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Archive - Jul 2015

July 16th

Partial Structure of Key Protein (Oskar) for Development of Reproductive Cells Is Revealed in EMBL Heidelberg Studies

The structure of two parts of the Oskar protein, known to be essential for the development of reproductive cells, has been solved by scientists from EMBL Heidelberg in Germany. This advance, published online on July 16, 2015 in Cell Reports, has also enabled the research team to gather the first insights into how this poorly understood protein functions. The research was carried out with fruit flies, but has implications for other animals, as many organisms, including humans, also possess part of the Oskar protein. Named after the main character from the Günter Grass novel “The Tin Drum,” who chose never to grow up, the Oskar protein is essential for development. Embryos that develop from fruit fly eggs lacking the normal amount of Oskar protein are unable to form germ cells – cells that allow reproduction – and so the resulting flies are sterile. Complete lack of the Oskar protein also prevents the embryo’s abdomen from forming normally which stunts its growth and causes such flies to die. In a healthy egg, the Oskar protein initiates the formation of what’s known as the germ plasm – a gathering of proteins and RNAs within the cytoplasm, which then goes on to form a new germ cell. Germ plasm normally forms in a particular position within the egg, but if Oskar is artificially moved elsewhere, the germ plasm will form in the new location. Co-author of the paper, Dr. Anne Ephrussi said: “While we’ve known Oskar’s genetic role in development for some time, we’ve not known the mechanism by which this takes place. Solving the structure has enabled us to start to see how the different parts of the protein function at a molecular level, which could help us to understand more about this stage of development in a wide range of organisms.”

Reducing High Levels of Ceramides May Improve Insulin Sensitivity and Provide an Effective Treatment for Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Reducing high concentrations of a fatty molecule that is commonly found in people with diabetes and nonalcoholic fatty liver disease rapidly improves insulin sensitivity, Univeristy of Texas (UT) Southwestern Medical Center diabetes researchers have found. Insulin is a crucial hormone that helps the body convert sugar into energy, absorb nutrients, and reduce the storage of sugars as fat. Poor insulin sensitivity reduces the effectiveness of these processes and results in diabetes and fatty liver disease. UT Southwestern researchers showed that introducing an enzyme called ceramidase in diabetic mice returned their insulin sensitivity to normal. “Lowering ceramides (image) may also make people more insulin-sensitive,” said study senior author Dr. Philipp Scherer, Director of the Touchstone Center for Diabetes Research at UT Southwestern. “Our findings suggest a new means to potentially treat Type 2 diabetes and nonalcoholic fatty liver disease.” Though no such therapy currently exists, Dr. Scherer said a drug form of the enzyme ceramidase likely could be developed. The findings were published online on July 16, 2015 in the journal Cell Metabolism. The article is titled “Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis.” When more fatty acids are consumed than the body burns off, some excess fat is converted to ceramide. When too much ceramide builds up, the lipid interferes with insulin signaling, resulting in insulin resistance and possibly diabetes or nonalcoholic fatty liver disease. “It is a nasty lipid at times,” said Dr. Scherer, Professor of Internal Medicine and Cell Biology who holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research at UT Southwestern.

Improved Treatment for Vitiligo Skin Discoloration

According to a July 16, 2015 press release, a University of Texas (UT) Southwestern Medical Center dermatologist has improved a technique to transplant pigment cells that can repair the affected area of skin discoloration from vitiligo. Dr. Amit Pandya, Professor of Dermatology at UT Southwestern, refined and enhanced this technique, which uses a less painful process, rather than cutting into the skin, to obtain the cells needed for the transplant. The cells are harvested from a painless blister raised on the skin, then transferred to the area of involvement to replace the missing pigment cells and restore the individual’s natural skin color. UT Southwestern is the only center in the United States to use this technique and one of only two centers to perform this type of cell transplant surgery, called non-cultured epidermal suspension (NCES) grafting, cellular grafting, or melanocyte keratinocyte transplant procedure (MKTP). “This provides new hope for patients with vitiligo,” said Dr. Pandya, who holds the Dr. J.B. Shelmire Professorship in Dermatology. “The unique aspect of our procedure, which no one else in the world is doing, is the formation of blisters as the source of donor cells combined with laser surgery to prepare the grafted areas. The older method of cutting the skin leaves a scar.” Dr. Pandya, the only full-time pigmentary disorders specialist in Texas, has spent more than a decade treating vitiligo patients in the Pigmentation Disorders Clinic at UT Southwestern. Vitiligo affects about 2 million people in the United States. Vitiligo occurs when the body is triggered to look at melanocytes, cells which give color to the skin, as foreign or abnormal. With vitiligo, the body’s own immune system starts attacking those cells, which is why it’s considered an autoimmune disease.

