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Archive - Jul 2019


July 27th

Newly Identified Pluripotent Liver Cell May Ultimately Provide Alternative to Liver Transplants; Single-Cell RNA Sequencing Key to This Major Discovery

Researchers at King's College London have used single cell RNA sequencing to identify a type of cell that may be able to regenerate liver tissue, treating liver failure without the need for transplants. In a paper published online on July 26, 2019 in Nature Communications, the scientists describe identying a new type of cell called a hepatobiliary hybrid progenitor (HHyP), that forms during our early development in the womb. The open-access article is titled “Single Cell Analysis of Human Foetal Liver Captures the Transcriptional Profile of Hepatobiliary Hybrid Progenitors.” Surprisingly, HHyP also persist in small quantities in adults and these cells can grow into the two main cell types of the adult liver (hepatocytes and cholangiocytes) giving HHyPs stem cell like properties. The team examined HHyPs and found that they resemble mouse stem cells which have been found to rapidly repair mice liver following major injury, such as occurs in cirrhosis. Senior author Dr. Tamir Rashid (photo) from the Centre for Stem Cells & Regenerative Medicine at King's College London said: "For the first time, we have found that cells with true stem-cell-like properties may well exist in the human liver. This in turn could provide a wide range of regenerative medicine applications for treating liver disease, including the possibility of bypassing the need for liver transplants." Liver disease is the fifth biggest killer in the UK and the third most common cause of premature death, and the number of cases is continuing to rise. It can be caused by lifestyle issues such as obesity, viruses, alcohol misuse, or by non-lifestyle issues such as autoimmune and genetic-mediated disease.

Unexpected Developmental Hierarchy Revealed in New Study of Highly Unusual Disease (Langerhans Cell Histiocytosis)--Epigenomics and Single-Cell Sequencing Were Key

Langerhans cell histiocytosis (LCH) is a very unusual disease: Often classified as a cancer because of uncontrolled cell growth in different parts of the body, it also has features of an autoimmune disease, as LCH lesions attract immune cells and show characteristic tissue inflammation. LCH is clinically variable and often difficult to diagnose. Skin involvement in babies with LCH can look like a nappy rash, whereas bone involvement can be mistaken as sarcoma in an X-ray picture. In its most aggressive form, LCH can present as leukemia-like disease and lead to organ failure. These diverse manifestations and the enormous clinical heterogeneity of LCH continue to puzzle medical doctors and scientists around the world. Studying LCH lesions under the microscope, Caroline Hutter, MD, PhD-- a pediatric oncologist at St. Anna Children's Hospital Research Center (CCHR) in Vienna, Austria, principal investigator at CCRI and co-lead investigator of this study -- observed striking heterogeneity among LCH cells. To investigate this diversity in full molecular detail, she assembled an interdisciplinary team including experimental and computational researchers from CCRI and CeMM (Research Center in Molecular Medicine—Vienna Austria), as well as medical doctors from St. Anna Children's Hospital and Vienna General Hospital. Her aim was to answer two fundamental questions: What are the mechanisms behind LCH, and how can we improve treatment of children affected by this disease? Utilizing state-of-the-art technology in the laboratory of co-lead investigator Christoph Bock (CeMM), PhD, LCH lesions were analyzed for their molecular composition at single-cell resolution.

July 26th

CRISPR Activation Screen Identifies Genes That Protect Cells from Zika Virus Infection and Also Prevent Death of Zika-Infected Cells

