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Archive - Aug 2014

August 2nd

Hearing Gene Prestin Adapted for Echolocation in Bats and Dolphins

A little over a decade ago, prestin was found to be a key gene responsible for hearing in mammals. Prestin makes a protein found in the hair cells of the inner ear that contracts and expands rapidly to transmit signals that help the cochlea, like an antique phonograph horn, amplify sound waves to make hearing more sensitivity. Now, in a new study published in the online on June 19, 2014 in Molecular Biology and Evolution, Dr. Peng Shi, et al., have shown that prestin has also independently evolved to play a critical role in the ultrasonic hearing range of animal sonar, or echolocation, to help dolphins navigate through murky waters or bats to find food in the dark. Although both toothed whales and echolocating bats can emit high frequency echolocation calls, which show a substantial diversity in terms of their shape, duration, and amplitude, they receive and analyze the echoes returned from objects by their high-frequency hearing. The research team finely dissected the function of the prestin protein from 2 sonar-guided bats and the bottlenose dolphin compared with non-sonar mammals. Evolutionary analyses of the prestin protein sequences showed that a single amino acid change in prestin, from a threonine (Thr or T) in all sonar mammals to an asparagine (Asn or N) in all non-sonar mammals, was subject to parallel evolution, suggesting that it may play a critical role for mammalian echolocation. Further experiments supported this assumption and identified 4 key amino acid differences amongst the sonar mammals, which may contribute to their unique features . Taken along side evolutionary analyses, these findings offered the first functional evidence supporting the notion that the hearing gene of prestin evolved to play a key role in the sonar system of mammals.

New Molecular Test Kit Predicts Patient’s Survival and Drug Response in Kidney Cancer

Researchers and doctors at the Institute of Bioengineering and Nanotechnology (IBN), Singapore General Hospital (SGH) and National Cancer Centre Singapore (NCCS) have co-developed the first molecular test kit that can predict treatment and survival outcomes in kidney cancer patients. This breakthrough was reported online on July 17, 2014 in European Urology, the world’s top urology journal. According to IBN Executive Director Professor Jackie Y. Ying, “By combining our expertise in molecular diagnostics and cancer research, we have developed the first genetic test to help doctors prescribe the appropriate treatment for kidney cancer patients based on their tumor profile.” Dr. Min-Han Tan, who is IBN Team Leader and Principal Research Scientist and a visiting consultant at the Division of Medical Oncology NCCS, shared his motivation, “As a practicing oncologist, I have cared for many patients with kidney cancer. I see the high costs of cancer care, the unpredictable outcomes, and occasional futility of even the best available drugs. This experience inspired our development of this assay to improve all these for patients.” The study was conducted retrospectively with tissue samples collected from close to 280 clear cell renal cell carcinoma (ccRCC) patients who underwent surgery at SGH between 1999 and 2012. “High-quality tissue samples are crucial in achieving significant findings in biomedical research. As an Academic Medical Center, we wish to promote the translation of research into advances in healthcare and personalized medicine. The development of this test kit for patient care, utilizing the robust tissue archive that we have at SGH, is a good example of this,” said Professor Tan Puay Hoon, Head and Senior Consultant, Department of Pathology, SGH.

Switching on Brown Fat Thermogenesis

Biologists at The Scripps Research Institute (TSRI) in La Jolla, California, have identified a signaling pathway that switches on a powerful calorie-burning process in brown fat cells. The study, which was reported online on July 28, 2014 in PNAS, sheds light on a process known as "brown fat thermogenesis," which is of great interest to medical researchers because it naturally stimulates weight loss and may also protect against diabetes. "This finding offers new possibilities for the therapeutic activation of brown fat thermogenesis," said team leader Dr. Anastasia Kralli, associate professor in TSRI's Departments of Chemical Physiology and Cell Biology. Most fat cells in our bodies are "white fat" cells that store fat as a reserve energy supply. But we and other mammals also have depots of "brown fat" cells. These apparently evolved not to store but to burn energy—quickly, as a way of generating heat and keeping the body warm in cold conditions, as well as possibly to get rid of excess caloric intake. Human babies as well as mammals that hibernate have relatively extensive brown fat tissues. Scientists have found in recent years that many adult humans have significant levels of brown fat, which are located mostly in the neck and shoulders, and appear to help regulate body weight and blood sugar. Low temperatures activate the brown-fat thermogenesis process via the sympathetic nervous system: Nerve ends in brown fat tissue release the neurotransmitter norepinephrine, and that triggers a shift in metabolism within the brown fat cells, which are densely packed with tiny biological energy reactors called mitochondria. "The mitochondria start generating heat instead of useful chemical energy; it's like revving the engines of a lot of parked cars," said first author Dr.