July 13th

New Genetic Alterations Identified in Development of Skin Squamous Cell Carcinoma; Study Seeks to Define Relevant Mutational Landscape

Squamous cell carcinoma (SCC) of the skin is one of the most frequent cancers in humans affecting more than half a million new persons every year in the world. The transformation of a normal cell to a cancer cell is caused by an accumulation of genetic abnormalities in the progeny of single cells. The spectrum of genetic anomalies found in a variety of human cancers has been described. Squamous cell carcinoma (SCC), arising from various organs including head-and-neck, lung, esophagus and skin, are induced by carcinogens, such as tobacco and UV exposure. Mouse models of carcinogen-induced skin SCCs have been used for a century and have become the most extensively used model to study cancer in vivo. However, it is still unclear whether mouse carcinogen-induced skin SCCs are mediated by the same spectrum of mutations as found in human cancer. In a new study. published online on July 13, 2015 in Nature Medicine, researchers led by Professor Cédric Blanpain, M.D./Ph.D., Professor and WELBIO Investigator at the IRIBHM, Université libre de Bruxelles-ULB, Belgium, and Professor Diether Lambrechs, Professor and VIB Investigator at the VRC, KU Leuven, Belgium, identify the genetic abnormalities leading to the development, progression, and metastasis of mouse skin SCC and demonstrate interesting similarities with human cancers. The Nature Medicine article is titled “Genomic Landscape of Carcinogen-Induced and Genetically Induced Mouse Skin Squamous Cell Carcinoma.” Dr.

July 13th

DNA-PKcs Protein Is a Master Regulator of the Pathways and Signals That Lead to the Development of Metastases in Prostate Cancer

Cancer is a disease of cell growth, but most tumors only become lethal once they metastasize or spread from their first location to sites throughout the body. For the first time, researchers at Thomas Jefferson University in Philadelphia report a single molecule that appears to be the central regulator driving metastasis in prostate cancer. The study, published in the July 13, 2015 issue of Cancer Cell, offers a target for the development of a drug that could prevent metastasis in prostate cancer, and possibly other cancers as well. The Cancer Cell article is titled “DNA-PKcs Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.” "Finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs (DNA-dependent protein kinase, catalytic subunit--see image) could give us a means of knocking out major pathways that control metastasis before it begins," says Karen Knudsen, Ph.D., Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia. Dr. Knudson is the Hilary Koprowski Professor and Chair of Cancer Biology, Professor of Urology, Radiation Oncology, and Medical Oncology at Jefferson. Metastasis is thought of as the last stage of cancer. The tumor undergoes a number of changes to its DNA - mutations - that make the cells more mobile, able to enter the bloodstream, and then also sticky enough to anchor down in a new location, such as the bone, the lungs, the liver, or other organs, where new tumors start to grow. Although these processes are fairly well characterized, there appeared to be many non-overlapping pathways that ultimately lead to these traits. Now, Dr. Knudsen and colleagues have shown that one molecule appears to be central to many of the processes required for a cancer to spread.

New Drug Approach Employing GABA-NAMs Relieves Depression in 24 Hours with Minimal Side-Effects; Animal Study Points to Possible Revolution in Treatment of Depression

A new study by researchers at University of Maryland School of Medicine has identified promising compounds that could successfully treat depression in less than 24 hours while minimizing side effects. Although they have not yet been tested in people, the compounds could offer significant advantages over current antidepressant medications. The research, led by Scott Thompson, Ph.D., Professor and Chair of the Department of Physiology at the University of Maryland School of Medicine (UM SOM), was published online on April 22, 2015 in the journal Neuropsychopharmacology. The article is titled “Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors. "Our results open up a whole new class of potential antidepressant medications," said Dr. Thompson. "We have evidence that these compounds can relieve the devastating symptoms of depression in less than one day, and can do so in a way that limits some of the key disadvantages of current approaches." Currently, most people with depression take medications that increase levels of the neurochemical serotonin in the brain. The most common of these drugs, such as Prozac and Lexapro, are selective serotonin re-uptake inhibitors, or SSRIs. Unfortunately, SSRIs are effective in only a third of patients with depression. In addition, even when these drugs work, they typically take between three and eight weeks to relieve symptoms. As a result, patients often suffer for months before finding a medicine that makes them feel better. This is not only emotionally excruciating; in the case of patients who are suicidal, it can be deadly. Better treatments for depression are clearly needed. Dr. Thompson and his team focused on another neurotransmitter besides serotonin, an inhibitory compound called GABA.

Male Black Widow Spiders Destroy Female’s Web to Deter Rivals; New Study Shows Home-Wrecking Behavior Could Protect Females from Harassment

Male black widow spiders destroy large sections of the female’s web during courtship and wrap it up in their own silk. New research recently published online in an open-access article in Animal Behaviour shows that this home-wrecking behavior deters rival males, by making the female’s web less attractive to them. The article is titled “Web Reduction by Courting Male Black Widows Renders Pheromone-Emitting Females' Webs Less Attractive to Rival Males.” Surprisingly, the females don’t seem to mind the destruction. The authors of the study, from Simon Fraser University in Canada, say the males’ behavior could protect the female from harassment, enabling her to get on with parenting. The western black widow spider – Latrodectus hesperus – is native to western North America. Female black widows (image) are approximately 15 mm long and black, with a distinctive red hourglass-shaped mark on the abdomen. The male is much smaller, and a lighter tan color with a striped abdomen. Black widows build messy webs, which they use to communicate via vibrations and pheromones. “The silk pheromones that female black widows produce are like scent-based personal ads,” said Dr. Catherine Scott, lead author of the study. “One whiff of the pheromone can tell a male about the age, mating history, and even hunger level of the female. These complex chemical messages are just one part of the spiders’ communication system, and web reduction is a fascinating behavior that allows a male to interfere with a female’s message.” Competition for females is fierce: as many as 40 male suitors may arrive at a female’s web in one night. Because of this, males have developed ways to fend off the competition, such as guarding females and applying mating plugs.