The Zika virus (image) has affected over 60 million people, mostly in South America. It has potentially devastating consequences for pregnant women and their unborn children, many of whom are born with severe microcephaly and other developmental and neurological abnormalities. There is currently no vaccine or specific treatment for the virus. A new Tel Aviv University (TAU) study uses a genetic screen to identify genes that protect cells from Zika viral infection. The research, led by Dr. Ella H. Sklan of TAU's Sackler School of Medicine, was published online on May 29, 2019 in the Journal of Virology. It may one day lead to the development of a treatment for the Zika virus and other infections. The article is titled “A CRISPR Activation Screen Identifies Genes Protecting from Zika Virus Infection.” The study was based on a modification of the CRISPR-Cas9 gene-editing technique. CRISPR-Cas9 is a naturally occurring bacterial genome editing system that has been adapted to gene editing in mammalian cells. The system is based on the bacterial enzyme Cas9, which can locate and modify specific locations along the human genome. A modification of this system, known as CRISPR activation, is accomplished by genetically changing Cas9 in a way that enables the expression of specific genes in their original DNA locations. "CRISPR activation can be used to identify genes protecting against viral infection," Dr. Sklan says. "We used this adapted system to activate every gene in the genome in cultured cells. We then infected the cells with the Zika virus. While most cells die following the infection, some survived due to the over-expression of some protective genes. We then used next-generation sequencing and bioinformatic analysis to identify a number of genes that enabled survival, focusing on one of these genes called IFI6.

How Pufferfish Developed Its Unusual Spines

Pufferfish are known for their strange and extreme skin ornaments, but how they came to possess the spiky skin structures known as spines has largely remained a mystery. Now, researchers have identified the genes responsible for the evolution and development of pufferfish spines in a study published online on July 25, 2019 in iScience. The open-access article is titled “Evolution and Developmental Diversity of Skin Spines in Pufferfishes.” It turns out that the process is pretty similar to how other vertebrates get their hair or feathers--and might have allowed the pufferfish to fill unique ecological niches. "Pufferfish are some of the strangest fish in the ocean, particularly because they have a reduced skeleton, beak-like dentition and they form spines instead of scales--not everywhere, but just in certain patches around the body," says corresponding author Gareth Fraser (@garethjfraser), PhD, an Assistant Professor at the University of Florida. Dr. Fraser and his team followed the development of pufferfish spines in embryos. While the scientists had initially hypothesized that the spines formed from scales--that the pufferfish lost its scale component but retained the spine--they found that the spines are developmentally unique from scales. They also found that the development of pufferfish spines relies on the same network of genes that are commonly expressed within feathers and hairs of other vertebrate animals. "It just blows me away that regardless of how evolutionarily-different skin structures in animals are, they still use the same collection of genes during development," Dr. Fraser says.

Vitamin D Supplementation May Slow Diabetes Progression, New Study Suggests

Vitamin D supplementation may slow the progression of type 2 diabetes in newly diagnosed patients and those with prediabetes, according to a study published online on July 1, 2019 in the European Journal of Endocrinology. The open-access article is titled “Effects of 6-Month Vitamin D Supplementation on Insulin Sensitivity and Secretion: A Randomized, Placebo-Controlled Trial.” The study findings suggest that high-dose supplementation of vitamin D can improve glucose metabolism to help prevent the development and progression of diabetes. Type 2 diabetes is an increasingly prevalent disease that places a huge burden on patients and society and can lead to serious health problems including nerve damage, blindness, and kidney failure. People at high risk of developing type 2 diabetes (prediabetics) can be identified by several risk factors, including obesity or a family history of the disease. Although low vitamin D levels have previously been associated with an increased risk of developing type 2 diabetes, some studies have reported no improvement in metabolic function. However, these studies often had a low number of participants or included individuals with normal vitamin D levels at the start who were metabolically healthy, or who had long-standing type 2 diabetes. Whether vitamin D supplementation has any beneficial effect in patients with prediabetes or with newly diagnosed diabetes, especially in those who have low vitamin D levels, has remained uncertain. In this study, Dr. Claudia Gagnon, and colleagues from Université Laval in Quebec, examined the effect of vitamin D supplementation on glucose metabolism in patients newly diagnosed with type 2 diabetes or identified as at high risk of developing the condition.