Sustained Efficacy, Immunogenicity, and Safety Shown for GlaxoSmithKline's HPV Vaccine

A long-term follow-up study (HPV-023; NCT00518336) shows the sustained efficacy, immunogenicity, and safety of GlaxoSmithKline's human papilloma virus (HPV) vaccine Cervarix. Women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine were followed for more than nine years, and vaccine efficacy (VE) against incident infection was 100%. This is the longest follow-up report for a licensed HPV vaccine. Visit https://www.landesbioscience.com/journals/vaccines/article/29532/ for the full paper. The article was published on June 19, 2014 in Human Vaccines & Immunotherapeutics. Persistent infection with HPV has been clearly established as the necessary cause of the overwhelming majority of cervical cancer cases. At least 40 different HPV types are known to infect the genital mucosa, of which approximately 15 are associated with cervical cancer. Among these types, HPV-16 and HPV-18 are the most common and responsible for approximately 70% of cervical cancers. Both HPV-16 and HPV-18 are included in the two licensed HPV vaccines (GSK's Cervarix and Merck's Gardasil), which are now widely available and used. Evidence of long-term efficacy against vaccine HPV-types is very important, particularly with respect to maintaining public confidence in mass vaccination programs. HPV vaccines initially were recommended for young girls and women 9-25 years of age who have not been exposed to HPV. Because HPV causes not only cervical cancer but also genital warts and anal cancer, HPV vaccines are also recommended for boys in many countries. An initial double-blind, randomized, multi-center vaccination study (HPV-001; NCT00689741) was started in 2001, followed for up to 27 months, and then followed by a long-term study of the entire cohort for up to 77 months (6,4 years) post initial vaccination (HPV-007; NCT00120848).

Twin Study Reveals Altered Gene for Short Sleep Requirement and More Rapid Recovery from Lost Sleep

Researchers who studied 100 twin pairs (dizygotic and monozygotic) have identified a gene mutation that may allow the carrier to function normally on less than six hours of sleep per night. The genetic variant also appears to provide greater resistance to the effects of sleep deprivation. Results show that a participant with p.Tyr362His – a variant of the BHLHE41 gene – had an average nightly sleep duration of only five hours, which was more than one hour shorter than the non-carrier twin, who slept for about six hours and five minutes per night. The twin with the gene mutation also had 40 percent fewer average lapses of performance during 38 hours without sleep and required less recovery sleep afterward – sleeping only eight hours after the period of extended sleep deprivation compared with his twin brother, who slept for 9.5 hours. According to the authors, this is only the second study to link a mutation of the BHLHE41 gene – also known as DEC2 - to short sleep duration. The study provides new insights into the genetic basis of short sleep in humans and the molecular mechanisms involved in setting the duration of sleep that individuals need. “This work provides an important second gene variant associated with sleep deprivation and for the first time shows the role of BHLHE41 in resistance to sleep deprivation in humans,” said lead author Renata Pellegrino, Ph.D., senior research associate in the Center for Applied Genomics at The Children’s Hospital of Philadelphia. “The mutation was associated with resistance to the neurobehavioral effects of sleep deprivation.” Study results are published in the August 1, 2014 issue of the journal Sleep. The study group comprised 100 twin pairs – 59 monozygotic pairs and 41 dizygotic pairs – who were recruited at the University of Pennsylvania.

August 1st

Study Tells Butterfly Evolutionary History Using Large-Scale, Next-Gen Sequencing

By tracing nearly 3,000 genes to the earliest common ancestor of butterflies and moths, University of Florida (UF) scientists have created an extensive “Tree of Lepidoptera” in the first study to use large-scale, next-generation DNA sequencing. Among the study’s more surprising findings: Butterflies are more closely related to small moths than to large ones, which completely changes scientists’ understanding of how butterflies evolved. The study also found that some insects once classified as moths are actually butterflies, increasing the number of butterfly species higher than previously thought. “This project advances biodiversity research by providing an evolutionary foundation for a very diverse group of insects, with nearly 160,000 described species,” said Dr. Akito Kawahara, lead author and assistant curator of Lepidoptera at the Florida Museum of Natural History on the UF campus. “With a tree, we can now understand how the majority of butterfly and moth species evolved.” Available online and to be published in the August print edition of the Proceedings of the Royal Society B: Biological Sciences, the study builds the evolutionary framework for future ecological and genetics research of insects, Dr. Kawahara said. “There is a DNA revolution taking place,” Dr. Kawahara said. "This is an important time in the history of science when we can use DNA sequencing on a very large scale.” Dr. Kawahara said the year-long study is one of the first to utilize a massive amount of genetic data to answer questions about the history of butterflies and moths. The analysis reveals monumental discoveries about the lineage of Lepidoptera, including strongly contradicting the traditional placement of butterflies in evolutionary history, Dr. Kawahara said.