July 12th

Bi-Alllelic Mutations in RORC Gene Impair Human Immunity to Both Candida and Mycobacterium

The discovery of bi-allelic mutations in the RORC (retinoic-acid-related orphan receptor C) gene in patients with candidiasis and mycobacteriosis has revealed the pivotal role of RORC in mucocutaneous immunity to Candida and in systemic immunity to Mycobacterium in humans. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis (CMC), which is characterized by chronic or recurrent infections of the skin, nails, and oral and genital mucosae by Candida albicans, and inborn errors of human IFN-gamma immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD), a rare congenital disorder characterized by susceptibility to infections by poorly virulent intracellular pathogens such as non-tuberculosis Mycobacterium. Five genetic etiologies of CMC and eighteen genetic etiologies of MSMD have been reported so far. Only a few patients were affected by both candidiasis and mycobacteriosis, including some patients with IL-12p40 and IL-12R-beta-1 deficiencies that impair both IFN-gamma immunity and IL-17 immunity. The new study was published online on July 9, 2015 in Science. The article is titled “Impairment of Immunity to Candida and Mycobacterium in Humans with Bi-Allelic RORC Mutations.” In an international collaboration study with St. Giles Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University in New York City, researchers at Hiroshima University identified bi-allelic mutations in RORC, which encoded RORgamma (image) and RORgammaT, in seven patients from three kindreds of diverse ethnic origins, with an unusual combination of candidiasis and mycobacteriosis. RORgammaT is a well-known key transcription factor of Th17 cells, which produce IL-17 and IL-22.

Poweful Anti-Microtubule Drugs for Cancer Treatment Made Light-Sensitive and Switched On and Off with Single-Cell Precision; Common Systemic Side-Effects Eliminated; Broader Applications Envisioned

A new technique that uses light to activate chemotherapy drugs in specific cells shows promise as a way to improve the effectiveness of cancer therapies while preventing severe side effects, according to a study published online on July 9, 2015 in Cell. Tha article is titled “Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death.” The so-called “photopharmacology” approach could be used to treat a broad range of tumors with unprecedented precision simply by making existing cancer drugs sensitive to light--an approach that requires less time and effort compared with traditional drug discovery programs. "We hope that our compounds will one day be used in medicine to deliver a killer blow to many types of localized cancer tumors, without producing side effects, thus improving on standards of care and also providing chemotherapy options for currently untreatable tumors," says co-senior author Dr. Oliver Thorn-Seshold of Ludwig-Maximilians-Universität München in Germany. Some of the most successful and widely used chemotherapeutic drugs are inhibitors that interfere with the function of microtubules--components of the cell's skeleton that play a key role in cell proliferation, migration, and survival. But because these drugs do not specifically target cancer cells, they also interfere with the function of normal cells and cause severe side effects, such as heart and nerve damage. As a result, microtubule inhibitors are often limited to relatively low doses that do not provide the best therapeutic benefit. To overcome this challenge, Dr. Thorn-Seshold and his collaborators developed a method for optically controlling microtubule inhibitor drugs currently in clinical trials, with high spatial precision.

Underactive Thyroid and Numerous Other Energy-Saving Traits Permit Giant Pandas to Survive Almost Exclusively on Bamboo

A suite of energy-saving traits, including underactive thyroid glands, allows giant panda bears to survive almost exclusively on bamboo, according to a new study. Dr. Yonggang Nie and colleagues report the first measurements of daily energy expenditure (DEE) in these bears, which do not have stomachs designed for such low-nutrient, high-cellulose plants. The work was published in the July 10, 2015 issue of Science. The article is titled “Exceptionally Low Daily Energy Expenditure in the Bamboo-Eating Giant Panda.” The researchers studied five captive pandas and three wild ones, discovering that the animal's DEE was just about 38% of the average for a terrestrial mammal with the same body mass. The DEE values for giant pandas are substantially lower than those for koalas, for example, and more akin to those of three-toed sloths, according to the researchers. Dr. Nie and colleagues used GPS loggers to track the bears and found that giant pandas are much less active than other bears. Further research revealed that the animal's brain, liver, and kidney are relatively small compared to those of other bears, and that the giant panda’s thyroid hormone levels are only a fraction of the mammalian norm -- comparable to a hibernating black bear's hormone levels. Finally, the researchers compared the giant panda genome to those of other mammals, identifying a panda-specific variation on the DUOX2 gene, loss of which is associated with underactive thyroids in humans. Taken together, these results suggest that particularly low energy expenditures and low thyroid hormone levels enable the carnivorous-looking panda bears to surviving by simply munching on bamboo all day.