July 23rd

Chemists Find Simplest Organic Molecules Can Self-Assemble to Give Cell-Like Structures Under Early Earth Conditions

Before life began on Earth, the environment likely contained a massive number of chemicals that reacted with each other more or less randomly, and it is unclear how things as complex as cells could have emerged from such chemical chaos. Now, a team led by Tony Z. Jia, PhD, of the Earth-Life Science Institute (ELSI) at the Tokyo Institute of Technology and Kuhan Chandru, PhD, of the National University of Malaysia, has shown that simple α-hydroxy acids, like glycolic and lactic acid (which is used in common store-bought facial peels), spontaneously polymerize and self-assemble into polyester microdroplets when dried at moderate temperatures followed by rehydration, as might have happened along primitive beaches and river banks or in drying puddles. These form a new type of cell-like compartment which can trap and concentrate biomolecules like nucleic acids and proteins. These droplets, unlike most modern cells, are able to easily merge and reform and thus could have hosted versatile early genetic and metabolic systems potentially critical for the origins of life. The new work was published online on July 22, 2019 in PNAS in an article titled “Membraneless Polyester Microdroplets As Primordial Compartments at the Origins of Life.” Scientists from around the world are actively working to understand how life began. All modern Earth life, from bacteria to humans, is made up of cells. Cells are comprised of lipids, proteins, and nucleic acids, with the lipid forming the cell membrane, an enclosure that keeps the other components together and interfaces with the environment, exchanging food and waste. How molecular assemblages as complex as cells originally formed remains a mystery.

Molecular Sensor Scouts DNA Damage and Supervises Repair; Xeroderma Pigmentosa Connection

In the time it takes you to read this sentence, every cell in your body suffers some form of DNA damage. Without vigilant repair, cancer would run rampant, and now scientists at the University of Pittsburgh have gotten a glimpse of how one protein in particular keeps DNA damage in check. According to a study published online on July 22, 2019 in Nature Structural & Molecular Biology, a protein called UV-DDB--which stands for ultraviolet-damaged DNA-binding--is useful beyond safeguarding against the sun. This new evidence points to UV-DDB being a scout for general DNA damage and an overseer of the molecular repair crew that fixes it. The article is titled “Damage Sensor Role of UV-DDB During Base Excision Repair.” "If you're going to fix a pothole, you have to find it first. That's what UV-DDB does. It identifies DNA damage so that another crew can come in and patch and seal it," said study senior author Bennett Van Houten, PhD, Professor of Pharmacology and Chemical Biology at the Pitt School of Medicine and UPMC Hillman Cancer Center. Surveying 3 billion base pairs, packed into a nucleus just a few microns wide, is a tall order, Dr. Van Houten said. Not only is it a lot of material to search through, but it's wound up so tightly that many molecules can't access it. Keeping with the pothole analogy, one possible search strategy is to walk along the road, waiting to step in a hole. Another option is to fly around in a helicopter, but because molecules can't "see," this approach would require frequently landing to look for rough patches. To get around these shortcomings, UV-DDB combines both search strategies. "UV-DDB is like a helicopter that can land and then roll for a couple blocks," Dr. Van Houten said.

Exosomes May Have “Huge Relevance” to Treating & Diagnosing Developmental Brain Disorders; New Work at Scripps Suggests Cellular Cargo Transporters Play Profound Role in Creating Brain Cells & Circuits

Like overpacked suitcases unloaded from the underbelly of a jet, molecular satchels called exosomes are continuously deployed from all cells in the body—many brimming with an assortment of contents that another cell may unpack and use. By sending off these biological parcels, cells communicate with each other via shared proteins and genetic material. Once simply thought to be microscopic sacks of cellular “garbage,” exosomes are now understood to hold immense importance for our health. An outflowing of research in recent years has even shown they can transport molecules that are linked to the spread of cancer and neurodegenerative disorders such as Alzheimer’s. Yet, until recently, their role in brain development has remained a mystery. In new research published online on July 22, 2019 in PNAS, Hollis Cline (photo), PhD, and her colleagues at Scripps Research begin to close that knowledge gap by showing that exosomes are not only integral to the development of neurons and neural circuits, but they can restore health to brain cells affected by developmental disease. The open-access PNAS article is titled “Exosomes Regulate Neurogenesis and Circuit Assembly.” “During different stages of brain development, signaling between cells is absolutely essential,” says Dr. Cline, Co-Chair of the Department of Neuroscience at Scripps Research and Director of the Dorris Neuroscience Center at Scripps. “We found that exosomes are one of the ways cells communicate these signals.” Our bodies use spherical containers called “vesicles” to traffic different materials within and among cells. Exosomes are a type of vesicle tasked specifically with transporting various biological cargo—lipids, proteins, RNA,—from one cell to another. Dr.

