). Inactivation of CD59 decreases its protective effect and promotes complement-mediated damage that reportedly plays a role in the processes leading to complications of diabetes such as nephropathy, neuropathy and retinopathy.
The study published evaluated levels of GCD59 in plasma samples from 1,000 women undergoing routine screening and diagnosis of GDM at week 24-28 of gestation at Brigham and Women’s Hospital in Boston. 500 of the samples were from women who had a normal GCT (controls) and another 500 were from women who had failed the GCT and completed a subsequent OGTT (cases). Of the cases, 127 were diagnosed with GDM. The primary objective of the study was to assess the accuracy of plasma GCD59 to predict the results of the GCT. Secondary aims were to assess the accuracy of plasma GCD59 in predicting the diagnosis of GDM by OGTT and the association of plasma GCD59 with the prevalence of LGA newborns.
The study found that, compared to controls, median levels of plasma GCD59 were 8.5-fold higher in women who failed the GCT and 10-fold higher in women diagnosed with GDM. Results also demonstrated that measurement of plasma GCD59 independently discriminated cases from controls with high sensitivity and specificity, even after adjustment for covariates such as maternal age, BMI, race/ethnicity, multiplicity, gestational age and previous history of diabetes. More detailed results can be found in the Diabetes Care paper.
"This is the first study to demonstrate that a single measurement of plasma GCD59 can be used as a simplified method to identify women who would have failed a GCT and are at higher risk of GDM," said Dr. Halperin. "These results indicate that measurement of this novel disease-associated biomarker may be a convenient and effective alternative to the cumbersome methods currently used to screen and diagnose GDM; the study opens the door to future multi-center studies to confirm the clinical utility of plasma GCD59 as a biomarker for detection and diagnosis of GDM."

EurekAlert
www.eurekalert.org/pub_releases/2017-04/mbci-ssg042517.php

Think of life as a house: if DNA molecules are blueprints, then messenger RNAs (mRNAs) are orders, describing the required parts (proteins) and when they should arrive. But putting in many orders doesn’t always mean you’ll get all of the parts on time — maybe there’s a delay with your vendor or delivery service. Similarly, mRNA levels alone do not dictate protein levels. Today in ACS Central Science, researchers report a method to address that issue.

David Tirrell, Kelly Burke and Katie Antilla note that in order to better understand how genes are regulated, one needs to see the mRNA when it is at the site of protein synthesis. Using fluorescence probes, the researchers designed a technique that shows mRNA when it comes in contact with giant protein synthesizing machines called ribosomes. They used this method to record the synthesis of proteins and to measure cellular responses to iron. Unlike previous methods, their tool works without the need to engineer an mRNA of interest. Tirrell notes that the method is applicable to essentially any type of RNA, and could be modified to visualize other types of interactions in the cell.

American Chemical Societywww.acs.org/content/acs/en/pressroom/newsreleases/2017/may/imaging-mrna-right-where-it-is-made-at-the-site-of-translation.html