Strict Genomic Partitioning by Biological Clock Separates Key Metabolic Functions

Much of the liver’s metabolic function is governed by circadian rhythms – our own body clock – and UC Irvine (UCI) researchers have now found two independent mechanisms by which this occurs. The study, published online today July 31, 2014 in Cell, reveals new information about the body clock’s sway over metabolism and points the way to more focused drug treatments for liver disease and such metabolic disorders as obesity and diabetes. Dr. Paolo Sassone-Corsi, UCI’s Donald Bren Professor of Biological Chemistry, and postdoctoral scholar Dr. Selma Masri report that two of these circadian-linked proteins, SIRT1 and SIRT6, manage important liver processes – lipid storage and energy usage in liver cells – separately and distinctly from each other. This surprising discovery of genomic partitioning, Dr. Masri noted, reveals how strictly regulated circadian control of metabolism can be. “The ability of the genome and epigenome to cross-talk with metabolic pathways is critical for cellular and organismal functions. What’s remarkable is that the circadian clock is intimately involved in this dialogue,” she said. Circadian rhythms of 24 hours govern fundamental physiological functions in virtually all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Changes to these rhythms can profoundly influence human health. Up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms; nearly 50 percent of those involved with metabolic pathways in the liver are influenced by these rhythms.

Oldest Beetle in Omaliini Tribe Found in Amber

An international team of scientists from Spain, France, and the U.S. has discovered and described a rove beetle that is the oldest definitive member of the tribe Omaliini that has ever been found in amber. The discovery and description were made possible through the use of the propagation phase-contrast X-ray synchrotron imaging technique, which allows the detailed study of otherwise invisible specimens in opaque amber. The new species is described in the journal Annals of the Entomological Society of America in an article called "Oldest Omaliini (Coleoptera: Staphylinidae: Omaliinae) Discovered in the Opaque Cretaceous Amber of Charentes." The tribe Omaliini belongs to the subfamily Omaliinae, which belongs to the family Staphylinidae, the largest of all of the beetle families, with more than 60,000 described species. Two specimens of the “new” species, called Duocalcar geminum, were found in a single piece of opaque amber, along with other arthropods that were embedded in the same piece of amber. The genus name, Duocalcar, means “two spurs” in Latin, “alluding to the two distinctive projections on each hind leg, at the trochanteral apex and near the tibial apex.” The specific epithet, geminum, is a Latin adjective meaning “twin-born,” in reference to the discovery of both specimens in the same piece of amber.“ D. geminum is the first Omaliinae described from any amber, increasing the minimum age of Omaliini to ≈100 million years, from Eocene to latest Albian,” the authors wrote. [Press release] [Annals of the Entomological Society of America abstract]

Molecular Gate That Could Keep Cancer Cells Locked Up

In a study published ton August 1, 2014 in Genes & Development, Dr Christian Speck from the MRC Clinical Sciences Centre's DNA Replication group, in collaboration with Brookhaven National Laboratory (BNL), New York, reveals the intricate mechanisms involved in the enzyme that governs DNA duplication during cell division. By developing a sophisticated system using synthetic, chemical and structural biology approaches, the study reveals how a key enzyme involved in duplicating genetic information embraces DNA through a gated system, which opens up at precise positions allowing for a highly regulated replication process. This work enhances current understanding of an essential biological process and suggests a route for stopping cell division in disease such as cancer. When a cell divides, genetic information is duplicated in a process known as DNA replication. For this to occur, a 'replication machine' is assembled on top of the DNA prior to duplication. A protein complex known as ORC that recognises the DNA replication origin initiates the whole process. Next, an enzyme, MCM2-7 helicase, whose role is to unwind and separate the two strands of the DNA helix, is loaded onto the DNA by the machine system ORC. The helicase is a ring-shaped enzyme composed of six subunits (hexamer), though how the ring structure opens and encircles the DNA has, until now, remained a mystery. Initial theories within the field assumed the helicase to exist in an open ring conformation. Dr. Speck's team argued that this would undoubtedly lead to poorly regulated DNA replication with no control or specificity. To examine the helicase activity in more detail, Jingchuan Sun at BNL used an electron microscope and revealed, contrary to initial theories, the helicase actually existed as a closed ring conformation.

How DNA Avoids Damage from UV Light

In the same week that the U.S. surgeon general issued a 101-page report about the dangers of skin cancer, researchers at Montana State University (MSU) published a paper breaking new ground on how DNA – the genetic code in every cell – responds when exposed to ultraviolet (UV) light. The findings advance fundamental understanding of DNA damage by the UV rays found in sunlight. This damage can lead to skin cancer, aging, and some degenerative eye diseases. "Our paper advances foundational knowledge about how DNA responds to UV radiation. In our experiments, we observe the earliest events immediately after DNA is energized by UV radiation. These events determine whether or not DNA is damaged," said one of the paper's co-authors, Dr. Bern Kohler, an MSU professor in the Department of Chemistry and Biochemistry. DNA is built like a staircase and carries genetic instructions that are unique to each person. It's very hardy and generally able to stand up to ultraviolet rays, but UV rays sometimes cause mutations. UV exposure is a major cause of skin cancer, and while there are nearly 5 million cases of skin cancer each year in the U.S. alone – and 9,000 related deaths – the numbers would be far worse if DNA were more easily damaged. "UV is actually very damaging, yet our DNA is damaged less than expected," Dr. Kohler said. "In the early evolution of life on Earth when there was no ozone layer, the amount of UV would have been far higher and yet life, and the DNA that is central to life, survived. We've been trying to understand the molecular mechanisms that make DNA resist UV damage." In a paper published July 28, 2014 in the online version of the scientific journal PNAS, Dr.