July 22nd

Nunavik Inuit in Canada’s Arctic Are Genetically Unique & Share Variants That May Correlate with Brain Aneurysms, Among Distinct Genetic Signatures In Pathways Involving Lipid Metabolism & Cell Adhesion, Possibly Adaptive to High-Fat Diets & Extreme Cold

A new study has found that an Inuit population in Canada's Arctic are genetically distinct from any known group, and certain genetic variants in the population are correlated with brain aneurysm. Geographically isolated populations often develop unique genetic traits that result from their successful adaptation to specific environments. Unfortunately, these adaptations sometimes predispose them to certain health issues if the environment is changed. The genetic background of these populations are often poorly understood because they live far from scientific research centres. Canada's Inuit have a higher prevalence of cardiovascular disorders, as well as increased incidence of brain aneurysms, relative to the the general population. To learn about the possible genetic origin of these disorders, researchers at The Neuro (Montreal Neurological Institute and Hospital) of McGill University analyzed the genetic characteristics of 170 Inuit volunteers from Nunavik, a region of northern Quebec. This was done with approval from the Nunavik Nutrition and Health Committee in Kuujjuaq, Nunavik. Using exome sequencing and genome-wide genotyping, the researchers found several interesting traits among the Nunavik Inuit. They are a distinct genetic population, whose closest relatives are the Paleo-Eskimos, a people that inhabited the Arctic before the Inuit. The Nunavik Inuit have distinct genetic signatures in pathways involving lipid metabolism and cell adhesion. These may be adaptations to adjust to the high-fat diet and extreme cold of the Canadian north. One of these unique genetic variants correlates with a higher risk of brain aneurysm, also known as intracranial aneurysm, a weakening in the wall of a cerebral artery that causes ballooning of the artery.

New Study Explains Molecular Mechanism for Therapeutic Anti-Convulsive Effects of Cilantro

Herbs, including cilantro, have a long history of use as folk medicine anticonvulsants. Until now, many of the underlying mechanisms of how the herbs worked remained unknown. In a new study, researchers have uncovered the molecular action that enables cilantro to effectively delay certain seizures common in epilepsy and other diseases. The study, published online on July 16, 2019 in The FASEB Journal, explains the molecular action of cilantro (Coriandrum sativum) as a highly potent KCNQ channel activator This new understanding may lead to improvements in therapeutics and the development of more efficacious drugs. The article is titled “Cilantro Leaf Harbors A Potent Potassium Channel–Activating Anticonvulsant.” "We discovered that cilantro, which has been used as a traditional anticonvulsant medicine, activates a class of potassium channels in the brain to reduce seizure activity," said Geoff Abbott, PhD, Professor of Physiology and Biophysics at the UC-Irvine School of Medicine and principal investigator on the study. "Specifically, we found one component of cilantro, called dodecenal, binds to a specific part of the potassium channels to open them, reducing cellular excitability. This specific discovery is important as it may lead to more effective use of cilantro as an anticonvulsant, or to modifications of dodecenal to develop safer and more effective anticonvulsant drugs." Researchers screened cilantro leaf metabolites, revealing that one - the long-chain fatty aldehyde (E)-2-dodecenal - activates multiple potassium channels including the predominant neuronal isoform and the predominant cardiac isoform, which are responsible for regulating electrical activity in the brain and heart.